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Diagnosing Porokeratosis of Mibelli Every Time: A Novel Biopsy Technique to Maximize Histopathologic Confirmation

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Diagnosing Porokeratosis of Mibelli Every Time: A Novel Biopsy Technique to Maximize Histopathologic Confirmation

Porokeratosis of Mibelli (PM) is a lesion characterized by a surrounding cornoid lamella with variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) in the center of the lesion that typically presents in infancy to early childhood.1 We report a case of PM in which a prior biopsy from the center of the lesion demonstrated papulosquamous dermatitis. We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM.

Case Report

A 3-year-old girl presented with an erythematous, hypopigmented, scaling plaque on the posterior aspect of the left ankle surrounded by a hard rim. The plaque was first noted at 12 months of age and had slowly enlarged as the patient grew. Six months prior, a biopsy from the center of the lesion performed at another facility demonstrated a papulosquamous dermatitis.

Physical examination revealed a lesion that was 4.2-cm long, 2.2-cm wide at the superior pole, and 3.5-cm wide at the inferior pole (Figure 1). A line was drawn with a skin marker perpendicular to the rim of the lesion (Figure 2A) and a 6-mm punch biopsy was performed, centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). The tissue was then bisected at the bedside along the skin marker line with a #15 blade (Figure 2C) and submitted in formalin for histologic processing. Histologic examination revealed an invagination of the epidermis producing a tier of parakeratotic cells with its apex pointed away from the center of the lesion. Dyskeratotic cells were noted at the base of the parakeratosis (Figure 3). Verrucous hyperplasia was present in the central portion of the specimen adjacent to the cornoid lamella. Based on these histopathologic findings, the correct diagnosis of PM was made.

Figure 1. An erythematous scaling patch surrounded by a thin rim (cornoid lamella) typical of porokeratosis of Mibelli.

 

Figure 2. A skin marker was used to draw a line perpendicular to the cornoid lamella at the end of the lesion (A). After local anesthesia was administered, a 6-mm punch was centered at the intersection of the drawn line and the cornoid lamella (B). The punch specimen was bisected with a #15 blade along the line that was previously drawn (C). Illustrations by Kyle Cunningham, University of Mississippi Medical Center (Jackson, Mississippi).

 

Figure 3. Histology revealed a broad cornoid lamella that erupted from a depression within the epidermis (A) (H&E, original magnification ×100). A close-up view of the cornoid lamella showed dyskeratotic cells beneath the column of parakeratosis (B)(H&E, original magnification ×400).

 

 

Comment

Porokeratosis of Mibelli is a rare condition that typically presents in infancy to early childhood.1 It may appear as small keratotic papules or larger plaques that reach several centimeters in diameter.2 There is a 7.5% risk for malignant transformation (eg, basal cell carcinoma, squamous cell carcinoma, Bowen disease).3 Variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) typically are present in the center of the lesion. In our case, a biopsy from the center of the plaque demonstrated verrucous hyperplasia. The incorrect diagnosis of PM as psoriasis also has been reported.4

We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM. First, draw a line perpendicular to the rim of the lesion to mark the biopsy site (Figure 2A). Second, perform a punch biopsy centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). Third, section the biopsied tissue with a #15 blade along the perpendicular line at the bedside (Figure 2C). The surgical pathology requisition should mention that the specimen has been transected and the cut edges should be placed down in the cassette, ensuring that the cornoid lamella will be present in cross-section on the slides.

If the punch biopsy specimen is not bisected, it can be difficult to orient it in the pathology laboratory, especially if the cornoid lamellae are not prominent. Furthermore, the technician processing the tissue may not be aware of the importance of sectioning the specimen perpendicular to the cornoid lamella. Following this procedure, diagnosis can be confirmed in virtually every case of PM.

References
  1. Richard G, Irvine A, Traupe H, et al. Ichthyosis and disorders of other conification. In: Schachner L, Hansen R, Krafchik B, et al, eds. Pediatric Dermatology. Philadelphia, PA: Elsevier Health Sciences; 2011:640-643.
  2. Pierson D, Bandel C, Ehrig, et al. Benign epidermal tumors and proliferations. In: Bolognia J, Jorizzo J, Rapini R, et al, eds. Dermatology. 1st ed. Vol 2. Edinburgh, Scotland: Elsevier; 2003:1707-1709.
  3. Cort DF, Abdel-Aziz AH. Epithelioma arising in porokeratosis of Mibelli. Br J Plast Surg. 1972;25:318-328.
  4. De Simone C, Paradisi A, Massi G, et al. Giant verrucous porokeratosis of Mibelli mimicking psoriasis in a patient with psoriasis. J Am Acad Dermatol. 2007;57:665-668.
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All from the University of Mississippi Medical Center, Jackson. Dr. Brodell also is from the School of Medicine and Dentistry, University of Rochester Medical Center, New York.

The authors report no conflict of interest.

Correspondence: Robert T. Brodell, MD, Division of Dermatology, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216 ([email protected]).

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All from the University of Mississippi Medical Center, Jackson. Dr. Brodell also is from the School of Medicine and Dentistry, University of Rochester Medical Center, New York.

The authors report no conflict of interest.

Correspondence: Robert T. Brodell, MD, Division of Dermatology, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216 ([email protected]).

Author and Disclosure Information

All from the University of Mississippi Medical Center, Jackson. Dr. Brodell also is from the School of Medicine and Dentistry, University of Rochester Medical Center, New York.

The authors report no conflict of interest.

Correspondence: Robert T. Brodell, MD, Division of Dermatology, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216 ([email protected]).

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Porokeratosis of Mibelli (PM) is a lesion characterized by a surrounding cornoid lamella with variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) in the center of the lesion that typically presents in infancy to early childhood.1 We report a case of PM in which a prior biopsy from the center of the lesion demonstrated papulosquamous dermatitis. We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM.

Case Report

A 3-year-old girl presented with an erythematous, hypopigmented, scaling plaque on the posterior aspect of the left ankle surrounded by a hard rim. The plaque was first noted at 12 months of age and had slowly enlarged as the patient grew. Six months prior, a biopsy from the center of the lesion performed at another facility demonstrated a papulosquamous dermatitis.

Physical examination revealed a lesion that was 4.2-cm long, 2.2-cm wide at the superior pole, and 3.5-cm wide at the inferior pole (Figure 1). A line was drawn with a skin marker perpendicular to the rim of the lesion (Figure 2A) and a 6-mm punch biopsy was performed, centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). The tissue was then bisected at the bedside along the skin marker line with a #15 blade (Figure 2C) and submitted in formalin for histologic processing. Histologic examination revealed an invagination of the epidermis producing a tier of parakeratotic cells with its apex pointed away from the center of the lesion. Dyskeratotic cells were noted at the base of the parakeratosis (Figure 3). Verrucous hyperplasia was present in the central portion of the specimen adjacent to the cornoid lamella. Based on these histopathologic findings, the correct diagnosis of PM was made.

Figure 1. An erythematous scaling patch surrounded by a thin rim (cornoid lamella) typical of porokeratosis of Mibelli.

 

Figure 2. A skin marker was used to draw a line perpendicular to the cornoid lamella at the end of the lesion (A). After local anesthesia was administered, a 6-mm punch was centered at the intersection of the drawn line and the cornoid lamella (B). The punch specimen was bisected with a #15 blade along the line that was previously drawn (C). Illustrations by Kyle Cunningham, University of Mississippi Medical Center (Jackson, Mississippi).

 

Figure 3. Histology revealed a broad cornoid lamella that erupted from a depression within the epidermis (A) (H&E, original magnification ×100). A close-up view of the cornoid lamella showed dyskeratotic cells beneath the column of parakeratosis (B)(H&E, original magnification ×400).

 

 

Comment

Porokeratosis of Mibelli is a rare condition that typically presents in infancy to early childhood.1 It may appear as small keratotic papules or larger plaques that reach several centimeters in diameter.2 There is a 7.5% risk for malignant transformation (eg, basal cell carcinoma, squamous cell carcinoma, Bowen disease).3 Variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) typically are present in the center of the lesion. In our case, a biopsy from the center of the plaque demonstrated verrucous hyperplasia. The incorrect diagnosis of PM as psoriasis also has been reported.4

We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM. First, draw a line perpendicular to the rim of the lesion to mark the biopsy site (Figure 2A). Second, perform a punch biopsy centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). Third, section the biopsied tissue with a #15 blade along the perpendicular line at the bedside (Figure 2C). The surgical pathology requisition should mention that the specimen has been transected and the cut edges should be placed down in the cassette, ensuring that the cornoid lamella will be present in cross-section on the slides.

If the punch biopsy specimen is not bisected, it can be difficult to orient it in the pathology laboratory, especially if the cornoid lamellae are not prominent. Furthermore, the technician processing the tissue may not be aware of the importance of sectioning the specimen perpendicular to the cornoid lamella. Following this procedure, diagnosis can be confirmed in virtually every case of PM.

Porokeratosis of Mibelli (PM) is a lesion characterized by a surrounding cornoid lamella with variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) in the center of the lesion that typically presents in infancy to early childhood.1 We report a case of PM in which a prior biopsy from the center of the lesion demonstrated papulosquamous dermatitis. We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM.

Case Report

A 3-year-old girl presented with an erythematous, hypopigmented, scaling plaque on the posterior aspect of the left ankle surrounded by a hard rim. The plaque was first noted at 12 months of age and had slowly enlarged as the patient grew. Six months prior, a biopsy from the center of the lesion performed at another facility demonstrated a papulosquamous dermatitis.

Physical examination revealed a lesion that was 4.2-cm long, 2.2-cm wide at the superior pole, and 3.5-cm wide at the inferior pole (Figure 1). A line was drawn with a skin marker perpendicular to the rim of the lesion (Figure 2A) and a 6-mm punch biopsy was performed, centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). The tissue was then bisected at the bedside along the skin marker line with a #15 blade (Figure 2C) and submitted in formalin for histologic processing. Histologic examination revealed an invagination of the epidermis producing a tier of parakeratotic cells with its apex pointed away from the center of the lesion. Dyskeratotic cells were noted at the base of the parakeratosis (Figure 3). Verrucous hyperplasia was present in the central portion of the specimen adjacent to the cornoid lamella. Based on these histopathologic findings, the correct diagnosis of PM was made.

Figure 1. An erythematous scaling patch surrounded by a thin rim (cornoid lamella) typical of porokeratosis of Mibelli.

 

Figure 2. A skin marker was used to draw a line perpendicular to the cornoid lamella at the end of the lesion (A). After local anesthesia was administered, a 6-mm punch was centered at the intersection of the drawn line and the cornoid lamella (B). The punch specimen was bisected with a #15 blade along the line that was previously drawn (C). Illustrations by Kyle Cunningham, University of Mississippi Medical Center (Jackson, Mississippi).

 

Figure 3. Histology revealed a broad cornoid lamella that erupted from a depression within the epidermis (A) (H&E, original magnification ×100). A close-up view of the cornoid lamella showed dyskeratotic cells beneath the column of parakeratosis (B)(H&E, original magnification ×400).

 

 

Comment

Porokeratosis of Mibelli is a rare condition that typically presents in infancy to early childhood.1 It may appear as small keratotic papules or larger plaques that reach several centimeters in diameter.2 There is a 7.5% risk for malignant transformation (eg, basal cell carcinoma, squamous cell carcinoma, Bowen disease).3 Variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) typically are present in the center of the lesion. In our case, a biopsy from the center of the plaque demonstrated verrucous hyperplasia. The incorrect diagnosis of PM as psoriasis also has been reported.4

We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM. First, draw a line perpendicular to the rim of the lesion to mark the biopsy site (Figure 2A). Second, perform a punch biopsy centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). Third, section the biopsied tissue with a #15 blade along the perpendicular line at the bedside (Figure 2C). The surgical pathology requisition should mention that the specimen has been transected and the cut edges should be placed down in the cassette, ensuring that the cornoid lamella will be present in cross-section on the slides.

If the punch biopsy specimen is not bisected, it can be difficult to orient it in the pathology laboratory, especially if the cornoid lamellae are not prominent. Furthermore, the technician processing the tissue may not be aware of the importance of sectioning the specimen perpendicular to the cornoid lamella. Following this procedure, diagnosis can be confirmed in virtually every case of PM.

References
  1. Richard G, Irvine A, Traupe H, et al. Ichthyosis and disorders of other conification. In: Schachner L, Hansen R, Krafchik B, et al, eds. Pediatric Dermatology. Philadelphia, PA: Elsevier Health Sciences; 2011:640-643.
  2. Pierson D, Bandel C, Ehrig, et al. Benign epidermal tumors and proliferations. In: Bolognia J, Jorizzo J, Rapini R, et al, eds. Dermatology. 1st ed. Vol 2. Edinburgh, Scotland: Elsevier; 2003:1707-1709.
  3. Cort DF, Abdel-Aziz AH. Epithelioma arising in porokeratosis of Mibelli. Br J Plast Surg. 1972;25:318-328.
  4. De Simone C, Paradisi A, Massi G, et al. Giant verrucous porokeratosis of Mibelli mimicking psoriasis in a patient with psoriasis. J Am Acad Dermatol. 2007;57:665-668.
References
  1. Richard G, Irvine A, Traupe H, et al. Ichthyosis and disorders of other conification. In: Schachner L, Hansen R, Krafchik B, et al, eds. Pediatric Dermatology. Philadelphia, PA: Elsevier Health Sciences; 2011:640-643.
  2. Pierson D, Bandel C, Ehrig, et al. Benign epidermal tumors and proliferations. In: Bolognia J, Jorizzo J, Rapini R, et al, eds. Dermatology. 1st ed. Vol 2. Edinburgh, Scotland: Elsevier; 2003:1707-1709.
  3. Cort DF, Abdel-Aziz AH. Epithelioma arising in porokeratosis of Mibelli. Br J Plast Surg. 1972;25:318-328.
  4. De Simone C, Paradisi A, Massi G, et al. Giant verrucous porokeratosis of Mibelli mimicking psoriasis in a patient with psoriasis. J Am Acad Dermatol. 2007;57:665-668.
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Cutis - 97(3)
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Diagnosing Porokeratosis of Mibelli Every Time: A Novel Biopsy Technique to Maximize Histopathologic Confirmation
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Diagnosing Porokeratosis of Mibelli Every Time: A Novel Biopsy Technique to Maximize Histopathologic Confirmation
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Practice Points

  • A biopsy from the center of a plaque of porokeratosis will produce nonspecific findings.
  • Bisecting the punch specimen at the bedside along a line drawn perpendicular to the cornoid lamella guarantees proper orientation of the specimen.
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MRSA incidence decreased in children as clindamycin resistance increased

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MRSA incidence decreased in children as clindamycin resistance increased

The incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections has decreased in children in recent years, but resistance to clindamycin has increased over the same period, a study showed.

“The epidemic of skin and soft tissue infections and invasive MRSA led to modifications of antimicrobial prescribing practices for suspected S. aureus infections,” reported Dr. Deena E. Sutter of the San Antonio Military Medical Center in Fort Sam Houston, Tex., and her associates. “Over the study period, erythromycin susceptibility among methicillin-susceptible S. aureus (MSSA) remained stable, suggesting that declining clindamycin susceptibility is a result of an increase in inducible resistance.”

The steady decline in clindamycin susceptibility “may lead to some concern about the continued reliance on clindamycin for the empirical treatment of presumptive S. aureus infections, although it is probably premature to abandon this effective antibiotic choice,” they wrote (Pediatrics. 2016 Mar. 1. doi: 10.1542/peds.2015-3099). “It is crucial that clinicians remain knowledgeable about local susceptibility rates as it would be prudent to consider [alternative] antimicrobial agents for empirical use when the local clindamycin susceptibility rate drops below 85%.”

(c) CDC/Janice Haney Carr

The researchers retrospectively analyzed lab results from 39,209 patients under age 18 who were treated for S. aureus infections at one of the 266 U.S. facilities of the Military Health System from 2005 to 2014. The data included 41,745 S. aureus isolates, classified as MRSA if found resistant to cefoxitin, methicillin, or oxacillin and as methicillin susceptible (MSSA) if susceptible to those antimicrobials. The isolates had also been tested for susceptibility to ciprofloxacin, clindamycin, erythromycin, gentamicin, oxacillin, penicillin, rifampin, tetracycline, and trimethoprim/sulfamethoxazole (TMP/SMX).

During that decade, overall S. aureus susceptibility to clindamycin, ciprofloxacin, and TMP/SMX decreased – although susceptibility to TMP/SMX in 2014 stayed high at 98% – while overall susceptibility to erythromycin, gentamicin, and oxacillin increased. Specifically, 59% of S. aureus isolates were susceptible to oxacillin in 2005, which dropped briefly to 54% in 2007 before climbing to the 2014 rate of 68%.

Meanwhile, overall susceptibility to clindamycin dropped from 91% in 2005 to 86% in 2014, and MSSA susceptibility to clindamycin dropped from 91% in 2005 to 84% in 2014. “Erythromycin susceptibility remained stable among MSSA isolates throughout the study period at 63.5%, whereas MRSA susceptibility to erythromycin increased from 12.1% to 20.5%,” Dr. Sutter and her associates reported. “Ciprofloxacin susceptibility significantly decreased overall, although an initial decrease of 10.6% over the first 7 years of the study was subsequently followed by an increase of 6% between 2011 and 2014.”

Most of the isolates came from patients with skin and soft tissue infections, which were less likely to be susceptible to oxacillin than were other infections. Infections in children aged 1-5 years also were less likely to be susceptible to oxacillin, compared with infections in children of other age groups.

If the local clindamycin susceptibility rate falls below 85%, “beta-lactams, TMP/SMX, or tetracyclines may be used for less severe infections with intravenous vancomycin employed in severe cases,” the investigators said. “If overall MRSA rates continue to decline and clindamycin resistance among MSSA continues to increase, we may see a return to antistaphylococcal beta-lactam antimicrobial agents such as oxacillin or first-generation cephalosporins as preferred empirical therapy for presumed S. aureus infections.”

The research did not use external funding, and the authors reported no relevant financial disclosures.

References

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Staphylococcus aureus is one of the most common organisms isolated from children with health care–associated infections, regardless of whether these infections had their onset in the community or were acquired in the hospital. Thus, the initial empiric treatment of a skin or soft tissue infection or invasive infection in a child almost always includes an antibiotic effective against S. aureus.

However, over the years, clindamycin susceptibility among S. aureus isolates has declined, likely related to the increased use of this agent for empiric as well as definitive treatment of community-acquired (CA) MRSA infections, encouraging the transmission of the genes associated with clindamycin resistance.

What are the implications of the findings from the report by Sutter et al. with respect to the selection of empiric antibiotics for children with suspected S. aureus infections? Currently, considering the still substantial MRSA resistance rates that exceed the 10%-15% level suggested by many experts as the threshold above which agents effective against CA-MRSA isolates should be administered for empiric treatment, changes in the selection of empiric antibiotics are not warranted. If rates of MRSA among S. aureus isolates from otherwise normal children are documented to drop below the 10%-15% threshold in different communities, a modification of current recommendations should be considered. It would also be important to understand why methicillin resistance is declining among S. aureus isolates from CA infections; this information may provide clues for preventing CA-MRSA infections with the use of vaccines or other means. The epidemiology of S. aureus infections in children has been changing over the past 2 decades, which is why it is critical to keep a very close eye on this common pathogen.

These comments were excerpted from an accompanying commentary by Dr. Sheldon L. Kaplan of the infectious disease service at Texas Children’s Hospital in Houston (Pediatrics. 2016 Mar 1. doi: 10.1542/peds.2016-0101). Dr. Kaplan has received research funds from Pfizer, Forest Laboratories, and Cubist.

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Staphylococcus aureus is one of the most common organisms isolated from children with health care–associated infections, regardless of whether these infections had their onset in the community or were acquired in the hospital. Thus, the initial empiric treatment of a skin or soft tissue infection or invasive infection in a child almost always includes an antibiotic effective against S. aureus.

However, over the years, clindamycin susceptibility among S. aureus isolates has declined, likely related to the increased use of this agent for empiric as well as definitive treatment of community-acquired (CA) MRSA infections, encouraging the transmission of the genes associated with clindamycin resistance.

What are the implications of the findings from the report by Sutter et al. with respect to the selection of empiric antibiotics for children with suspected S. aureus infections? Currently, considering the still substantial MRSA resistance rates that exceed the 10%-15% level suggested by many experts as the threshold above which agents effective against CA-MRSA isolates should be administered for empiric treatment, changes in the selection of empiric antibiotics are not warranted. If rates of MRSA among S. aureus isolates from otherwise normal children are documented to drop below the 10%-15% threshold in different communities, a modification of current recommendations should be considered. It would also be important to understand why methicillin resistance is declining among S. aureus isolates from CA infections; this information may provide clues for preventing CA-MRSA infections with the use of vaccines or other means. The epidemiology of S. aureus infections in children has been changing over the past 2 decades, which is why it is critical to keep a very close eye on this common pathogen.

These comments were excerpted from an accompanying commentary by Dr. Sheldon L. Kaplan of the infectious disease service at Texas Children’s Hospital in Houston (Pediatrics. 2016 Mar 1. doi: 10.1542/peds.2016-0101). Dr. Kaplan has received research funds from Pfizer, Forest Laboratories, and Cubist.

Body

Staphylococcus aureus is one of the most common organisms isolated from children with health care–associated infections, regardless of whether these infections had their onset in the community or were acquired in the hospital. Thus, the initial empiric treatment of a skin or soft tissue infection or invasive infection in a child almost always includes an antibiotic effective against S. aureus.

However, over the years, clindamycin susceptibility among S. aureus isolates has declined, likely related to the increased use of this agent for empiric as well as definitive treatment of community-acquired (CA) MRSA infections, encouraging the transmission of the genes associated with clindamycin resistance.

What are the implications of the findings from the report by Sutter et al. with respect to the selection of empiric antibiotics for children with suspected S. aureus infections? Currently, considering the still substantial MRSA resistance rates that exceed the 10%-15% level suggested by many experts as the threshold above which agents effective against CA-MRSA isolates should be administered for empiric treatment, changes in the selection of empiric antibiotics are not warranted. If rates of MRSA among S. aureus isolates from otherwise normal children are documented to drop below the 10%-15% threshold in different communities, a modification of current recommendations should be considered. It would also be important to understand why methicillin resistance is declining among S. aureus isolates from CA infections; this information may provide clues for preventing CA-MRSA infections with the use of vaccines or other means. The epidemiology of S. aureus infections in children has been changing over the past 2 decades, which is why it is critical to keep a very close eye on this common pathogen.

These comments were excerpted from an accompanying commentary by Dr. Sheldon L. Kaplan of the infectious disease service at Texas Children’s Hospital in Houston (Pediatrics. 2016 Mar 1. doi: 10.1542/peds.2016-0101). Dr. Kaplan has received research funds from Pfizer, Forest Laboratories, and Cubist.

Title
Keep a close eye
Keep a close eye

The incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections has decreased in children in recent years, but resistance to clindamycin has increased over the same period, a study showed.

“The epidemic of skin and soft tissue infections and invasive MRSA led to modifications of antimicrobial prescribing practices for suspected S. aureus infections,” reported Dr. Deena E. Sutter of the San Antonio Military Medical Center in Fort Sam Houston, Tex., and her associates. “Over the study period, erythromycin susceptibility among methicillin-susceptible S. aureus (MSSA) remained stable, suggesting that declining clindamycin susceptibility is a result of an increase in inducible resistance.”

The steady decline in clindamycin susceptibility “may lead to some concern about the continued reliance on clindamycin for the empirical treatment of presumptive S. aureus infections, although it is probably premature to abandon this effective antibiotic choice,” they wrote (Pediatrics. 2016 Mar. 1. doi: 10.1542/peds.2015-3099). “It is crucial that clinicians remain knowledgeable about local susceptibility rates as it would be prudent to consider [alternative] antimicrobial agents for empirical use when the local clindamycin susceptibility rate drops below 85%.”

(c) CDC/Janice Haney Carr

The researchers retrospectively analyzed lab results from 39,209 patients under age 18 who were treated for S. aureus infections at one of the 266 U.S. facilities of the Military Health System from 2005 to 2014. The data included 41,745 S. aureus isolates, classified as MRSA if found resistant to cefoxitin, methicillin, or oxacillin and as methicillin susceptible (MSSA) if susceptible to those antimicrobials. The isolates had also been tested for susceptibility to ciprofloxacin, clindamycin, erythromycin, gentamicin, oxacillin, penicillin, rifampin, tetracycline, and trimethoprim/sulfamethoxazole (TMP/SMX).

During that decade, overall S. aureus susceptibility to clindamycin, ciprofloxacin, and TMP/SMX decreased – although susceptibility to TMP/SMX in 2014 stayed high at 98% – while overall susceptibility to erythromycin, gentamicin, and oxacillin increased. Specifically, 59% of S. aureus isolates were susceptible to oxacillin in 2005, which dropped briefly to 54% in 2007 before climbing to the 2014 rate of 68%.

Meanwhile, overall susceptibility to clindamycin dropped from 91% in 2005 to 86% in 2014, and MSSA susceptibility to clindamycin dropped from 91% in 2005 to 84% in 2014. “Erythromycin susceptibility remained stable among MSSA isolates throughout the study period at 63.5%, whereas MRSA susceptibility to erythromycin increased from 12.1% to 20.5%,” Dr. Sutter and her associates reported. “Ciprofloxacin susceptibility significantly decreased overall, although an initial decrease of 10.6% over the first 7 years of the study was subsequently followed by an increase of 6% between 2011 and 2014.”

Most of the isolates came from patients with skin and soft tissue infections, which were less likely to be susceptible to oxacillin than were other infections. Infections in children aged 1-5 years also were less likely to be susceptible to oxacillin, compared with infections in children of other age groups.

If the local clindamycin susceptibility rate falls below 85%, “beta-lactams, TMP/SMX, or tetracyclines may be used for less severe infections with intravenous vancomycin employed in severe cases,” the investigators said. “If overall MRSA rates continue to decline and clindamycin resistance among MSSA continues to increase, we may see a return to antistaphylococcal beta-lactam antimicrobial agents such as oxacillin or first-generation cephalosporins as preferred empirical therapy for presumed S. aureus infections.”

The research did not use external funding, and the authors reported no relevant financial disclosures.

The incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections has decreased in children in recent years, but resistance to clindamycin has increased over the same period, a study showed.

“The epidemic of skin and soft tissue infections and invasive MRSA led to modifications of antimicrobial prescribing practices for suspected S. aureus infections,” reported Dr. Deena E. Sutter of the San Antonio Military Medical Center in Fort Sam Houston, Tex., and her associates. “Over the study period, erythromycin susceptibility among methicillin-susceptible S. aureus (MSSA) remained stable, suggesting that declining clindamycin susceptibility is a result of an increase in inducible resistance.”

The steady decline in clindamycin susceptibility “may lead to some concern about the continued reliance on clindamycin for the empirical treatment of presumptive S. aureus infections, although it is probably premature to abandon this effective antibiotic choice,” they wrote (Pediatrics. 2016 Mar. 1. doi: 10.1542/peds.2015-3099). “It is crucial that clinicians remain knowledgeable about local susceptibility rates as it would be prudent to consider [alternative] antimicrobial agents for empirical use when the local clindamycin susceptibility rate drops below 85%.”

(c) CDC/Janice Haney Carr

The researchers retrospectively analyzed lab results from 39,209 patients under age 18 who were treated for S. aureus infections at one of the 266 U.S. facilities of the Military Health System from 2005 to 2014. The data included 41,745 S. aureus isolates, classified as MRSA if found resistant to cefoxitin, methicillin, or oxacillin and as methicillin susceptible (MSSA) if susceptible to those antimicrobials. The isolates had also been tested for susceptibility to ciprofloxacin, clindamycin, erythromycin, gentamicin, oxacillin, penicillin, rifampin, tetracycline, and trimethoprim/sulfamethoxazole (TMP/SMX).

During that decade, overall S. aureus susceptibility to clindamycin, ciprofloxacin, and TMP/SMX decreased – although susceptibility to TMP/SMX in 2014 stayed high at 98% – while overall susceptibility to erythromycin, gentamicin, and oxacillin increased. Specifically, 59% of S. aureus isolates were susceptible to oxacillin in 2005, which dropped briefly to 54% in 2007 before climbing to the 2014 rate of 68%.

Meanwhile, overall susceptibility to clindamycin dropped from 91% in 2005 to 86% in 2014, and MSSA susceptibility to clindamycin dropped from 91% in 2005 to 84% in 2014. “Erythromycin susceptibility remained stable among MSSA isolates throughout the study period at 63.5%, whereas MRSA susceptibility to erythromycin increased from 12.1% to 20.5%,” Dr. Sutter and her associates reported. “Ciprofloxacin susceptibility significantly decreased overall, although an initial decrease of 10.6% over the first 7 years of the study was subsequently followed by an increase of 6% between 2011 and 2014.”

Most of the isolates came from patients with skin and soft tissue infections, which were less likely to be susceptible to oxacillin than were other infections. Infections in children aged 1-5 years also were less likely to be susceptible to oxacillin, compared with infections in children of other age groups.

If the local clindamycin susceptibility rate falls below 85%, “beta-lactams, TMP/SMX, or tetracyclines may be used for less severe infections with intravenous vancomycin employed in severe cases,” the investigators said. “If overall MRSA rates continue to decline and clindamycin resistance among MSSA continues to increase, we may see a return to antistaphylococcal beta-lactam antimicrobial agents such as oxacillin or first-generation cephalosporins as preferred empirical therapy for presumed S. aureus infections.”

The research did not use external funding, and the authors reported no relevant financial disclosures.

References

References

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MRSA incidence decreased in children as clindamycin resistance increased
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MRSA incidence decreased in children as clindamycin resistance increased
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Key clinical point: The incidence of methicillin-resistant Staphylococcus aureus infections has decreased in children in recent years while resistance to clindamycin has increased.

Major finding: MRSA susceptibility to oxacillin increased to 68.4% in 2014, and susceptibility dropped to 86% for clindamycin.

Data source: A retrospective analysis of 41,745 S. aureus isolates from 39,209 patients under age 18 years in the U.S. Military Health System between 2005 and 2014.

Disclosures: The research did not use external funding, and the authors reported no relevant financial disclosures.

Piebaldism in Children

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Piebaldism in Children

Case Report

A 14-year-old adolescent girl presented with multiple asymptomatic light-colored patches on the forehead, bilateral arms, and legs that had been present since birth. The patient reported that the size of the patches had increased in proportion to her overall growth and that “brown spots” had gradually started to form within and around the patches. She noted that her father and paternal grandfather also had similar clinical findings. A review of systems was negative for hearing impairment, ocular abnormalities, and recurrent infections.

Physical examination revealed an otherwise healthy adolescent girl with Fitzpatrick skin type I and homogeneous blue eyes. Large symmetric depigmented patches were noted on the extensor surfaces of the mid legs and mid forearms (Figure). Macules of baseline pigment and hyperpigmentation were irregularly scattered within and at the periphery of the patches. A triangular hypopigmented patch at the hairline on the mid frontal scalp hairline was accompanied by depigmentation of terminal hairs in this region.

Large symmetric depigmented patches on the extensor surfaces of the mid legs (A) and mid forearm (B).

A clinical diagnosis of piebaldism was made and was discussed at length with the patient. Due to the benign nature of the condition and patient preference, no therapeutic intervention was pursued. It was recommended that she apply sunscreen daily for protection of the depigmented areas.

Comment

Piebaldism is a rare hereditary disorder of melanocyte development characterized clinically by the presence of congenital poliosis and leukoderma.1 The exact prevalence of piebaldism is unknown, but it has been estimated that less than 1 in 20,000 children are born with this condition.2 Poliosis circumscripta, traditionally known as white forelock, may be the only manifestation in 80% to 90% of cases and is present at birth.3 The white forelock typically appears in a triangular shape and the underlying skin of the scalp also is amelanotic. The eyebrows and eyelashes also may be involved.3

Characteristically, lesions of leukoderma are well-circumscribed, irregular, white patches that are often accompanied by hyperpigmented macules noted on both depigmented and unaffected adjacent skin.1 The lesions are classically distributed on the central forehead and anterior trunk, with extension to the flanks, anterior mid arms, and mid legs. Sparing of the dorsal midline, hands, feet, and periorificial area is characteristic.1

Depigmented patches typically are nonprogressive and persist into adulthood. Additional hyperpigmented macules may develop at or within the margins of the white patches. Partial or complete repigmentation may occur spontaneously or after trauma in some patients.2 Some children may develop café au lait lesions and may be misdiagnosed as concurrently having neurofibromatosis type I and piebaldism. If neurofibromatosis type I is suspected, patients should be thoroughly evaluated for other diagnostic criteria of this syndrome, as there may be cases of coexistence and overlap with piebaldism.4

Piebaldism is an autosomal-dominant inherited disorder and most commonly develops as a consequence of a mutation in the c-kit proto-oncogene (located on chromosome arm 14q12), which affects melanoblast migration, proliferation, differentiation, and survival.2 In piebaldism, the site of mutation within the gene correlates with the severity of the phenotype.5 Melanocytes are histologically and ultrastructurally absent or considerably reduced in depigmented patches but are normal in number in the hyperpigmented areas.2

Rare cases of piebaldism have been reported in association with other diseases, including congenital megacolon, congenital dyserythropoietic anemia type II, Diamond-Blackfan anemia, Grover disease (transient acantholytic dermatosis), and glycogen-storage disease type 1a.1,6 Poliosis alone may be the initial presentation of certain genetic syndromes, including Waardenburg syndrome (WS) and tuberous sclerosis; it also may be acquired in the setting of several conditions, including vitiligo, Vogt-Koyanagi-Harada syndrome, Alezzandrini syndrome, alopecia areata, and sarcoidosis.3

 

 

Notably, the diagnosis of piebaldism should alert the clinician to the possibility of WS, an autosomal-dominant disease characterized by a congenital white forelock, leukoderma in a piebaldlike distribution, lateral displacement of the medial canthi, a hypertrophic nasal root, heterochromia iridis, and progressive sensorineural hearing loss.7 Four clinical subtypes of WS have been described, with various gene mutations implicated: type 1 is the classic form, type 2 lacks dystopia canthorum and has a stonger association with deafness, type 3 is associated with limb abnormalities, and type 4 is associated with congenital megacolon. A case of WS type 1 has been described in association with facial nerve palsy and lingua plicata, 2 main features of Melkerson-Rosenthal syndrome.8 Depigmentation in WS is caused by the absence of melanocytes in the affected areas as well as failed migration of melanocytes to the ears and eyes.3 Waardenburg syndrome may be distinguished from piebaldism by characteristic facial features of the disease and should prompt a thorough ocular and auditory examination in affected patients.9

Although not a diagnostic criterion, poliosis rarely has been reported as one of the earliest associated findings of tuberous sclerosis.3,10 Major cutaneous features of this disease include facial angiofibromas, hypomelanotic macules, shagreen patches (connective tissue nevi), periungual fibromas, molluscum pendulum, and café au lait macules.

Vitiligo also may be considered in the differential diagnosis of piebaldism and can be distinguished by the presence of depigmented patches in a typical acral and periorificial distribution, lack of congential presentation, and relatively progressive course. Vitiligo is characterized by an acquired loss of epidermal melanocytes, leading to depigmented macules and patches.1,3

Vitiligo, poliosis, and alopecia areata usually are late clinical manifestations of Vogt-Koyanagi-Harada syndrome, a rare condition characterized by an autoimmune response to melanocyte-associated antigens. This condition initially presents with neurologic and ocular manifestations including headache, muscle weakness, tinnitus, uveitis, and choroiditis prior to dermatologic manifestations.11

Alezzandrini syndrome, a rare and closely related disorder, is distinctly characterized by whitening of scalp hair, eyebrows, and eyelashes, along with unilateral depigmentation of facial skin. This presentation is associated with ipsilateral visual changes and hearing abnormalities.12

The absence of abnormal ocular, auditory, and neurologic examinations, along with lack of characteristic cutaneous features indicating any of the aforementioned disorders, highly suggests a diagnosis of piebaldism.

Piebaldism is considered a relatively benign disorder but can be highly socially disabling, which presents a therapeutic challenge in affected children. Depigmented skin in piebaldism generally is considered unresponsive to medical or light therapy.1 Topical treatments with makeup or artificial pigmenting agents (eg, dihydroxyacetone [an ingredient used in sunless tanning products]) are useful but temporary. Sunscreen should be used judiciously to avoid sunburn and reduce carcinogenic potential.13

Several surgical techniques have been reported for treatment of leukoderma but with variable success. Of those reported, micropunch transplantation (minigrafting) using epidermal donor sites of 1 to 1.25 mm is a relatively inexpensive and effective method but is limited by scarring at the donor site.14 Autologous cultured epidermal cellular grafting with a controlled number of melanocytes is reported to achieve greater than 75% repigmentation. It requires fewer donor sites and, therefore, results in less scarring.15 Additionally, use of the erbium-doped:YAG laser aids in deepithelialization of the recipient site, allowing for treatment of large piebald lesions during a single operation.16 Despite these advances, additional studies are needed to improve quality of life in those affected.

References
  1. Janjua SA, Khachemoune A, Guldbakke KK. Piebaldism: a case report and a concise review of the literature. Cutis. 2007;80:411-414.
  2. Agarwal S, Ojha A. Piebaldism: a brief report and review of the literature. Indian Dermatol Online J. 2012;3:144-147.
  3. Sleiman R, Kurban M, Succaria F, et al. Poliosis circumscripta: overview and underlying causes. J Am Acad Dermatol. 2013;69:625-633.
  4. Oiso N, Fukai K, Kawada A, et al. Piebaldism. J Dermatol. 2013;40:330-355.
  5. López V, Jordá E. Piebaldism in a 2-year-old girl. Dermatol Online J. 2011;17:13.
  6. Ghoshal B, Sarkar N, Bhattacharjee M, et al. Glycogen storage disease 1a with piebaldism. Indian Pediatr. 2012;49:235-236.
  7. Salvatore S, Carnevale C, Infussi R, et al. Waardenburg syndrome: a review of literature and case reports. Clin Ter. 2012;163:e85-e94.
  8. Dourmishev AL, Dourmishev LA, Schwartz RA, et al. Waardenburg syndrome. Int J Dermatol. 1999;38:656-663.
  9. Fistarol SK, Itin PH. Disorders of pigmentation. J Dtsch Dermatol Ges. 2010;8:187-201.
  10. McWilliam RC, Stephenson JB. Depigmented hair. the earliest sign of tuberous sclerosis. Arch Dis Child. 1978;53:961-963.
  11. Chan EW, Sanjay S, Chang BC. Headache, red eyes, blurred vision and hearing loss. diagnosis: Vogt-Koyanagi-Harada syndrome. CMAJ. 2010;182:1205-1209.
  12. Andrade A, Pithon M. Alezzandrini syndrome: report of a sixth clinical case. Dermatology (Basel). 2011;222:8-9.
  13. Suga Y, Ikejima A, Matsuba S, et al. Medical pearl: DHA application for camouflaging segmental vitiligo and piebald lesions. J Am Acad Dermatol. 2002;47:436-438.
  14. Neves DR, Régis Júnior JR, Oliveira PJ, et al. Melanocyte transplant in piebaldism: case report. An Bras Dermatol. 2010;85:384-388.
  15. Van geel N, Wallaeys E, Goh BK, et al. Long-term results of noncultured epidermal cellular grafting in vitiligo, halo naevi, piebaldism and naevus depigmentosus. Br J Dermatol. 2010;163:1186-1193.
  16. Guerra L, Primavera G, Raskovic D, et al. Permanent repigmentation of piebaldism by erbium:YAG laser and autologous cultured epidermis. Br J Dermatol. 2004;150:715-721.
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From the Department of Dermatology, Beaumont Health, Trenton, Michigan.

The authors report no conflict of interest.

Correspondence: Alexandra Grob, DO, 1500 Eureka Rd, Wyandotte, MI 48192 ([email protected]).

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The authors report no conflict of interest.

Correspondence: Alexandra Grob, DO, 1500 Eureka Rd, Wyandotte, MI 48192 ([email protected]).

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From the Department of Dermatology, Beaumont Health, Trenton, Michigan.

The authors report no conflict of interest.

Correspondence: Alexandra Grob, DO, 1500 Eureka Rd, Wyandotte, MI 48192 ([email protected]).

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Case Report

A 14-year-old adolescent girl presented with multiple asymptomatic light-colored patches on the forehead, bilateral arms, and legs that had been present since birth. The patient reported that the size of the patches had increased in proportion to her overall growth and that “brown spots” had gradually started to form within and around the patches. She noted that her father and paternal grandfather also had similar clinical findings. A review of systems was negative for hearing impairment, ocular abnormalities, and recurrent infections.

Physical examination revealed an otherwise healthy adolescent girl with Fitzpatrick skin type I and homogeneous blue eyes. Large symmetric depigmented patches were noted on the extensor surfaces of the mid legs and mid forearms (Figure). Macules of baseline pigment and hyperpigmentation were irregularly scattered within and at the periphery of the patches. A triangular hypopigmented patch at the hairline on the mid frontal scalp hairline was accompanied by depigmentation of terminal hairs in this region.

Large symmetric depigmented patches on the extensor surfaces of the mid legs (A) and mid forearm (B).

A clinical diagnosis of piebaldism was made and was discussed at length with the patient. Due to the benign nature of the condition and patient preference, no therapeutic intervention was pursued. It was recommended that she apply sunscreen daily for protection of the depigmented areas.

Comment

Piebaldism is a rare hereditary disorder of melanocyte development characterized clinically by the presence of congenital poliosis and leukoderma.1 The exact prevalence of piebaldism is unknown, but it has been estimated that less than 1 in 20,000 children are born with this condition.2 Poliosis circumscripta, traditionally known as white forelock, may be the only manifestation in 80% to 90% of cases and is present at birth.3 The white forelock typically appears in a triangular shape and the underlying skin of the scalp also is amelanotic. The eyebrows and eyelashes also may be involved.3

Characteristically, lesions of leukoderma are well-circumscribed, irregular, white patches that are often accompanied by hyperpigmented macules noted on both depigmented and unaffected adjacent skin.1 The lesions are classically distributed on the central forehead and anterior trunk, with extension to the flanks, anterior mid arms, and mid legs. Sparing of the dorsal midline, hands, feet, and periorificial area is characteristic.1

Depigmented patches typically are nonprogressive and persist into adulthood. Additional hyperpigmented macules may develop at or within the margins of the white patches. Partial or complete repigmentation may occur spontaneously or after trauma in some patients.2 Some children may develop café au lait lesions and may be misdiagnosed as concurrently having neurofibromatosis type I and piebaldism. If neurofibromatosis type I is suspected, patients should be thoroughly evaluated for other diagnostic criteria of this syndrome, as there may be cases of coexistence and overlap with piebaldism.4

Piebaldism is an autosomal-dominant inherited disorder and most commonly develops as a consequence of a mutation in the c-kit proto-oncogene (located on chromosome arm 14q12), which affects melanoblast migration, proliferation, differentiation, and survival.2 In piebaldism, the site of mutation within the gene correlates with the severity of the phenotype.5 Melanocytes are histologically and ultrastructurally absent or considerably reduced in depigmented patches but are normal in number in the hyperpigmented areas.2

Rare cases of piebaldism have been reported in association with other diseases, including congenital megacolon, congenital dyserythropoietic anemia type II, Diamond-Blackfan anemia, Grover disease (transient acantholytic dermatosis), and glycogen-storage disease type 1a.1,6 Poliosis alone may be the initial presentation of certain genetic syndromes, including Waardenburg syndrome (WS) and tuberous sclerosis; it also may be acquired in the setting of several conditions, including vitiligo, Vogt-Koyanagi-Harada syndrome, Alezzandrini syndrome, alopecia areata, and sarcoidosis.3

 

 

Notably, the diagnosis of piebaldism should alert the clinician to the possibility of WS, an autosomal-dominant disease characterized by a congenital white forelock, leukoderma in a piebaldlike distribution, lateral displacement of the medial canthi, a hypertrophic nasal root, heterochromia iridis, and progressive sensorineural hearing loss.7 Four clinical subtypes of WS have been described, with various gene mutations implicated: type 1 is the classic form, type 2 lacks dystopia canthorum and has a stonger association with deafness, type 3 is associated with limb abnormalities, and type 4 is associated with congenital megacolon. A case of WS type 1 has been described in association with facial nerve palsy and lingua plicata, 2 main features of Melkerson-Rosenthal syndrome.8 Depigmentation in WS is caused by the absence of melanocytes in the affected areas as well as failed migration of melanocytes to the ears and eyes.3 Waardenburg syndrome may be distinguished from piebaldism by characteristic facial features of the disease and should prompt a thorough ocular and auditory examination in affected patients.9

Although not a diagnostic criterion, poliosis rarely has been reported as one of the earliest associated findings of tuberous sclerosis.3,10 Major cutaneous features of this disease include facial angiofibromas, hypomelanotic macules, shagreen patches (connective tissue nevi), periungual fibromas, molluscum pendulum, and café au lait macules.

Vitiligo also may be considered in the differential diagnosis of piebaldism and can be distinguished by the presence of depigmented patches in a typical acral and periorificial distribution, lack of congential presentation, and relatively progressive course. Vitiligo is characterized by an acquired loss of epidermal melanocytes, leading to depigmented macules and patches.1,3

Vitiligo, poliosis, and alopecia areata usually are late clinical manifestations of Vogt-Koyanagi-Harada syndrome, a rare condition characterized by an autoimmune response to melanocyte-associated antigens. This condition initially presents with neurologic and ocular manifestations including headache, muscle weakness, tinnitus, uveitis, and choroiditis prior to dermatologic manifestations.11

Alezzandrini syndrome, a rare and closely related disorder, is distinctly characterized by whitening of scalp hair, eyebrows, and eyelashes, along with unilateral depigmentation of facial skin. This presentation is associated with ipsilateral visual changes and hearing abnormalities.12

The absence of abnormal ocular, auditory, and neurologic examinations, along with lack of characteristic cutaneous features indicating any of the aforementioned disorders, highly suggests a diagnosis of piebaldism.

Piebaldism is considered a relatively benign disorder but can be highly socially disabling, which presents a therapeutic challenge in affected children. Depigmented skin in piebaldism generally is considered unresponsive to medical or light therapy.1 Topical treatments with makeup or artificial pigmenting agents (eg, dihydroxyacetone [an ingredient used in sunless tanning products]) are useful but temporary. Sunscreen should be used judiciously to avoid sunburn and reduce carcinogenic potential.13

Several surgical techniques have been reported for treatment of leukoderma but with variable success. Of those reported, micropunch transplantation (minigrafting) using epidermal donor sites of 1 to 1.25 mm is a relatively inexpensive and effective method but is limited by scarring at the donor site.14 Autologous cultured epidermal cellular grafting with a controlled number of melanocytes is reported to achieve greater than 75% repigmentation. It requires fewer donor sites and, therefore, results in less scarring.15 Additionally, use of the erbium-doped:YAG laser aids in deepithelialization of the recipient site, allowing for treatment of large piebald lesions during a single operation.16 Despite these advances, additional studies are needed to improve quality of life in those affected.

Case Report

A 14-year-old adolescent girl presented with multiple asymptomatic light-colored patches on the forehead, bilateral arms, and legs that had been present since birth. The patient reported that the size of the patches had increased in proportion to her overall growth and that “brown spots” had gradually started to form within and around the patches. She noted that her father and paternal grandfather also had similar clinical findings. A review of systems was negative for hearing impairment, ocular abnormalities, and recurrent infections.

Physical examination revealed an otherwise healthy adolescent girl with Fitzpatrick skin type I and homogeneous blue eyes. Large symmetric depigmented patches were noted on the extensor surfaces of the mid legs and mid forearms (Figure). Macules of baseline pigment and hyperpigmentation were irregularly scattered within and at the periphery of the patches. A triangular hypopigmented patch at the hairline on the mid frontal scalp hairline was accompanied by depigmentation of terminal hairs in this region.

Large symmetric depigmented patches on the extensor surfaces of the mid legs (A) and mid forearm (B).

A clinical diagnosis of piebaldism was made and was discussed at length with the patient. Due to the benign nature of the condition and patient preference, no therapeutic intervention was pursued. It was recommended that she apply sunscreen daily for protection of the depigmented areas.

Comment

Piebaldism is a rare hereditary disorder of melanocyte development characterized clinically by the presence of congenital poliosis and leukoderma.1 The exact prevalence of piebaldism is unknown, but it has been estimated that less than 1 in 20,000 children are born with this condition.2 Poliosis circumscripta, traditionally known as white forelock, may be the only manifestation in 80% to 90% of cases and is present at birth.3 The white forelock typically appears in a triangular shape and the underlying skin of the scalp also is amelanotic. The eyebrows and eyelashes also may be involved.3

Characteristically, lesions of leukoderma are well-circumscribed, irregular, white patches that are often accompanied by hyperpigmented macules noted on both depigmented and unaffected adjacent skin.1 The lesions are classically distributed on the central forehead and anterior trunk, with extension to the flanks, anterior mid arms, and mid legs. Sparing of the dorsal midline, hands, feet, and periorificial area is characteristic.1

Depigmented patches typically are nonprogressive and persist into adulthood. Additional hyperpigmented macules may develop at or within the margins of the white patches. Partial or complete repigmentation may occur spontaneously or after trauma in some patients.2 Some children may develop café au lait lesions and may be misdiagnosed as concurrently having neurofibromatosis type I and piebaldism. If neurofibromatosis type I is suspected, patients should be thoroughly evaluated for other diagnostic criteria of this syndrome, as there may be cases of coexistence and overlap with piebaldism.4

Piebaldism is an autosomal-dominant inherited disorder and most commonly develops as a consequence of a mutation in the c-kit proto-oncogene (located on chromosome arm 14q12), which affects melanoblast migration, proliferation, differentiation, and survival.2 In piebaldism, the site of mutation within the gene correlates with the severity of the phenotype.5 Melanocytes are histologically and ultrastructurally absent or considerably reduced in depigmented patches but are normal in number in the hyperpigmented areas.2

Rare cases of piebaldism have been reported in association with other diseases, including congenital megacolon, congenital dyserythropoietic anemia type II, Diamond-Blackfan anemia, Grover disease (transient acantholytic dermatosis), and glycogen-storage disease type 1a.1,6 Poliosis alone may be the initial presentation of certain genetic syndromes, including Waardenburg syndrome (WS) and tuberous sclerosis; it also may be acquired in the setting of several conditions, including vitiligo, Vogt-Koyanagi-Harada syndrome, Alezzandrini syndrome, alopecia areata, and sarcoidosis.3

 

 

Notably, the diagnosis of piebaldism should alert the clinician to the possibility of WS, an autosomal-dominant disease characterized by a congenital white forelock, leukoderma in a piebaldlike distribution, lateral displacement of the medial canthi, a hypertrophic nasal root, heterochromia iridis, and progressive sensorineural hearing loss.7 Four clinical subtypes of WS have been described, with various gene mutations implicated: type 1 is the classic form, type 2 lacks dystopia canthorum and has a stonger association with deafness, type 3 is associated with limb abnormalities, and type 4 is associated with congenital megacolon. A case of WS type 1 has been described in association with facial nerve palsy and lingua plicata, 2 main features of Melkerson-Rosenthal syndrome.8 Depigmentation in WS is caused by the absence of melanocytes in the affected areas as well as failed migration of melanocytes to the ears and eyes.3 Waardenburg syndrome may be distinguished from piebaldism by characteristic facial features of the disease and should prompt a thorough ocular and auditory examination in affected patients.9

Although not a diagnostic criterion, poliosis rarely has been reported as one of the earliest associated findings of tuberous sclerosis.3,10 Major cutaneous features of this disease include facial angiofibromas, hypomelanotic macules, shagreen patches (connective tissue nevi), periungual fibromas, molluscum pendulum, and café au lait macules.

Vitiligo also may be considered in the differential diagnosis of piebaldism and can be distinguished by the presence of depigmented patches in a typical acral and periorificial distribution, lack of congential presentation, and relatively progressive course. Vitiligo is characterized by an acquired loss of epidermal melanocytes, leading to depigmented macules and patches.1,3

Vitiligo, poliosis, and alopecia areata usually are late clinical manifestations of Vogt-Koyanagi-Harada syndrome, a rare condition characterized by an autoimmune response to melanocyte-associated antigens. This condition initially presents with neurologic and ocular manifestations including headache, muscle weakness, tinnitus, uveitis, and choroiditis prior to dermatologic manifestations.11

Alezzandrini syndrome, a rare and closely related disorder, is distinctly characterized by whitening of scalp hair, eyebrows, and eyelashes, along with unilateral depigmentation of facial skin. This presentation is associated with ipsilateral visual changes and hearing abnormalities.12

The absence of abnormal ocular, auditory, and neurologic examinations, along with lack of characteristic cutaneous features indicating any of the aforementioned disorders, highly suggests a diagnosis of piebaldism.

Piebaldism is considered a relatively benign disorder but can be highly socially disabling, which presents a therapeutic challenge in affected children. Depigmented skin in piebaldism generally is considered unresponsive to medical or light therapy.1 Topical treatments with makeup or artificial pigmenting agents (eg, dihydroxyacetone [an ingredient used in sunless tanning products]) are useful but temporary. Sunscreen should be used judiciously to avoid sunburn and reduce carcinogenic potential.13

Several surgical techniques have been reported for treatment of leukoderma but with variable success. Of those reported, micropunch transplantation (minigrafting) using epidermal donor sites of 1 to 1.25 mm is a relatively inexpensive and effective method but is limited by scarring at the donor site.14 Autologous cultured epidermal cellular grafting with a controlled number of melanocytes is reported to achieve greater than 75% repigmentation. It requires fewer donor sites and, therefore, results in less scarring.15 Additionally, use of the erbium-doped:YAG laser aids in deepithelialization of the recipient site, allowing for treatment of large piebald lesions during a single operation.16 Despite these advances, additional studies are needed to improve quality of life in those affected.

References
  1. Janjua SA, Khachemoune A, Guldbakke KK. Piebaldism: a case report and a concise review of the literature. Cutis. 2007;80:411-414.
  2. Agarwal S, Ojha A. Piebaldism: a brief report and review of the literature. Indian Dermatol Online J. 2012;3:144-147.
  3. Sleiman R, Kurban M, Succaria F, et al. Poliosis circumscripta: overview and underlying causes. J Am Acad Dermatol. 2013;69:625-633.
  4. Oiso N, Fukai K, Kawada A, et al. Piebaldism. J Dermatol. 2013;40:330-355.
  5. López V, Jordá E. Piebaldism in a 2-year-old girl. Dermatol Online J. 2011;17:13.
  6. Ghoshal B, Sarkar N, Bhattacharjee M, et al. Glycogen storage disease 1a with piebaldism. Indian Pediatr. 2012;49:235-236.
  7. Salvatore S, Carnevale C, Infussi R, et al. Waardenburg syndrome: a review of literature and case reports. Clin Ter. 2012;163:e85-e94.
  8. Dourmishev AL, Dourmishev LA, Schwartz RA, et al. Waardenburg syndrome. Int J Dermatol. 1999;38:656-663.
  9. Fistarol SK, Itin PH. Disorders of pigmentation. J Dtsch Dermatol Ges. 2010;8:187-201.
  10. McWilliam RC, Stephenson JB. Depigmented hair. the earliest sign of tuberous sclerosis. Arch Dis Child. 1978;53:961-963.
  11. Chan EW, Sanjay S, Chang BC. Headache, red eyes, blurred vision and hearing loss. diagnosis: Vogt-Koyanagi-Harada syndrome. CMAJ. 2010;182:1205-1209.
  12. Andrade A, Pithon M. Alezzandrini syndrome: report of a sixth clinical case. Dermatology (Basel). 2011;222:8-9.
  13. Suga Y, Ikejima A, Matsuba S, et al. Medical pearl: DHA application for camouflaging segmental vitiligo and piebald lesions. J Am Acad Dermatol. 2002;47:436-438.
  14. Neves DR, Régis Júnior JR, Oliveira PJ, et al. Melanocyte transplant in piebaldism: case report. An Bras Dermatol. 2010;85:384-388.
  15. Van geel N, Wallaeys E, Goh BK, et al. Long-term results of noncultured epidermal cellular grafting in vitiligo, halo naevi, piebaldism and naevus depigmentosus. Br J Dermatol. 2010;163:1186-1193.
  16. Guerra L, Primavera G, Raskovic D, et al. Permanent repigmentation of piebaldism by erbium:YAG laser and autologous cultured epidermis. Br J Dermatol. 2004;150:715-721.
References
  1. Janjua SA, Khachemoune A, Guldbakke KK. Piebaldism: a case report and a concise review of the literature. Cutis. 2007;80:411-414.
  2. Agarwal S, Ojha A. Piebaldism: a brief report and review of the literature. Indian Dermatol Online J. 2012;3:144-147.
  3. Sleiman R, Kurban M, Succaria F, et al. Poliosis circumscripta: overview and underlying causes. J Am Acad Dermatol. 2013;69:625-633.
  4. Oiso N, Fukai K, Kawada A, et al. Piebaldism. J Dermatol. 2013;40:330-355.
  5. López V, Jordá E. Piebaldism in a 2-year-old girl. Dermatol Online J. 2011;17:13.
  6. Ghoshal B, Sarkar N, Bhattacharjee M, et al. Glycogen storage disease 1a with piebaldism. Indian Pediatr. 2012;49:235-236.
  7. Salvatore S, Carnevale C, Infussi R, et al. Waardenburg syndrome: a review of literature and case reports. Clin Ter. 2012;163:e85-e94.
  8. Dourmishev AL, Dourmishev LA, Schwartz RA, et al. Waardenburg syndrome. Int J Dermatol. 1999;38:656-663.
  9. Fistarol SK, Itin PH. Disorders of pigmentation. J Dtsch Dermatol Ges. 2010;8:187-201.
  10. McWilliam RC, Stephenson JB. Depigmented hair. the earliest sign of tuberous sclerosis. Arch Dis Child. 1978;53:961-963.
  11. Chan EW, Sanjay S, Chang BC. Headache, red eyes, blurred vision and hearing loss. diagnosis: Vogt-Koyanagi-Harada syndrome. CMAJ. 2010;182:1205-1209.
  12. Andrade A, Pithon M. Alezzandrini syndrome: report of a sixth clinical case. Dermatology (Basel). 2011;222:8-9.
  13. Suga Y, Ikejima A, Matsuba S, et al. Medical pearl: DHA application for camouflaging segmental vitiligo and piebald lesions. J Am Acad Dermatol. 2002;47:436-438.
  14. Neves DR, Régis Júnior JR, Oliveira PJ, et al. Melanocyte transplant in piebaldism: case report. An Bras Dermatol. 2010;85:384-388.
  15. Van geel N, Wallaeys E, Goh BK, et al. Long-term results of noncultured epidermal cellular grafting in vitiligo, halo naevi, piebaldism and naevus depigmentosus. Br J Dermatol. 2010;163:1186-1193.
  16. Guerra L, Primavera G, Raskovic D, et al. Permanent repigmentation of piebaldism by erbium:YAG laser and autologous cultured epidermis. Br J Dermatol. 2004;150:715-721.
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  • Poliosis circumscripta (or white forelock) is commonly the only manifestation of piebaldism in children.
  • Affected areas of leukoderma in piebaldism are classically distributed on the central forehead, anterior trunk, and mid extremities.
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A Case of Bloom Syndrome With Uncommon Clinical Manifestations Confirmed on Genetic Testing

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A Case of Bloom Syndrome With Uncommon Clinical Manifestations Confirmed on Genetic Testing

Bloom syndrome, also called congenital telangiectatic erythema and stunted growth, was first described by David Bloom in 1954.1 It is a rare autosomal-recessive disorder (Online Mendelian Inheritance in Man 210900) characterized by specific clinical manifestations including photosensitivity, telangiectatic facial erythema, proportionate growth deficiency, hypogonadism, immunodeficiency, and a tendency to develop various malignancies.2 Linkage analysis revealed that the Bloom syndrome gene locus resides on chromosome arm 15q26.1,3 and the BLM gene in this region has been identified as being responsible for the development of Bloom syndrome.4,5 We report the case of a 12-year-old Chinese girl with Bloom syndrome and detected BLM gene. The evaluation was approved by the Institutional Ethical Review Boards of Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China).

Case Report

We evaluated a Bloom syndrome family, which consisted of the patient and her parents. The patient was a 12-year-old Chinese girl who was apparently healthy until 3 months of age when her parents noticed an erythematous eruption with blisters on the face. Exacerbation after exposure to sunlight is usual, which results in the eruption becoming prominent in summer and fainter in winter.2 Gradually, the patient’s skin lesions became more progressive, extending to the forehead, nose, and ears, with oozing, crusting, atrophy, and telangiectases developing on the face despite treatment. In the last 3 years, no blisters were present on the patient’s face because of her efforts to avoid sun exposure. She had no history of recurrent infections.

On physical examination, the patient was generally healthy with normal intelligence and short stature. She weighed 26 kg and was approximately 122-cm tall. Telangiectatic erythema and slight scaling were noted on the face, which simulated lupus erythematosus (Figures 1A and 1B). She had additional abnormalities including alopecia areata (Figure 1C), eyebrow hair loss, flat nose, reticular pigmentation on the forehead and trunk, and finger swelling. The distal phalanges on all 10 fingers became short and sharpened and the fingernails became wider than they were long (Figure 1D). Laboratory investigations, including a complete blood cell count, liver and kidney function tests, stool examination, serum complement, and albumin and globulin levels, were within reference range.

Figure 1. Uncommon clinical findings of telangiectatic facial erythema, eyebrow hair loss, and reticular pigmentation on the forehead (A), flat nose (B), alopecia areata (C), and short sharpened distal phalanges that were wider than the length of the fingernails (D) in a 12-year-old Chinese girl with Bloom syndrome that was confirmed on genetic testing.

After informed consent was obtained, a mutation analysis of the BLM gene was performed in the patient and her parents. We used a genomic DNA purification kit to extract genomic DNA from peripheral blood according to the manufacturer’s protocol. Genomic DNA was used to amplify the exons of the BLM gene with intron flanking sequences by polymerase chain reaction with the primer described elsewhere.6 After the amplification, the polymerase chain reaction products were purified and the BLM gene was sequenced. Sequence comparisons and analysis were performed using Phred/Phrap/Consed version 12.0.

The patient was found to carry changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene. The patient’s father was found to carry c.2603C>T and her mother carried c.3961G>A (Figure 2).

Figure 2. Changes in 2 heterozygous nucleotide sites: c.2603C>T in exon 13 (A) and c.3961G>A in exon 21 (B) of the BLM gene. The patient’s father was found to carry c.2603C>T and her mother carried c.3961G>A.

 

 

Comment

Patients with Bloom syndrome have a characteristic clinical appearance that typically includes photosensitivity, telangiectatic facial erythema, and growth deficiency. Telangiectatic erythema of the face develops during infancy or early childhood as red macules or plaques and may simulate lupus erythematosus. The lesions are described as a butterfly rash affecting the bridge of the nose and cheeks but also may involve the margins of the eyelids, forehead, ears, and sometimes the dorsa of the hands and forearms. Moderate and proportionate growth deficiencies develop both in utero and postnatally. Patients with Bloom syndrome characteristically have narrow, slender, distinct facial features with micrognathism and a relatively prominent nose. They usually may have mild microcephaly, meaning the head is longer and narrower than normal.2,7-10

German and Takebe11 reported 14 Japanese patients with Bloom syndrome. The phenotype differs somewhat from most cases recognized elsewhere in that dolichocephaly was a less constant feature, the facial skin was less prominent, and life-threatening infections were less common. Our patient had typical telangiectatic facial erythema without microcephaly, dolichocephaly, or any infections. She also had some uncommon manifestations such as alopecia areata, eyebrow hair loss, flat nose, reticular pigmentation, and short sharpened distal phalanges with fingernails that were wider than they were long. Although she had no recurrent infections and laboratory tests were within reference range, the alopecia areata and eyebrow hair loss may be associated with an abnormal immune response. The reasons for the short sharpened distal phalanges and the fingernail findings are unclear. The presence of reticular pigmentation also is unclear but may be associated with photosensitivity. Since the BLM gene was discovered to be the disease-causing gene of Bloom syndrome in 1995,4,5 approximately 70 mutations were reported. The BLM gene encodes for the Bloom syndrome protein, a DNA helicase of the highly conserved RecQ subfamily of helicases, a group of nuclear proteins important in the maintenance of genomic stability.12

Mutation analysis of the BLM gene in our patient showed changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene, which altered proline residue with leucine residue at 868 and valine residue with isoleucine residue at 1321, respectively. According to GenBank,13,14 c.2603C>T and c.3961G>A are single nucleotide polymorphisms of the BLM gene. The genotypic distribution of International HapMap Project15 showed that C=602/602 and T=0/602 on c.2603 in 301 unrelated Chinese patients and G=585/602 and A=17/602 on c.3961 in 301 unrelated Chinese patients. Because of the low prevalence of genotypes c.2603T and c.3961A in China, the relationship between clinical features and c.2603C>T and c.3961G>A of the BLM gene in our patient requires further study.

In conclusion, we report a patient with Bloom syndrome with uncommon clinical manifestations. Our findings indicate that c.2603C>T and c.3961G>A of the BLM gene may be the pathogenic nature for Bloom syndrome in China.

Acknowledgments

The authors would like to thank the patient and her family for their participation in the study. The authors also thank Li Qi, BA, Beijing, China, for his contribution to the review of the data in the literature.

References
  1. Bloom D. Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs; probably a syndrome entity. AMA Am J Dis Child. 1954;88:754-758.
  2. German J. Bloom’s syndrome, I: genetical and clinical observations in the first twenty-seven patients. Am J Hum Genet. 1969;21:196-227.
  3. German J, Roe AM, Leppert MF, et al. Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1. Proc Natl Acad Sci U S A. 1994;91:6669-6673.
  4. Passarge E. A DNA helicase in full Bloom. Nat Genet. 1995;11:356-357.
  5. Ellis NA, Groden J, Ye TZ, et al. The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell. 1995;83:655-666.
  6. German J, Sanz MM, Ciocci S, et al. Syndrome-causing mutations of the BLM gene in persons in the Bloom’s Syndrome Registry. Hum Mutat. 2007;28:743-753.
  7. Landau JW, Sasaki MS, Newcomer VD, et al. Bloom’s syndrome: the syndrome of telangiectatic erythema and growth retardation. Arch Dermatol. 1966;94:687-694.
  8. Gretzula JC, Hevia O, Weber PJ. Bloom’s syndrome. J Am Acad Dermatol. 1987;17:479-488.
  9. Passarge E. Bloom’s syndrome: the German experience. Ann Genet. 1991;34:179-197.
  10. German J. Bloom’s syndrome. Dermatol Clin. 1995;13:7-18.
  11. German J, Takebe H. Bloom’s syndrome, XIV: the disorder in Japan. Clin Genet. 1989;35:93-110.
  12. Bennett RJ, Keck JL. Structure and function of RecQ DNA helicases. Crit Rev Biochem Mol Biol. 2004;39:79-97.
  13. Reference SNP (refSNP) Cluster Report: rs2227935. National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=2227935. Accessed February 3, 2016.
  14. Reference SNP (refSNP) Cluster Report: rs7167216. National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=7167216. Accessed February 3, 2016.
  15. Homo sapiens:GRCh37.p13 (GCF_000001405.25)Chr 1 (NC_000001.10):1 - 249.3M. National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/variationtools/1000genomes/?=%EF%BC%86=. Accessed February 3, 2016.
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From the Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China.

The authors report no conflict of interest.

This article was supported by the China Central Public Welfare Research Foundation (grant 303-05-7059) and the National Natural Science Foundation of China (grant 81472872).

Correspondence: Lin Lin, MD, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiang-Wang-Miao St, Nanjing, Jiangsu, 210042 China ([email protected]).

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From the Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China.

The authors report no conflict of interest.

This article was supported by the China Central Public Welfare Research Foundation (grant 303-05-7059) and the National Natural Science Foundation of China (grant 81472872).

Correspondence: Lin Lin, MD, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiang-Wang-Miao St, Nanjing, Jiangsu, 210042 China ([email protected]).

Author and Disclosure Information

From the Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China.

The authors report no conflict of interest.

This article was supported by the China Central Public Welfare Research Foundation (grant 303-05-7059) and the National Natural Science Foundation of China (grant 81472872).

Correspondence: Lin Lin, MD, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiang-Wang-Miao St, Nanjing, Jiangsu, 210042 China ([email protected]).

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Bloom syndrome, also called congenital telangiectatic erythema and stunted growth, was first described by David Bloom in 1954.1 It is a rare autosomal-recessive disorder (Online Mendelian Inheritance in Man 210900) characterized by specific clinical manifestations including photosensitivity, telangiectatic facial erythema, proportionate growth deficiency, hypogonadism, immunodeficiency, and a tendency to develop various malignancies.2 Linkage analysis revealed that the Bloom syndrome gene locus resides on chromosome arm 15q26.1,3 and the BLM gene in this region has been identified as being responsible for the development of Bloom syndrome.4,5 We report the case of a 12-year-old Chinese girl with Bloom syndrome and detected BLM gene. The evaluation was approved by the Institutional Ethical Review Boards of Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China).

Case Report

We evaluated a Bloom syndrome family, which consisted of the patient and her parents. The patient was a 12-year-old Chinese girl who was apparently healthy until 3 months of age when her parents noticed an erythematous eruption with blisters on the face. Exacerbation after exposure to sunlight is usual, which results in the eruption becoming prominent in summer and fainter in winter.2 Gradually, the patient’s skin lesions became more progressive, extending to the forehead, nose, and ears, with oozing, crusting, atrophy, and telangiectases developing on the face despite treatment. In the last 3 years, no blisters were present on the patient’s face because of her efforts to avoid sun exposure. She had no history of recurrent infections.

On physical examination, the patient was generally healthy with normal intelligence and short stature. She weighed 26 kg and was approximately 122-cm tall. Telangiectatic erythema and slight scaling were noted on the face, which simulated lupus erythematosus (Figures 1A and 1B). She had additional abnormalities including alopecia areata (Figure 1C), eyebrow hair loss, flat nose, reticular pigmentation on the forehead and trunk, and finger swelling. The distal phalanges on all 10 fingers became short and sharpened and the fingernails became wider than they were long (Figure 1D). Laboratory investigations, including a complete blood cell count, liver and kidney function tests, stool examination, serum complement, and albumin and globulin levels, were within reference range.

Figure 1. Uncommon clinical findings of telangiectatic facial erythema, eyebrow hair loss, and reticular pigmentation on the forehead (A), flat nose (B), alopecia areata (C), and short sharpened distal phalanges that were wider than the length of the fingernails (D) in a 12-year-old Chinese girl with Bloom syndrome that was confirmed on genetic testing.

After informed consent was obtained, a mutation analysis of the BLM gene was performed in the patient and her parents. We used a genomic DNA purification kit to extract genomic DNA from peripheral blood according to the manufacturer’s protocol. Genomic DNA was used to amplify the exons of the BLM gene with intron flanking sequences by polymerase chain reaction with the primer described elsewhere.6 After the amplification, the polymerase chain reaction products were purified and the BLM gene was sequenced. Sequence comparisons and analysis were performed using Phred/Phrap/Consed version 12.0.

The patient was found to carry changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene. The patient’s father was found to carry c.2603C>T and her mother carried c.3961G>A (Figure 2).

Figure 2. Changes in 2 heterozygous nucleotide sites: c.2603C>T in exon 13 (A) and c.3961G>A in exon 21 (B) of the BLM gene. The patient’s father was found to carry c.2603C>T and her mother carried c.3961G>A.

 

 

Comment

Patients with Bloom syndrome have a characteristic clinical appearance that typically includes photosensitivity, telangiectatic facial erythema, and growth deficiency. Telangiectatic erythema of the face develops during infancy or early childhood as red macules or plaques and may simulate lupus erythematosus. The lesions are described as a butterfly rash affecting the bridge of the nose and cheeks but also may involve the margins of the eyelids, forehead, ears, and sometimes the dorsa of the hands and forearms. Moderate and proportionate growth deficiencies develop both in utero and postnatally. Patients with Bloom syndrome characteristically have narrow, slender, distinct facial features with micrognathism and a relatively prominent nose. They usually may have mild microcephaly, meaning the head is longer and narrower than normal.2,7-10

German and Takebe11 reported 14 Japanese patients with Bloom syndrome. The phenotype differs somewhat from most cases recognized elsewhere in that dolichocephaly was a less constant feature, the facial skin was less prominent, and life-threatening infections were less common. Our patient had typical telangiectatic facial erythema without microcephaly, dolichocephaly, or any infections. She also had some uncommon manifestations such as alopecia areata, eyebrow hair loss, flat nose, reticular pigmentation, and short sharpened distal phalanges with fingernails that were wider than they were long. Although she had no recurrent infections and laboratory tests were within reference range, the alopecia areata and eyebrow hair loss may be associated with an abnormal immune response. The reasons for the short sharpened distal phalanges and the fingernail findings are unclear. The presence of reticular pigmentation also is unclear but may be associated with photosensitivity. Since the BLM gene was discovered to be the disease-causing gene of Bloom syndrome in 1995,4,5 approximately 70 mutations were reported. The BLM gene encodes for the Bloom syndrome protein, a DNA helicase of the highly conserved RecQ subfamily of helicases, a group of nuclear proteins important in the maintenance of genomic stability.12

Mutation analysis of the BLM gene in our patient showed changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene, which altered proline residue with leucine residue at 868 and valine residue with isoleucine residue at 1321, respectively. According to GenBank,13,14 c.2603C>T and c.3961G>A are single nucleotide polymorphisms of the BLM gene. The genotypic distribution of International HapMap Project15 showed that C=602/602 and T=0/602 on c.2603 in 301 unrelated Chinese patients and G=585/602 and A=17/602 on c.3961 in 301 unrelated Chinese patients. Because of the low prevalence of genotypes c.2603T and c.3961A in China, the relationship between clinical features and c.2603C>T and c.3961G>A of the BLM gene in our patient requires further study.

In conclusion, we report a patient with Bloom syndrome with uncommon clinical manifestations. Our findings indicate that c.2603C>T and c.3961G>A of the BLM gene may be the pathogenic nature for Bloom syndrome in China.

Acknowledgments

The authors would like to thank the patient and her family for their participation in the study. The authors also thank Li Qi, BA, Beijing, China, for his contribution to the review of the data in the literature.

Bloom syndrome, also called congenital telangiectatic erythema and stunted growth, was first described by David Bloom in 1954.1 It is a rare autosomal-recessive disorder (Online Mendelian Inheritance in Man 210900) characterized by specific clinical manifestations including photosensitivity, telangiectatic facial erythema, proportionate growth deficiency, hypogonadism, immunodeficiency, and a tendency to develop various malignancies.2 Linkage analysis revealed that the Bloom syndrome gene locus resides on chromosome arm 15q26.1,3 and the BLM gene in this region has been identified as being responsible for the development of Bloom syndrome.4,5 We report the case of a 12-year-old Chinese girl with Bloom syndrome and detected BLM gene. The evaluation was approved by the Institutional Ethical Review Boards of Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China).

Case Report

We evaluated a Bloom syndrome family, which consisted of the patient and her parents. The patient was a 12-year-old Chinese girl who was apparently healthy until 3 months of age when her parents noticed an erythematous eruption with blisters on the face. Exacerbation after exposure to sunlight is usual, which results in the eruption becoming prominent in summer and fainter in winter.2 Gradually, the patient’s skin lesions became more progressive, extending to the forehead, nose, and ears, with oozing, crusting, atrophy, and telangiectases developing on the face despite treatment. In the last 3 years, no blisters were present on the patient’s face because of her efforts to avoid sun exposure. She had no history of recurrent infections.

On physical examination, the patient was generally healthy with normal intelligence and short stature. She weighed 26 kg and was approximately 122-cm tall. Telangiectatic erythema and slight scaling were noted on the face, which simulated lupus erythematosus (Figures 1A and 1B). She had additional abnormalities including alopecia areata (Figure 1C), eyebrow hair loss, flat nose, reticular pigmentation on the forehead and trunk, and finger swelling. The distal phalanges on all 10 fingers became short and sharpened and the fingernails became wider than they were long (Figure 1D). Laboratory investigations, including a complete blood cell count, liver and kidney function tests, stool examination, serum complement, and albumin and globulin levels, were within reference range.

Figure 1. Uncommon clinical findings of telangiectatic facial erythema, eyebrow hair loss, and reticular pigmentation on the forehead (A), flat nose (B), alopecia areata (C), and short sharpened distal phalanges that were wider than the length of the fingernails (D) in a 12-year-old Chinese girl with Bloom syndrome that was confirmed on genetic testing.

After informed consent was obtained, a mutation analysis of the BLM gene was performed in the patient and her parents. We used a genomic DNA purification kit to extract genomic DNA from peripheral blood according to the manufacturer’s protocol. Genomic DNA was used to amplify the exons of the BLM gene with intron flanking sequences by polymerase chain reaction with the primer described elsewhere.6 After the amplification, the polymerase chain reaction products were purified and the BLM gene was sequenced. Sequence comparisons and analysis were performed using Phred/Phrap/Consed version 12.0.

The patient was found to carry changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene. The patient’s father was found to carry c.2603C>T and her mother carried c.3961G>A (Figure 2).

Figure 2. Changes in 2 heterozygous nucleotide sites: c.2603C>T in exon 13 (A) and c.3961G>A in exon 21 (B) of the BLM gene. The patient’s father was found to carry c.2603C>T and her mother carried c.3961G>A.

 

 

Comment

Patients with Bloom syndrome have a characteristic clinical appearance that typically includes photosensitivity, telangiectatic facial erythema, and growth deficiency. Telangiectatic erythema of the face develops during infancy or early childhood as red macules or plaques and may simulate lupus erythematosus. The lesions are described as a butterfly rash affecting the bridge of the nose and cheeks but also may involve the margins of the eyelids, forehead, ears, and sometimes the dorsa of the hands and forearms. Moderate and proportionate growth deficiencies develop both in utero and postnatally. Patients with Bloom syndrome characteristically have narrow, slender, distinct facial features with micrognathism and a relatively prominent nose. They usually may have mild microcephaly, meaning the head is longer and narrower than normal.2,7-10

German and Takebe11 reported 14 Japanese patients with Bloom syndrome. The phenotype differs somewhat from most cases recognized elsewhere in that dolichocephaly was a less constant feature, the facial skin was less prominent, and life-threatening infections were less common. Our patient had typical telangiectatic facial erythema without microcephaly, dolichocephaly, or any infections. She also had some uncommon manifestations such as alopecia areata, eyebrow hair loss, flat nose, reticular pigmentation, and short sharpened distal phalanges with fingernails that were wider than they were long. Although she had no recurrent infections and laboratory tests were within reference range, the alopecia areata and eyebrow hair loss may be associated with an abnormal immune response. The reasons for the short sharpened distal phalanges and the fingernail findings are unclear. The presence of reticular pigmentation also is unclear but may be associated with photosensitivity. Since the BLM gene was discovered to be the disease-causing gene of Bloom syndrome in 1995,4,5 approximately 70 mutations were reported. The BLM gene encodes for the Bloom syndrome protein, a DNA helicase of the highly conserved RecQ subfamily of helicases, a group of nuclear proteins important in the maintenance of genomic stability.12

Mutation analysis of the BLM gene in our patient showed changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene, which altered proline residue with leucine residue at 868 and valine residue with isoleucine residue at 1321, respectively. According to GenBank,13,14 c.2603C>T and c.3961G>A are single nucleotide polymorphisms of the BLM gene. The genotypic distribution of International HapMap Project15 showed that C=602/602 and T=0/602 on c.2603 in 301 unrelated Chinese patients and G=585/602 and A=17/602 on c.3961 in 301 unrelated Chinese patients. Because of the low prevalence of genotypes c.2603T and c.3961A in China, the relationship between clinical features and c.2603C>T and c.3961G>A of the BLM gene in our patient requires further study.

In conclusion, we report a patient with Bloom syndrome with uncommon clinical manifestations. Our findings indicate that c.2603C>T and c.3961G>A of the BLM gene may be the pathogenic nature for Bloom syndrome in China.

Acknowledgments

The authors would like to thank the patient and her family for their participation in the study. The authors also thank Li Qi, BA, Beijing, China, for his contribution to the review of the data in the literature.

References
  1. Bloom D. Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs; probably a syndrome entity. AMA Am J Dis Child. 1954;88:754-758.
  2. German J. Bloom’s syndrome, I: genetical and clinical observations in the first twenty-seven patients. Am J Hum Genet. 1969;21:196-227.
  3. German J, Roe AM, Leppert MF, et al. Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1. Proc Natl Acad Sci U S A. 1994;91:6669-6673.
  4. Passarge E. A DNA helicase in full Bloom. Nat Genet. 1995;11:356-357.
  5. Ellis NA, Groden J, Ye TZ, et al. The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell. 1995;83:655-666.
  6. German J, Sanz MM, Ciocci S, et al. Syndrome-causing mutations of the BLM gene in persons in the Bloom’s Syndrome Registry. Hum Mutat. 2007;28:743-753.
  7. Landau JW, Sasaki MS, Newcomer VD, et al. Bloom’s syndrome: the syndrome of telangiectatic erythema and growth retardation. Arch Dermatol. 1966;94:687-694.
  8. Gretzula JC, Hevia O, Weber PJ. Bloom’s syndrome. J Am Acad Dermatol. 1987;17:479-488.
  9. Passarge E. Bloom’s syndrome: the German experience. Ann Genet. 1991;34:179-197.
  10. German J. Bloom’s syndrome. Dermatol Clin. 1995;13:7-18.
  11. German J, Takebe H. Bloom’s syndrome, XIV: the disorder in Japan. Clin Genet. 1989;35:93-110.
  12. Bennett RJ, Keck JL. Structure and function of RecQ DNA helicases. Crit Rev Biochem Mol Biol. 2004;39:79-97.
  13. Reference SNP (refSNP) Cluster Report: rs2227935. National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=2227935. Accessed February 3, 2016.
  14. Reference SNP (refSNP) Cluster Report: rs7167216. National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=7167216. Accessed February 3, 2016.
  15. Homo sapiens:GRCh37.p13 (GCF_000001405.25)Chr 1 (NC_000001.10):1 - 249.3M. National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/variationtools/1000genomes/?=%EF%BC%86=. Accessed February 3, 2016.
References
  1. Bloom D. Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs; probably a syndrome entity. AMA Am J Dis Child. 1954;88:754-758.
  2. German J. Bloom’s syndrome, I: genetical and clinical observations in the first twenty-seven patients. Am J Hum Genet. 1969;21:196-227.
  3. German J, Roe AM, Leppert MF, et al. Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1. Proc Natl Acad Sci U S A. 1994;91:6669-6673.
  4. Passarge E. A DNA helicase in full Bloom. Nat Genet. 1995;11:356-357.
  5. Ellis NA, Groden J, Ye TZ, et al. The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell. 1995;83:655-666.
  6. German J, Sanz MM, Ciocci S, et al. Syndrome-causing mutations of the BLM gene in persons in the Bloom’s Syndrome Registry. Hum Mutat. 2007;28:743-753.
  7. Landau JW, Sasaki MS, Newcomer VD, et al. Bloom’s syndrome: the syndrome of telangiectatic erythema and growth retardation. Arch Dermatol. 1966;94:687-694.
  8. Gretzula JC, Hevia O, Weber PJ. Bloom’s syndrome. J Am Acad Dermatol. 1987;17:479-488.
  9. Passarge E. Bloom’s syndrome: the German experience. Ann Genet. 1991;34:179-197.
  10. German J. Bloom’s syndrome. Dermatol Clin. 1995;13:7-18.
  11. German J, Takebe H. Bloom’s syndrome, XIV: the disorder in Japan. Clin Genet. 1989;35:93-110.
  12. Bennett RJ, Keck JL. Structure and function of RecQ DNA helicases. Crit Rev Biochem Mol Biol. 2004;39:79-97.
  13. Reference SNP (refSNP) Cluster Report: rs2227935. National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=2227935. Accessed February 3, 2016.
  14. Reference SNP (refSNP) Cluster Report: rs7167216. National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=7167216. Accessed February 3, 2016.
  15. Homo sapiens:GRCh37.p13 (GCF_000001405.25)Chr 1 (NC_000001.10):1 - 249.3M. National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/variationtools/1000genomes/?=%EF%BC%86=. Accessed February 3, 2016.
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Postinflammatory Hyperpigmentation in Patients With Skin of Color

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Postinflammatory Hyperpigmentation in Patients With Skin of Color

Postinflammatory hyperpigmentation (PIH) develops as darkly pigmented macules that occur after an inflammatory process of the skin such as acne, folliculitis, eczema, or shaving irritation. Patients with Fitzpatrick skin types III to VI usually are most commonly affected, and for many, the remnant pigmentation can be an even greater concern than the original inflammatory process.1,2 Reported treatments of PIH include tretinoin, hydroquinone, azelaic acid, and chemical peels. The ideal combination of therapy has yet to be delineated.

Tretinoin (Vitamin A Derivative)

Bulengo-Ransby et al3 performed one of the first clinical trials testing tretinoin cream 0.1% for PIH in patients with Fitzpatrick skin types IV to VI . The study included 54 patients (24 applied tretinoin and 30 applied a vehicle) with moderate to severe PIH on the face and arms. The patients were divided into therapy and placebo groups and were evaluated for 40 weeks. Changes were evaluated through colorimetry, light microscopy, histology, and photography, with significant clinical improvement in the tretinoin-treated group (P<.001).3 A double-blind, randomized study of 45 photoaged Chinese and Japanese patients using tretinoin cream 0.1% also was conducted for treatment of photoaging-associated hyperpigmented lesions of the face and hands. Assessment was done with clinical, colorimetric, and histological evaluation, with an overall statistical improvement noted in hyperpigmentation.4 Both of the above studies showed mild irritation (ie, retinoid dermatitis) with application of tretinoin, which creates a compliance issue in patients who are recommended to continue therapy with higher-strength tretinoin. This side-effect profile can be circumvented through gradual elevation in the strength of tretinoin.5

Combination Therapies

Combination therapies with tretinoin also have been used to improve PIH. Callender et al6 conducted a study evaluating the efficacy of clindamycin phosphate 1.2%–tretinoin 0.025% gel for the treatment of PIH secondary to mild to moderate acne in patients with Fitzpatrick skin types IV to VI. Thirty patients participated in the randomized, double-blinded, placebo-controlled study, with 15 patients in the clindamycin-tretinoin gel group and 15 in the placebo control group. Based on objective assessment using a chromameter and evaluator global acne severity scale score, clinical efficacy was demonstrated for treating acne and PIH as well as preventing further PIH.6

Hydroquinone Formulation (Tyrosine Inhibitor)

Hydroquinone bleaching cream has been the standard therapy for hyperpigmentation. It works by blocking the conversion of dihydroxyphenylalanine to melanin by inhibiting tyrosinase.7 Topical steroids directly inhibit the synthesis of melanin, and when combined with hydroquinone and tretinoin, they can be effective for short periods of time and may decrease the irritation of application.7,8 The most widely accepted formula consists of a topical steroid (triamcinolone cream 0.1%) in combination with hydroquinone 4% and tretinoin cream 0.05%.8 In a similar 12-week open-label study of 25 patients with darker skin types, Grimes9 used an alternative combination formula of hydroquinone 4% and retinol 0.15%. Overall improvement and tolerance was demonstrated through the use of colorimetry measurement. A combination of hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% also has been used effectively for the treatment of melasma.10 This formulation has been used more anecdotally for the treatment of PIH and has yet to have a randomized-controlled trial. The concern with repeated long-term use of hydroquinone remains. Permanent leukoderma, exogenous ochronosis, and hyperpigmentation of the surrounding normal skin (halo effect) can occur.

Azelaic Acid (Tyrosinase Inhibitor)

Azelaic acid is a dicarboxylic acid isolated from pityriasis versicolor that acts similar to a tyrosine inhibitor and has an antiproliferative effect toward abnormal melanocytes. Lowe et al11 conducted a randomized, double-blind, vehicle-controlled trial in patients with Fitzpatrick skin types IV through VI with facial hyperpigmentation using azelaic acid cream 20%. Over the course of 24 weeks, patients noted a decrease in overall pigment using both an investigator subjective scale and chromometer analysis.11

Kojic Acid (Tyrosinase Inhibitor)

Kojic acid is a tyrosinase inhibitor found in fungal metabolite species such as Acetobacter, Aspergillus, and Penicillium. It is commonly combined with other skin lightening agents such as hydroquinone or vitamin C to further enhance its efficacy. A randomized, 12-week, split-face study of Chinese women with melasma compared treatment with a glycolic acid 10%–hydroquinone 2% gel versus the combination plus kojic acid 2%. The results showed that 60% (24/40) of patients improved with the use of kojic acid as compared to those using the medication without kojic acid.12 Anecdotal data suggest kojic acid may be effective for PIH13; however, no studies specifically for PIH have been conducted.

 

 

Chemical Peels

Chemical peels have been used for a number of years, though their benefits in patients with skin of color is still being elucidated. The ideal chemical peels for Fitzpatrick skin types IV through VI are superficial to medium-depth peeling agents and techniques.14 Glycolic acid is a naturally occurring α-hydroxy acid that causes an increase in collagen synthesis, stimulates epidermolysis, and disperses basal layer melanin. Neutralization of glycolic acid peels can be done with the use of water, sodium bicarbonate, or sodium hydroxide to avoid unnecessary epidermal damage. Multiple clinical trials have been conducted to determine the response of glycolic acid peels in clearing PIH in patients with skin of color. Kessler et al15 compared glycolic acid 30% to salicylic acid 30% in 20 patients with mild to moderate acne and associated PIH. Chemical peels were performed every 2 weeks for 12 weeks. The study showed that salicylic acid was better tolerated than glycolic acid and both were equally effective after the second application (P<.05) for PIH.15 Finally, another study conducted for PIH in patients with Fitzpatrick skin types III and IV utilized glycolic acid peels with 20%, 35%, and 70% concentrations. The results showed overall improvement of PIH and acne from the use of all concentrations of glycolic peels, though faster efficacy was noted at higher concentrations.16

Other self-neutralizing peeling agents include salicylic acid and Jessner solution. Salicylic acid is a β-hydroxy acid that works through keratolysis and disrupting intercellular linkages. Jessner solution is a combination of resorcinol 14%, lactic acid 14%, and salicylic acid 14% in an alcohol base. Salicylic acid is well-tolerated in patients with Fitzpatrick skin types I through VI and has been helpful in treating acne, rosacea, melasma, hyperpigmentation, texturally rough skin, and mild photoaging. Jessner peeling solution has been used for a number of years and works as a keratolytic agent causing intercellular and intracellular edema, and due to its self-neutralizing agent, it is fairly superficial.17 Overall, superficial peeling agents should be used on patients with darker skin types to avoid the risk for worsening dyspigmentation, keloid formation, or deep scarring.18

Conclusion

These treatments are only some of the topical and chemical modalities for PIH in patients with skin of color. The patient history, evaluation, skin type, and underlying medical problems should be considered prior to using any topical or peeling agent. Lastly, photoprotection should be heavily emphasized with both sun protective gear and use of broad-spectrum sunscreens with a high sun protection factor, as UV radiation can cause darkening of PIH areas regardless of skin type and can reverse the progress made by a given therapy.18

References
  1. Savory SA, Agim NG, Mao R, et al. Reliability assessment and validation of the postacne hyperpigmentation index (PAHPI), a new instrument to measure postinflammatory hyperpigmentation from acne vulgaris. J Am Acad Dermatol. 2014;70:108-114.
  2. Halder RM. The role of retinoids in the management of cutaneous conditions in blacks. J Am Acad Dermatol. 1998;39(2, pt 3):S98-S103.
  3. Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, et al. Topical tretinoin (retinoid acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med. 1993;328:1438-1443.
  4. Griffiths CE, Goldfarb MT, Finkel LJ, et al. Topical tretinoin (retinoic acid) treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients: a vehicle-controlled trial. J Am Acad Dermatol. 1994;30:76-84.
  5. Callendar VD. Acne in ethnic skin: special considerations for therapy. Dermatol Ther. 2004;17:184-195.
  6. Callender VD, Young CM, Kindred C, et al. Efficacy and safety of clindamycin phosphate 1.2% and tretinoin 0.025% gel for the treatment of acne and acne-induced post-inflammatory hyperpigmentation in patients with skin of color. J Clin Aesthet Dermatol. 2012;5:25-32.
  7. Badreshia-Bansal S, Draelos ZD. Insight into skin lightening cosmeceuticals for women of color. J Drugs Dermatol. 2007;6:32-39.
  8. Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol. 1975;111:40-48.
  9. Grimes PE. A microsponge formulation of hydroquinone 4% and retinol 0.15% in the treatment of melasma and postinflammatory hyperpigmentation. Cutis. 2004;74:326-328.
  10. Chan R, Park KC, Lee MH, et al. A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma. Br J Dermatol. 2008;159:697-703.
  11. Lowe NJ, Rizk D, Grimes P. Azelaic acid 20% cream in the treatment of facial hyperpigmentation in darker-skinned patients. Clin Ther. 1998;20:945-959.
  12. Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg. 1999;25:282-284.
  13. Alexis AF, Blackcloud P. Natural ingredients for darker skin types: growing options for hyperpigmentation. J Drugs Dermatol. 2013;12:123-127.
  14. Roberts WE. Chemical peeling in ethnic/dark skin. Dermatol Ther. 2004;17:196-205.
  15. Kessler E, Flanagan K, Chia C, et al. Comparison of alpha- and beta-hydroxy acid chemical peels in the treatment of mild to moderately severe facial acne vulgaris [published online December 5, 2007]. Dermatol Surg. 2008;34:45-50, discussion 51.
  16. Erbağci Z, Akçali C. Biweekly serial glycolic acid peels vs. long-term daily use of topical low-strength glycolic acid in the treatment of atrophic acne scars. Int J Dermatol. 2000;39:789-794.
  17. Jackson A. Chemical peels [published online January 31, 2014]. Facial Plast Surg. 2014;30:26-34.
  18. Davis EC, Callender VD. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet Dermatol. 2010;3:20-31.
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From the Department of Dermatology, University of Florida, Gainesville.

The author reports no conflict of interest.

Correspondence: Divya Shokeen, MD ([email protected]).

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Correspondence: Divya Shokeen, MD ([email protected]).

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The author reports no conflict of interest.

Correspondence: Divya Shokeen, MD ([email protected]).

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Postinflammatory hyperpigmentation (PIH) develops as darkly pigmented macules that occur after an inflammatory process of the skin such as acne, folliculitis, eczema, or shaving irritation. Patients with Fitzpatrick skin types III to VI usually are most commonly affected, and for many, the remnant pigmentation can be an even greater concern than the original inflammatory process.1,2 Reported treatments of PIH include tretinoin, hydroquinone, azelaic acid, and chemical peels. The ideal combination of therapy has yet to be delineated.

Tretinoin (Vitamin A Derivative)

Bulengo-Ransby et al3 performed one of the first clinical trials testing tretinoin cream 0.1% for PIH in patients with Fitzpatrick skin types IV to VI . The study included 54 patients (24 applied tretinoin and 30 applied a vehicle) with moderate to severe PIH on the face and arms. The patients were divided into therapy and placebo groups and were evaluated for 40 weeks. Changes were evaluated through colorimetry, light microscopy, histology, and photography, with significant clinical improvement in the tretinoin-treated group (P<.001).3 A double-blind, randomized study of 45 photoaged Chinese and Japanese patients using tretinoin cream 0.1% also was conducted for treatment of photoaging-associated hyperpigmented lesions of the face and hands. Assessment was done with clinical, colorimetric, and histological evaluation, with an overall statistical improvement noted in hyperpigmentation.4 Both of the above studies showed mild irritation (ie, retinoid dermatitis) with application of tretinoin, which creates a compliance issue in patients who are recommended to continue therapy with higher-strength tretinoin. This side-effect profile can be circumvented through gradual elevation in the strength of tretinoin.5

Combination Therapies

Combination therapies with tretinoin also have been used to improve PIH. Callender et al6 conducted a study evaluating the efficacy of clindamycin phosphate 1.2%–tretinoin 0.025% gel for the treatment of PIH secondary to mild to moderate acne in patients with Fitzpatrick skin types IV to VI. Thirty patients participated in the randomized, double-blinded, placebo-controlled study, with 15 patients in the clindamycin-tretinoin gel group and 15 in the placebo control group. Based on objective assessment using a chromameter and evaluator global acne severity scale score, clinical efficacy was demonstrated for treating acne and PIH as well as preventing further PIH.6

Hydroquinone Formulation (Tyrosine Inhibitor)

Hydroquinone bleaching cream has been the standard therapy for hyperpigmentation. It works by blocking the conversion of dihydroxyphenylalanine to melanin by inhibiting tyrosinase.7 Topical steroids directly inhibit the synthesis of melanin, and when combined with hydroquinone and tretinoin, they can be effective for short periods of time and may decrease the irritation of application.7,8 The most widely accepted formula consists of a topical steroid (triamcinolone cream 0.1%) in combination with hydroquinone 4% and tretinoin cream 0.05%.8 In a similar 12-week open-label study of 25 patients with darker skin types, Grimes9 used an alternative combination formula of hydroquinone 4% and retinol 0.15%. Overall improvement and tolerance was demonstrated through the use of colorimetry measurement. A combination of hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% also has been used effectively for the treatment of melasma.10 This formulation has been used more anecdotally for the treatment of PIH and has yet to have a randomized-controlled trial. The concern with repeated long-term use of hydroquinone remains. Permanent leukoderma, exogenous ochronosis, and hyperpigmentation of the surrounding normal skin (halo effect) can occur.

Azelaic Acid (Tyrosinase Inhibitor)

Azelaic acid is a dicarboxylic acid isolated from pityriasis versicolor that acts similar to a tyrosine inhibitor and has an antiproliferative effect toward abnormal melanocytes. Lowe et al11 conducted a randomized, double-blind, vehicle-controlled trial in patients with Fitzpatrick skin types IV through VI with facial hyperpigmentation using azelaic acid cream 20%. Over the course of 24 weeks, patients noted a decrease in overall pigment using both an investigator subjective scale and chromometer analysis.11

Kojic Acid (Tyrosinase Inhibitor)

Kojic acid is a tyrosinase inhibitor found in fungal metabolite species such as Acetobacter, Aspergillus, and Penicillium. It is commonly combined with other skin lightening agents such as hydroquinone or vitamin C to further enhance its efficacy. A randomized, 12-week, split-face study of Chinese women with melasma compared treatment with a glycolic acid 10%–hydroquinone 2% gel versus the combination plus kojic acid 2%. The results showed that 60% (24/40) of patients improved with the use of kojic acid as compared to those using the medication without kojic acid.12 Anecdotal data suggest kojic acid may be effective for PIH13; however, no studies specifically for PIH have been conducted.

 

 

Chemical Peels

Chemical peels have been used for a number of years, though their benefits in patients with skin of color is still being elucidated. The ideal chemical peels for Fitzpatrick skin types IV through VI are superficial to medium-depth peeling agents and techniques.14 Glycolic acid is a naturally occurring α-hydroxy acid that causes an increase in collagen synthesis, stimulates epidermolysis, and disperses basal layer melanin. Neutralization of glycolic acid peels can be done with the use of water, sodium bicarbonate, or sodium hydroxide to avoid unnecessary epidermal damage. Multiple clinical trials have been conducted to determine the response of glycolic acid peels in clearing PIH in patients with skin of color. Kessler et al15 compared glycolic acid 30% to salicylic acid 30% in 20 patients with mild to moderate acne and associated PIH. Chemical peels were performed every 2 weeks for 12 weeks. The study showed that salicylic acid was better tolerated than glycolic acid and both were equally effective after the second application (P<.05) for PIH.15 Finally, another study conducted for PIH in patients with Fitzpatrick skin types III and IV utilized glycolic acid peels with 20%, 35%, and 70% concentrations. The results showed overall improvement of PIH and acne from the use of all concentrations of glycolic peels, though faster efficacy was noted at higher concentrations.16

Other self-neutralizing peeling agents include salicylic acid and Jessner solution. Salicylic acid is a β-hydroxy acid that works through keratolysis and disrupting intercellular linkages. Jessner solution is a combination of resorcinol 14%, lactic acid 14%, and salicylic acid 14% in an alcohol base. Salicylic acid is well-tolerated in patients with Fitzpatrick skin types I through VI and has been helpful in treating acne, rosacea, melasma, hyperpigmentation, texturally rough skin, and mild photoaging. Jessner peeling solution has been used for a number of years and works as a keratolytic agent causing intercellular and intracellular edema, and due to its self-neutralizing agent, it is fairly superficial.17 Overall, superficial peeling agents should be used on patients with darker skin types to avoid the risk for worsening dyspigmentation, keloid formation, or deep scarring.18

Conclusion

These treatments are only some of the topical and chemical modalities for PIH in patients with skin of color. The patient history, evaluation, skin type, and underlying medical problems should be considered prior to using any topical or peeling agent. Lastly, photoprotection should be heavily emphasized with both sun protective gear and use of broad-spectrum sunscreens with a high sun protection factor, as UV radiation can cause darkening of PIH areas regardless of skin type and can reverse the progress made by a given therapy.18

Postinflammatory hyperpigmentation (PIH) develops as darkly pigmented macules that occur after an inflammatory process of the skin such as acne, folliculitis, eczema, or shaving irritation. Patients with Fitzpatrick skin types III to VI usually are most commonly affected, and for many, the remnant pigmentation can be an even greater concern than the original inflammatory process.1,2 Reported treatments of PIH include tretinoin, hydroquinone, azelaic acid, and chemical peels. The ideal combination of therapy has yet to be delineated.

Tretinoin (Vitamin A Derivative)

Bulengo-Ransby et al3 performed one of the first clinical trials testing tretinoin cream 0.1% for PIH in patients with Fitzpatrick skin types IV to VI . The study included 54 patients (24 applied tretinoin and 30 applied a vehicle) with moderate to severe PIH on the face and arms. The patients were divided into therapy and placebo groups and were evaluated for 40 weeks. Changes were evaluated through colorimetry, light microscopy, histology, and photography, with significant clinical improvement in the tretinoin-treated group (P<.001).3 A double-blind, randomized study of 45 photoaged Chinese and Japanese patients using tretinoin cream 0.1% also was conducted for treatment of photoaging-associated hyperpigmented lesions of the face and hands. Assessment was done with clinical, colorimetric, and histological evaluation, with an overall statistical improvement noted in hyperpigmentation.4 Both of the above studies showed mild irritation (ie, retinoid dermatitis) with application of tretinoin, which creates a compliance issue in patients who are recommended to continue therapy with higher-strength tretinoin. This side-effect profile can be circumvented through gradual elevation in the strength of tretinoin.5

Combination Therapies

Combination therapies with tretinoin also have been used to improve PIH. Callender et al6 conducted a study evaluating the efficacy of clindamycin phosphate 1.2%–tretinoin 0.025% gel for the treatment of PIH secondary to mild to moderate acne in patients with Fitzpatrick skin types IV to VI. Thirty patients participated in the randomized, double-blinded, placebo-controlled study, with 15 patients in the clindamycin-tretinoin gel group and 15 in the placebo control group. Based on objective assessment using a chromameter and evaluator global acne severity scale score, clinical efficacy was demonstrated for treating acne and PIH as well as preventing further PIH.6

Hydroquinone Formulation (Tyrosine Inhibitor)

Hydroquinone bleaching cream has been the standard therapy for hyperpigmentation. It works by blocking the conversion of dihydroxyphenylalanine to melanin by inhibiting tyrosinase.7 Topical steroids directly inhibit the synthesis of melanin, and when combined with hydroquinone and tretinoin, they can be effective for short periods of time and may decrease the irritation of application.7,8 The most widely accepted formula consists of a topical steroid (triamcinolone cream 0.1%) in combination with hydroquinone 4% and tretinoin cream 0.05%.8 In a similar 12-week open-label study of 25 patients with darker skin types, Grimes9 used an alternative combination formula of hydroquinone 4% and retinol 0.15%. Overall improvement and tolerance was demonstrated through the use of colorimetry measurement. A combination of hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% also has been used effectively for the treatment of melasma.10 This formulation has been used more anecdotally for the treatment of PIH and has yet to have a randomized-controlled trial. The concern with repeated long-term use of hydroquinone remains. Permanent leukoderma, exogenous ochronosis, and hyperpigmentation of the surrounding normal skin (halo effect) can occur.

Azelaic Acid (Tyrosinase Inhibitor)

Azelaic acid is a dicarboxylic acid isolated from pityriasis versicolor that acts similar to a tyrosine inhibitor and has an antiproliferative effect toward abnormal melanocytes. Lowe et al11 conducted a randomized, double-blind, vehicle-controlled trial in patients with Fitzpatrick skin types IV through VI with facial hyperpigmentation using azelaic acid cream 20%. Over the course of 24 weeks, patients noted a decrease in overall pigment using both an investigator subjective scale and chromometer analysis.11

Kojic Acid (Tyrosinase Inhibitor)

Kojic acid is a tyrosinase inhibitor found in fungal metabolite species such as Acetobacter, Aspergillus, and Penicillium. It is commonly combined with other skin lightening agents such as hydroquinone or vitamin C to further enhance its efficacy. A randomized, 12-week, split-face study of Chinese women with melasma compared treatment with a glycolic acid 10%–hydroquinone 2% gel versus the combination plus kojic acid 2%. The results showed that 60% (24/40) of patients improved with the use of kojic acid as compared to those using the medication without kojic acid.12 Anecdotal data suggest kojic acid may be effective for PIH13; however, no studies specifically for PIH have been conducted.

 

 

Chemical Peels

Chemical peels have been used for a number of years, though their benefits in patients with skin of color is still being elucidated. The ideal chemical peels for Fitzpatrick skin types IV through VI are superficial to medium-depth peeling agents and techniques.14 Glycolic acid is a naturally occurring α-hydroxy acid that causes an increase in collagen synthesis, stimulates epidermolysis, and disperses basal layer melanin. Neutralization of glycolic acid peels can be done with the use of water, sodium bicarbonate, or sodium hydroxide to avoid unnecessary epidermal damage. Multiple clinical trials have been conducted to determine the response of glycolic acid peels in clearing PIH in patients with skin of color. Kessler et al15 compared glycolic acid 30% to salicylic acid 30% in 20 patients with mild to moderate acne and associated PIH. Chemical peels were performed every 2 weeks for 12 weeks. The study showed that salicylic acid was better tolerated than glycolic acid and both were equally effective after the second application (P<.05) for PIH.15 Finally, another study conducted for PIH in patients with Fitzpatrick skin types III and IV utilized glycolic acid peels with 20%, 35%, and 70% concentrations. The results showed overall improvement of PIH and acne from the use of all concentrations of glycolic peels, though faster efficacy was noted at higher concentrations.16

Other self-neutralizing peeling agents include salicylic acid and Jessner solution. Salicylic acid is a β-hydroxy acid that works through keratolysis and disrupting intercellular linkages. Jessner solution is a combination of resorcinol 14%, lactic acid 14%, and salicylic acid 14% in an alcohol base. Salicylic acid is well-tolerated in patients with Fitzpatrick skin types I through VI and has been helpful in treating acne, rosacea, melasma, hyperpigmentation, texturally rough skin, and mild photoaging. Jessner peeling solution has been used for a number of years and works as a keratolytic agent causing intercellular and intracellular edema, and due to its self-neutralizing agent, it is fairly superficial.17 Overall, superficial peeling agents should be used on patients with darker skin types to avoid the risk for worsening dyspigmentation, keloid formation, or deep scarring.18

Conclusion

These treatments are only some of the topical and chemical modalities for PIH in patients with skin of color. The patient history, evaluation, skin type, and underlying medical problems should be considered prior to using any topical or peeling agent. Lastly, photoprotection should be heavily emphasized with both sun protective gear and use of broad-spectrum sunscreens with a high sun protection factor, as UV radiation can cause darkening of PIH areas regardless of skin type and can reverse the progress made by a given therapy.18

References
  1. Savory SA, Agim NG, Mao R, et al. Reliability assessment and validation of the postacne hyperpigmentation index (PAHPI), a new instrument to measure postinflammatory hyperpigmentation from acne vulgaris. J Am Acad Dermatol. 2014;70:108-114.
  2. Halder RM. The role of retinoids in the management of cutaneous conditions in blacks. J Am Acad Dermatol. 1998;39(2, pt 3):S98-S103.
  3. Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, et al. Topical tretinoin (retinoid acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med. 1993;328:1438-1443.
  4. Griffiths CE, Goldfarb MT, Finkel LJ, et al. Topical tretinoin (retinoic acid) treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients: a vehicle-controlled trial. J Am Acad Dermatol. 1994;30:76-84.
  5. Callendar VD. Acne in ethnic skin: special considerations for therapy. Dermatol Ther. 2004;17:184-195.
  6. Callender VD, Young CM, Kindred C, et al. Efficacy and safety of clindamycin phosphate 1.2% and tretinoin 0.025% gel for the treatment of acne and acne-induced post-inflammatory hyperpigmentation in patients with skin of color. J Clin Aesthet Dermatol. 2012;5:25-32.
  7. Badreshia-Bansal S, Draelos ZD. Insight into skin lightening cosmeceuticals for women of color. J Drugs Dermatol. 2007;6:32-39.
  8. Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol. 1975;111:40-48.
  9. Grimes PE. A microsponge formulation of hydroquinone 4% and retinol 0.15% in the treatment of melasma and postinflammatory hyperpigmentation. Cutis. 2004;74:326-328.
  10. Chan R, Park KC, Lee MH, et al. A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma. Br J Dermatol. 2008;159:697-703.
  11. Lowe NJ, Rizk D, Grimes P. Azelaic acid 20% cream in the treatment of facial hyperpigmentation in darker-skinned patients. Clin Ther. 1998;20:945-959.
  12. Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg. 1999;25:282-284.
  13. Alexis AF, Blackcloud P. Natural ingredients for darker skin types: growing options for hyperpigmentation. J Drugs Dermatol. 2013;12:123-127.
  14. Roberts WE. Chemical peeling in ethnic/dark skin. Dermatol Ther. 2004;17:196-205.
  15. Kessler E, Flanagan K, Chia C, et al. Comparison of alpha- and beta-hydroxy acid chemical peels in the treatment of mild to moderately severe facial acne vulgaris [published online December 5, 2007]. Dermatol Surg. 2008;34:45-50, discussion 51.
  16. Erbağci Z, Akçali C. Biweekly serial glycolic acid peels vs. long-term daily use of topical low-strength glycolic acid in the treatment of atrophic acne scars. Int J Dermatol. 2000;39:789-794.
  17. Jackson A. Chemical peels [published online January 31, 2014]. Facial Plast Surg. 2014;30:26-34.
  18. Davis EC, Callender VD. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet Dermatol. 2010;3:20-31.
References
  1. Savory SA, Agim NG, Mao R, et al. Reliability assessment and validation of the postacne hyperpigmentation index (PAHPI), a new instrument to measure postinflammatory hyperpigmentation from acne vulgaris. J Am Acad Dermatol. 2014;70:108-114.
  2. Halder RM. The role of retinoids in the management of cutaneous conditions in blacks. J Am Acad Dermatol. 1998;39(2, pt 3):S98-S103.
  3. Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, et al. Topical tretinoin (retinoid acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med. 1993;328:1438-1443.
  4. Griffiths CE, Goldfarb MT, Finkel LJ, et al. Topical tretinoin (retinoic acid) treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients: a vehicle-controlled trial. J Am Acad Dermatol. 1994;30:76-84.
  5. Callendar VD. Acne in ethnic skin: special considerations for therapy. Dermatol Ther. 2004;17:184-195.
  6. Callender VD, Young CM, Kindred C, et al. Efficacy and safety of clindamycin phosphate 1.2% and tretinoin 0.025% gel for the treatment of acne and acne-induced post-inflammatory hyperpigmentation in patients with skin of color. J Clin Aesthet Dermatol. 2012;5:25-32.
  7. Badreshia-Bansal S, Draelos ZD. Insight into skin lightening cosmeceuticals for women of color. J Drugs Dermatol. 2007;6:32-39.
  8. Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol. 1975;111:40-48.
  9. Grimes PE. A microsponge formulation of hydroquinone 4% and retinol 0.15% in the treatment of melasma and postinflammatory hyperpigmentation. Cutis. 2004;74:326-328.
  10. Chan R, Park KC, Lee MH, et al. A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma. Br J Dermatol. 2008;159:697-703.
  11. Lowe NJ, Rizk D, Grimes P. Azelaic acid 20% cream in the treatment of facial hyperpigmentation in darker-skinned patients. Clin Ther. 1998;20:945-959.
  12. Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg. 1999;25:282-284.
  13. Alexis AF, Blackcloud P. Natural ingredients for darker skin types: growing options for hyperpigmentation. J Drugs Dermatol. 2013;12:123-127.
  14. Roberts WE. Chemical peeling in ethnic/dark skin. Dermatol Ther. 2004;17:196-205.
  15. Kessler E, Flanagan K, Chia C, et al. Comparison of alpha- and beta-hydroxy acid chemical peels in the treatment of mild to moderately severe facial acne vulgaris [published online December 5, 2007]. Dermatol Surg. 2008;34:45-50, discussion 51.
  16. Erbağci Z, Akçali C. Biweekly serial glycolic acid peels vs. long-term daily use of topical low-strength glycolic acid in the treatment of atrophic acne scars. Int J Dermatol. 2000;39:789-794.
  17. Jackson A. Chemical peels [published online January 31, 2014]. Facial Plast Surg. 2014;30:26-34.
  18. Davis EC, Callender VD. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet Dermatol. 2010;3:20-31.
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Acquired Port-wine Stain With Superimposed Eczema Following Penetrating Abdominal Trauma

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Acquired Port-wine Stain With Superimposed Eczema Following Penetrating Abdominal Trauma

Port-wine stains (PWSs) are common congenital capillary vascular malformations with an incidence of 3 per 1000 neonates.1 Rarely, acquired PWSs are seen, sometimes appearing following trauma.2-5 Port-wine stains are diagnosed clinically and present as painless, partially or entirely blanchable pink patches that respect the median (midline) plane.6 Although histopathologic examination is not necessary for diagnosis of PWS, typical findings include dilated, ectatic capillaries.7,8 Since it was first reported by Traub9 in 1939, more than 60 cases of acquired PWSs have been reported.10 A PubMed search of articles indexed for MEDLINE using the search terms acquired port-wine stain and port-wine stain and eczema yielded no cases of acquired PWS with associated eczematous changes and only 30 cases of congenital PWS with superimposed eczema.11-18 We report the case of an acquired PWS with superimposed eczema in an 18-year-old man following penetrating abdominal trauma.

Case Report

An otherwise healthy 18-year-old man presented to our dermatology office for evaluation of an eruption that had developed at the site of an abdominal stab wound he sustained 2 to 3 years prior. One year after he was stabbed, the patient developed a nonpruritic, painless red patch located 1 cm anterior to the healed wound on the left abdomen. The patch gradually grew larger to involve the entire left abdomen, extending to the left lower back. The site of the healed stab wound also became raised and pruritic, and the patient noted another pruritic plaque that formed within the larger patch. The patient reported no other skin conditions prior to the current eruption. His medical history was notable for seasonal allergies and asthma, but no childhood eczema.

Physical examination revealed a healthy, well-nourished man with Fitzpatrick skin type IV. A red, purpuric, coalescent patch with slightly arcuate borders extending from the mid abdomen to the left posterior flank was noted. The left lateral aspect of the patch blanched with pressure and respected the median plane. Within the larger patch, a 4-cm×2-cm lichenified, slightly macerated, hyperpigmented plaque was noted at the site of the stab wound (Figure 1). Based on these clinical findings, a presumptive diagnosis of an acquired PWS with superimposed eczema was made.

Figure 1. A lichenified, macerated, hyperpigmented plaque on the left lower abdomen with a larger red, coalescent patch with slightly arcuate borders that respected the median plane.

Punch biopsy specimens were taken from the large vascular patch and the smaller lichenified plaque. Histopathologic examination of the vascular patch showed an increased number of small vessels in the superficial dermis with thickened vessel walls, ectatic lumens, and no vasculopathy, consistent with a vascular malformation or a reactive vascular proliferation (Figure 2). On histopathology, the plaque showed epidermal spongiosis and hyperplasia with serum crust and a papillary dermis containing a mixed inflammatory infiltrate with occasional eosinophils, consistent with an eczematous dermatitis (Figure 3). The histologic findings confirmed the clinical diagnosis.

Figure 2. A biopsy specimen from the large patch on the left flank showed an increased number of small vessels and thickened vessel walls consistent with vascular malformation (H&E, original magnification ×100).

Figure 3. A biopsy specimen from the hyperpigmented plaque showed serum crust, hyperplasia, spongiosis, and a mixed inflammatory infiltrate with occasional eosinophils in the papillary dermis consistent with eczematous dermatitis (H&E, original magnification ×100).

The pruritic, lichenified plaque improved with application of triamcinolone ointment 0.1% twice daily for 2 weeks. Magnetic resonance imaging to rule out an underlying arteriovenous malformation was recommended, but the patient declined.

 

 

Comment

The exact cause of PWS is unknown. There have been a multitude of genomic suspects for congenital lesions, including a somatic activating mutation (ie, a mutation acquired during fetal development) of the GNAQ (guanine nucleotide binding protein [G protein], q polypeptide) gene, which may contribute to abnormal cell proliferation including the regulation of blood vessels, and inactivating mutations in the RASA1 (RAS p21 protein activator [GTPase activating protein] 1) gene, which controls endothelial cell organization.19-22 Later mutations (ie, those occurring after the first trimester) may be more likely to result in isolated PWSs as opposed to syndromic PWSs.19 Whatever the source of genetic misinformation, it is thought that the diminished neuronal control of blood flow and the resulting alterations in dermal structure contribute to the pathogenesis of PWS and its associated histologic features.7,23

The clinical and histopathologic features of acquired PWSs are indistinguishable from those of congenital lesions, indicating that different processes may lead to the same presentation.4 Abnormal innervation and decreased supportive stroma have both been identified as contributing factors in the development of congenital and acquired PWSs.7,23-25 Rosen and Smoller23 found that diminished nerve density affects vascular tone and caliber in PWSs and had hypothesized in a prior report that decreased perivascular Schwann cells may indicate abnormal sympathetic innervation.7 Since then, PWS has been shown to lack both somatic and sensory innervation.24 Tsuji and Sawabe25 indicated that alterations to the perivascular stroma, whether congenital or as a result of trauma, decrease support for vessels, leading to ectasia.

In addition to an acquired PWS, our patient also had associated eczema within the PWS. Eczematous lesions were absent elsewhere, and he did not have a history of childhood eczema. Our review of the literature yielded 8 studies since 1996 that collectively described 30 cases of eczema within PWSs.11-18 Only 2 of these reports described adult patients with concomitant eczema and PWS and none described acquired PWS.13,18

Few studies have addressed the relationship between PWSs and eczema. It is unclear if concomitant PWS and localized eczema are collision dermatoses or if a PWS may predispose the affected skin to eczema.11-13 It has been hypothesized that the increased dermal vasculature in PWSs predisposes the skin to the development of eczema—more specifically, that ectasia may lead to increased inflammation.12,17 The concept of the “immunocompromised district” proposed by Ruocco et al26 is a unifying theory that may underlie the association noted between cases of trauma and later development of a PWS and superimposed eczematous dermatitis, such as in our case. Trauma is noted as one of a number of possible disruptive forces affecting both immunomodulation and neuromodulation within a local area of skin, leading to increased susceptibility of that district to various cutaneous diseases.26

Although our patient’s eczema responded to conservative treatment with a topical steroid, several case series have reported success with laser therapy in the treatment of PWS while preventing recurrence of associated eczematous dermatitis.12,17 Following the cessation of eczema treatment with topical steroid, which causes vasoconstriction, we suggest postponing laser therapy several weeks to allow resolution of vasoconstriction, thus providing enhanced therapeutic targeting with a vascular laser. Of particular relevance to our case, a recent study showed efficacy of the pulsed dye laser in treating PWSs in Fitzpatrick skin types IV and V.27

Conclusion

Although acquired PWS is rare, it can present later in life as an acquired lesion at a site of previous trauma.1-5 Congenital capillary malformations also can be associated with superimposed, localized eczema.11-18 We present a rarely reported case of an acquired PWS with superimposed, localized eczema. As in cases of congenital PWS with concomitant eczema, the associated eczema in our case was responsive to topical corticosteroid therapy. Additionally, pulsed dye laser has been shown to treat PWSs while preventing the recurrence of eczema, and it has been deemed effective for individuals with darker skin types.12,17, 27 Further studies are needed to explore the relationship between PWS and eczema.

References
  1. Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics. 1976;58:218-222.
  2. Fegeler F. Naevus flammeus im trigeminusgebiet nach trauma im rahmen eines posttraumatisch-vegetativen syndroms. Arch Dermatol Syphilol. 1949;188:416-422.
  3. Kirkland CR, Mutasim DF. Acquired port-wine stain following repetitive trauma. J Am Acad Dermatol. 2011;65:462-463.
  4. Adams BB, Lucky AW. Acquired port-wine stains and antecedent trauma: case report and review of the literature. Arch Dermatol. 2000;136:897-899.
  5. Colver GB, Ryan TJ. Acquired port-wine stain. Arch Dermatol. 1986;122:1415-1416.
  6. Nigro J, Swerlick RA, Sepp NT, et al. Angiogenesis, vascular malformations and proliferations. In: Arndt KA, LeBoit PE, Robinson JK, Wintroub BU, eds. Cutaneous Medicine and Surgery: An Integrated Program in Dermatology. Philadelphia, PA: WB Saunders Co; 1996:1492-1521.
  7. Smoller BR, Rosen S. Port-wine stains. a disease of altered neural modulation of blood vessels? Arch Dermatol. 1986;122:177-179.
  8. Chang CJ, Yu JS, Nelson JS. Confocal microscopy study of neurovascular distribution in facial port wine stains(capillary malformation). J Formos Med Assoc. 2008;107:559-666.
  9. Traub EF. Naevus flammeus appearing at the age of twenty three. Arch Dermatol. 1939;39:752.
  10. Freysz M, Cribier B, Lipsker, D. Fegelers syndrome, acquired port-wine stain or acquired capillary malformation: three cases and a literature review [article in French]. Ann Dermatol Venereol. 2013;140:341-346.
  11. Tay YK, Morelli J, Weston WL. Inflammatory nuchal-occipital port-wine stains. J Am Acad Dermatol. 1996;35:811-813.
  12. Sidwell RU, Syed S, Harper JI. Port-wine stains and eczema. Br J Dermatol. 2001;144:1269-1270.
  13. Hofer T. Meyerson phenomenon within a nevus flammeus. Dermatology. 2002;205:180-183.
  14. Raff K, Landthaler M, Hoheleutner U. Port-wine stains with eczema. Phlebologie. 2003;32:15-17.
  15. Tsuboi H, Miyata T, Katsuoka K. Eczema in a port-wine stain. Clin Exp Dermatol. 2003;28:322-323.
  16. Rajan N, Natarahan S. Impetiginized eczema arising within a port-wine stain of the arm. J Eur Acad Dermatol Venereol. 2006;20:1009-1010.
  17. Fonder MA, Mamelak AJ, Kazin RA, et al. Port-wine-stain-associated dermatitis: implications for cutaneous vascular laser therapy. Pediatr Dermatol. 2007;24:376-379.
  18. Simon V, Wolfgan H, Katharina F. Meyerson-Phenomenon hides a nevus flammeus. J Dtsch Dermatol Ges. 2011;9:305-307.
  19. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368:1971-1979.
  20. Hershkovitz D, Bercovich D, Sprecher E, et al. RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations. Br J Dermatol. 2008;158:1035-1040.
  21. Eerola I, Boon LM, Mulliken JB, et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;73:1240-1249.
  22. Henkemeyer M, Rossi DJ, Holmyard DP, et al. Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature. 1995;377:695-701.
  23. Rosen S, Smoller BR. Port-wine stains: a new hypothesis. J Am Acad Dermatol. 1987;17:164-166.
  24. Rydh M, Malm BM, Jernmeck J, et al. Ectatic blood vessels in port-wine stains lack innervation: possible role in pathogenesis. Plast Reconstr Surg. 1991;87:419-422.
  25. Tsuji T, Sawabe M. A new type of telangiectasia following trauma. J Cutan Pathol. 1988;15:22-26.
  26. Ruocco V, Ruocco E, Brunnetti G, et al. Opportunistic localization of skin lesions on vulnerable areas. Clin Dermatol. 2011;29:483-488.
  27. Thajudeheen CP, Jyothy K, Pryadarshi A. Treatment of port-wine stains with flash lamp pumped pulsed dye laser on Indian skin: a six year study. J Cutan Aesthet Surg. 2014;7:32-36.
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Dr. Langenhan is from the Perelman School of Medicine, University of Pennsylvania, Philadelphia. Dr. Novoa is from the Departments of Pathology and Dermatology, Stanford Medical Center, California. Dr. Pappas-Taffer is from the Department of Dermatology, Perelman Center for Advanced Medicine, University of Pennsylvania.

The authors report no conflicts of interest.

Correspondence: Lisa Pappas-Taffer, MD, Department of Dermatology, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA 19104 ([email protected]).

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The authors report no conflicts of interest.

Correspondence: Lisa Pappas-Taffer, MD, Department of Dermatology, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA 19104 ([email protected]).

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Dr. Langenhan is from the Perelman School of Medicine, University of Pennsylvania, Philadelphia. Dr. Novoa is from the Departments of Pathology and Dermatology, Stanford Medical Center, California. Dr. Pappas-Taffer is from the Department of Dermatology, Perelman Center for Advanced Medicine, University of Pennsylvania.

The authors report no conflicts of interest.

Correspondence: Lisa Pappas-Taffer, MD, Department of Dermatology, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA 19104 ([email protected]).

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Related Articles

Port-wine stains (PWSs) are common congenital capillary vascular malformations with an incidence of 3 per 1000 neonates.1 Rarely, acquired PWSs are seen, sometimes appearing following trauma.2-5 Port-wine stains are diagnosed clinically and present as painless, partially or entirely blanchable pink patches that respect the median (midline) plane.6 Although histopathologic examination is not necessary for diagnosis of PWS, typical findings include dilated, ectatic capillaries.7,8 Since it was first reported by Traub9 in 1939, more than 60 cases of acquired PWSs have been reported.10 A PubMed search of articles indexed for MEDLINE using the search terms acquired port-wine stain and port-wine stain and eczema yielded no cases of acquired PWS with associated eczematous changes and only 30 cases of congenital PWS with superimposed eczema.11-18 We report the case of an acquired PWS with superimposed eczema in an 18-year-old man following penetrating abdominal trauma.

Case Report

An otherwise healthy 18-year-old man presented to our dermatology office for evaluation of an eruption that had developed at the site of an abdominal stab wound he sustained 2 to 3 years prior. One year after he was stabbed, the patient developed a nonpruritic, painless red patch located 1 cm anterior to the healed wound on the left abdomen. The patch gradually grew larger to involve the entire left abdomen, extending to the left lower back. The site of the healed stab wound also became raised and pruritic, and the patient noted another pruritic plaque that formed within the larger patch. The patient reported no other skin conditions prior to the current eruption. His medical history was notable for seasonal allergies and asthma, but no childhood eczema.

Physical examination revealed a healthy, well-nourished man with Fitzpatrick skin type IV. A red, purpuric, coalescent patch with slightly arcuate borders extending from the mid abdomen to the left posterior flank was noted. The left lateral aspect of the patch blanched with pressure and respected the median plane. Within the larger patch, a 4-cm×2-cm lichenified, slightly macerated, hyperpigmented plaque was noted at the site of the stab wound (Figure 1). Based on these clinical findings, a presumptive diagnosis of an acquired PWS with superimposed eczema was made.

Figure 1. A lichenified, macerated, hyperpigmented plaque on the left lower abdomen with a larger red, coalescent patch with slightly arcuate borders that respected the median plane.

Punch biopsy specimens were taken from the large vascular patch and the smaller lichenified plaque. Histopathologic examination of the vascular patch showed an increased number of small vessels in the superficial dermis with thickened vessel walls, ectatic lumens, and no vasculopathy, consistent with a vascular malformation or a reactive vascular proliferation (Figure 2). On histopathology, the plaque showed epidermal spongiosis and hyperplasia with serum crust and a papillary dermis containing a mixed inflammatory infiltrate with occasional eosinophils, consistent with an eczematous dermatitis (Figure 3). The histologic findings confirmed the clinical diagnosis.

Figure 2. A biopsy specimen from the large patch on the left flank showed an increased number of small vessels and thickened vessel walls consistent with vascular malformation (H&E, original magnification ×100).

Figure 3. A biopsy specimen from the hyperpigmented plaque showed serum crust, hyperplasia, spongiosis, and a mixed inflammatory infiltrate with occasional eosinophils in the papillary dermis consistent with eczematous dermatitis (H&E, original magnification ×100).

The pruritic, lichenified plaque improved with application of triamcinolone ointment 0.1% twice daily for 2 weeks. Magnetic resonance imaging to rule out an underlying arteriovenous malformation was recommended, but the patient declined.

 

 

Comment

The exact cause of PWS is unknown. There have been a multitude of genomic suspects for congenital lesions, including a somatic activating mutation (ie, a mutation acquired during fetal development) of the GNAQ (guanine nucleotide binding protein [G protein], q polypeptide) gene, which may contribute to abnormal cell proliferation including the regulation of blood vessels, and inactivating mutations in the RASA1 (RAS p21 protein activator [GTPase activating protein] 1) gene, which controls endothelial cell organization.19-22 Later mutations (ie, those occurring after the first trimester) may be more likely to result in isolated PWSs as opposed to syndromic PWSs.19 Whatever the source of genetic misinformation, it is thought that the diminished neuronal control of blood flow and the resulting alterations in dermal structure contribute to the pathogenesis of PWS and its associated histologic features.7,23

The clinical and histopathologic features of acquired PWSs are indistinguishable from those of congenital lesions, indicating that different processes may lead to the same presentation.4 Abnormal innervation and decreased supportive stroma have both been identified as contributing factors in the development of congenital and acquired PWSs.7,23-25 Rosen and Smoller23 found that diminished nerve density affects vascular tone and caliber in PWSs and had hypothesized in a prior report that decreased perivascular Schwann cells may indicate abnormal sympathetic innervation.7 Since then, PWS has been shown to lack both somatic and sensory innervation.24 Tsuji and Sawabe25 indicated that alterations to the perivascular stroma, whether congenital or as a result of trauma, decrease support for vessels, leading to ectasia.

In addition to an acquired PWS, our patient also had associated eczema within the PWS. Eczematous lesions were absent elsewhere, and he did not have a history of childhood eczema. Our review of the literature yielded 8 studies since 1996 that collectively described 30 cases of eczema within PWSs.11-18 Only 2 of these reports described adult patients with concomitant eczema and PWS and none described acquired PWS.13,18

Few studies have addressed the relationship between PWSs and eczema. It is unclear if concomitant PWS and localized eczema are collision dermatoses or if a PWS may predispose the affected skin to eczema.11-13 It has been hypothesized that the increased dermal vasculature in PWSs predisposes the skin to the development of eczema—more specifically, that ectasia may lead to increased inflammation.12,17 The concept of the “immunocompromised district” proposed by Ruocco et al26 is a unifying theory that may underlie the association noted between cases of trauma and later development of a PWS and superimposed eczematous dermatitis, such as in our case. Trauma is noted as one of a number of possible disruptive forces affecting both immunomodulation and neuromodulation within a local area of skin, leading to increased susceptibility of that district to various cutaneous diseases.26

Although our patient’s eczema responded to conservative treatment with a topical steroid, several case series have reported success with laser therapy in the treatment of PWS while preventing recurrence of associated eczematous dermatitis.12,17 Following the cessation of eczema treatment with topical steroid, which causes vasoconstriction, we suggest postponing laser therapy several weeks to allow resolution of vasoconstriction, thus providing enhanced therapeutic targeting with a vascular laser. Of particular relevance to our case, a recent study showed efficacy of the pulsed dye laser in treating PWSs in Fitzpatrick skin types IV and V.27

Conclusion

Although acquired PWS is rare, it can present later in life as an acquired lesion at a site of previous trauma.1-5 Congenital capillary malformations also can be associated with superimposed, localized eczema.11-18 We present a rarely reported case of an acquired PWS with superimposed, localized eczema. As in cases of congenital PWS with concomitant eczema, the associated eczema in our case was responsive to topical corticosteroid therapy. Additionally, pulsed dye laser has been shown to treat PWSs while preventing the recurrence of eczema, and it has been deemed effective for individuals with darker skin types.12,17, 27 Further studies are needed to explore the relationship between PWS and eczema.

Port-wine stains (PWSs) are common congenital capillary vascular malformations with an incidence of 3 per 1000 neonates.1 Rarely, acquired PWSs are seen, sometimes appearing following trauma.2-5 Port-wine stains are diagnosed clinically and present as painless, partially or entirely blanchable pink patches that respect the median (midline) plane.6 Although histopathologic examination is not necessary for diagnosis of PWS, typical findings include dilated, ectatic capillaries.7,8 Since it was first reported by Traub9 in 1939, more than 60 cases of acquired PWSs have been reported.10 A PubMed search of articles indexed for MEDLINE using the search terms acquired port-wine stain and port-wine stain and eczema yielded no cases of acquired PWS with associated eczematous changes and only 30 cases of congenital PWS with superimposed eczema.11-18 We report the case of an acquired PWS with superimposed eczema in an 18-year-old man following penetrating abdominal trauma.

Case Report

An otherwise healthy 18-year-old man presented to our dermatology office for evaluation of an eruption that had developed at the site of an abdominal stab wound he sustained 2 to 3 years prior. One year after he was stabbed, the patient developed a nonpruritic, painless red patch located 1 cm anterior to the healed wound on the left abdomen. The patch gradually grew larger to involve the entire left abdomen, extending to the left lower back. The site of the healed stab wound also became raised and pruritic, and the patient noted another pruritic plaque that formed within the larger patch. The patient reported no other skin conditions prior to the current eruption. His medical history was notable for seasonal allergies and asthma, but no childhood eczema.

Physical examination revealed a healthy, well-nourished man with Fitzpatrick skin type IV. A red, purpuric, coalescent patch with slightly arcuate borders extending from the mid abdomen to the left posterior flank was noted. The left lateral aspect of the patch blanched with pressure and respected the median plane. Within the larger patch, a 4-cm×2-cm lichenified, slightly macerated, hyperpigmented plaque was noted at the site of the stab wound (Figure 1). Based on these clinical findings, a presumptive diagnosis of an acquired PWS with superimposed eczema was made.

Figure 1. A lichenified, macerated, hyperpigmented plaque on the left lower abdomen with a larger red, coalescent patch with slightly arcuate borders that respected the median plane.

Punch biopsy specimens were taken from the large vascular patch and the smaller lichenified plaque. Histopathologic examination of the vascular patch showed an increased number of small vessels in the superficial dermis with thickened vessel walls, ectatic lumens, and no vasculopathy, consistent with a vascular malformation or a reactive vascular proliferation (Figure 2). On histopathology, the plaque showed epidermal spongiosis and hyperplasia with serum crust and a papillary dermis containing a mixed inflammatory infiltrate with occasional eosinophils, consistent with an eczematous dermatitis (Figure 3). The histologic findings confirmed the clinical diagnosis.

Figure 2. A biopsy specimen from the large patch on the left flank showed an increased number of small vessels and thickened vessel walls consistent with vascular malformation (H&E, original magnification ×100).

Figure 3. A biopsy specimen from the hyperpigmented plaque showed serum crust, hyperplasia, spongiosis, and a mixed inflammatory infiltrate with occasional eosinophils in the papillary dermis consistent with eczematous dermatitis (H&E, original magnification ×100).

The pruritic, lichenified plaque improved with application of triamcinolone ointment 0.1% twice daily for 2 weeks. Magnetic resonance imaging to rule out an underlying arteriovenous malformation was recommended, but the patient declined.

 

 

Comment

The exact cause of PWS is unknown. There have been a multitude of genomic suspects for congenital lesions, including a somatic activating mutation (ie, a mutation acquired during fetal development) of the GNAQ (guanine nucleotide binding protein [G protein], q polypeptide) gene, which may contribute to abnormal cell proliferation including the regulation of blood vessels, and inactivating mutations in the RASA1 (RAS p21 protein activator [GTPase activating protein] 1) gene, which controls endothelial cell organization.19-22 Later mutations (ie, those occurring after the first trimester) may be more likely to result in isolated PWSs as opposed to syndromic PWSs.19 Whatever the source of genetic misinformation, it is thought that the diminished neuronal control of blood flow and the resulting alterations in dermal structure contribute to the pathogenesis of PWS and its associated histologic features.7,23

The clinical and histopathologic features of acquired PWSs are indistinguishable from those of congenital lesions, indicating that different processes may lead to the same presentation.4 Abnormal innervation and decreased supportive stroma have both been identified as contributing factors in the development of congenital and acquired PWSs.7,23-25 Rosen and Smoller23 found that diminished nerve density affects vascular tone and caliber in PWSs and had hypothesized in a prior report that decreased perivascular Schwann cells may indicate abnormal sympathetic innervation.7 Since then, PWS has been shown to lack both somatic and sensory innervation.24 Tsuji and Sawabe25 indicated that alterations to the perivascular stroma, whether congenital or as a result of trauma, decrease support for vessels, leading to ectasia.

In addition to an acquired PWS, our patient also had associated eczema within the PWS. Eczematous lesions were absent elsewhere, and he did not have a history of childhood eczema. Our review of the literature yielded 8 studies since 1996 that collectively described 30 cases of eczema within PWSs.11-18 Only 2 of these reports described adult patients with concomitant eczema and PWS and none described acquired PWS.13,18

Few studies have addressed the relationship between PWSs and eczema. It is unclear if concomitant PWS and localized eczema are collision dermatoses or if a PWS may predispose the affected skin to eczema.11-13 It has been hypothesized that the increased dermal vasculature in PWSs predisposes the skin to the development of eczema—more specifically, that ectasia may lead to increased inflammation.12,17 The concept of the “immunocompromised district” proposed by Ruocco et al26 is a unifying theory that may underlie the association noted between cases of trauma and later development of a PWS and superimposed eczematous dermatitis, such as in our case. Trauma is noted as one of a number of possible disruptive forces affecting both immunomodulation and neuromodulation within a local area of skin, leading to increased susceptibility of that district to various cutaneous diseases.26

Although our patient’s eczema responded to conservative treatment with a topical steroid, several case series have reported success with laser therapy in the treatment of PWS while preventing recurrence of associated eczematous dermatitis.12,17 Following the cessation of eczema treatment with topical steroid, which causes vasoconstriction, we suggest postponing laser therapy several weeks to allow resolution of vasoconstriction, thus providing enhanced therapeutic targeting with a vascular laser. Of particular relevance to our case, a recent study showed efficacy of the pulsed dye laser in treating PWSs in Fitzpatrick skin types IV and V.27

Conclusion

Although acquired PWS is rare, it can present later in life as an acquired lesion at a site of previous trauma.1-5 Congenital capillary malformations also can be associated with superimposed, localized eczema.11-18 We present a rarely reported case of an acquired PWS with superimposed, localized eczema. As in cases of congenital PWS with concomitant eczema, the associated eczema in our case was responsive to topical corticosteroid therapy. Additionally, pulsed dye laser has been shown to treat PWSs while preventing the recurrence of eczema, and it has been deemed effective for individuals with darker skin types.12,17, 27 Further studies are needed to explore the relationship between PWS and eczema.

References
  1. Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics. 1976;58:218-222.
  2. Fegeler F. Naevus flammeus im trigeminusgebiet nach trauma im rahmen eines posttraumatisch-vegetativen syndroms. Arch Dermatol Syphilol. 1949;188:416-422.
  3. Kirkland CR, Mutasim DF. Acquired port-wine stain following repetitive trauma. J Am Acad Dermatol. 2011;65:462-463.
  4. Adams BB, Lucky AW. Acquired port-wine stains and antecedent trauma: case report and review of the literature. Arch Dermatol. 2000;136:897-899.
  5. Colver GB, Ryan TJ. Acquired port-wine stain. Arch Dermatol. 1986;122:1415-1416.
  6. Nigro J, Swerlick RA, Sepp NT, et al. Angiogenesis, vascular malformations and proliferations. In: Arndt KA, LeBoit PE, Robinson JK, Wintroub BU, eds. Cutaneous Medicine and Surgery: An Integrated Program in Dermatology. Philadelphia, PA: WB Saunders Co; 1996:1492-1521.
  7. Smoller BR, Rosen S. Port-wine stains. a disease of altered neural modulation of blood vessels? Arch Dermatol. 1986;122:177-179.
  8. Chang CJ, Yu JS, Nelson JS. Confocal microscopy study of neurovascular distribution in facial port wine stains(capillary malformation). J Formos Med Assoc. 2008;107:559-666.
  9. Traub EF. Naevus flammeus appearing at the age of twenty three. Arch Dermatol. 1939;39:752.
  10. Freysz M, Cribier B, Lipsker, D. Fegelers syndrome, acquired port-wine stain or acquired capillary malformation: three cases and a literature review [article in French]. Ann Dermatol Venereol. 2013;140:341-346.
  11. Tay YK, Morelli J, Weston WL. Inflammatory nuchal-occipital port-wine stains. J Am Acad Dermatol. 1996;35:811-813.
  12. Sidwell RU, Syed S, Harper JI. Port-wine stains and eczema. Br J Dermatol. 2001;144:1269-1270.
  13. Hofer T. Meyerson phenomenon within a nevus flammeus. Dermatology. 2002;205:180-183.
  14. Raff K, Landthaler M, Hoheleutner U. Port-wine stains with eczema. Phlebologie. 2003;32:15-17.
  15. Tsuboi H, Miyata T, Katsuoka K. Eczema in a port-wine stain. Clin Exp Dermatol. 2003;28:322-323.
  16. Rajan N, Natarahan S. Impetiginized eczema arising within a port-wine stain of the arm. J Eur Acad Dermatol Venereol. 2006;20:1009-1010.
  17. Fonder MA, Mamelak AJ, Kazin RA, et al. Port-wine-stain-associated dermatitis: implications for cutaneous vascular laser therapy. Pediatr Dermatol. 2007;24:376-379.
  18. Simon V, Wolfgan H, Katharina F. Meyerson-Phenomenon hides a nevus flammeus. J Dtsch Dermatol Ges. 2011;9:305-307.
  19. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368:1971-1979.
  20. Hershkovitz D, Bercovich D, Sprecher E, et al. RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations. Br J Dermatol. 2008;158:1035-1040.
  21. Eerola I, Boon LM, Mulliken JB, et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;73:1240-1249.
  22. Henkemeyer M, Rossi DJ, Holmyard DP, et al. Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature. 1995;377:695-701.
  23. Rosen S, Smoller BR. Port-wine stains: a new hypothesis. J Am Acad Dermatol. 1987;17:164-166.
  24. Rydh M, Malm BM, Jernmeck J, et al. Ectatic blood vessels in port-wine stains lack innervation: possible role in pathogenesis. Plast Reconstr Surg. 1991;87:419-422.
  25. Tsuji T, Sawabe M. A new type of telangiectasia following trauma. J Cutan Pathol. 1988;15:22-26.
  26. Ruocco V, Ruocco E, Brunnetti G, et al. Opportunistic localization of skin lesions on vulnerable areas. Clin Dermatol. 2011;29:483-488.
  27. Thajudeheen CP, Jyothy K, Pryadarshi A. Treatment of port-wine stains with flash lamp pumped pulsed dye laser on Indian skin: a six year study. J Cutan Aesthet Surg. 2014;7:32-36.
References
  1. Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics. 1976;58:218-222.
  2. Fegeler F. Naevus flammeus im trigeminusgebiet nach trauma im rahmen eines posttraumatisch-vegetativen syndroms. Arch Dermatol Syphilol. 1949;188:416-422.
  3. Kirkland CR, Mutasim DF. Acquired port-wine stain following repetitive trauma. J Am Acad Dermatol. 2011;65:462-463.
  4. Adams BB, Lucky AW. Acquired port-wine stains and antecedent trauma: case report and review of the literature. Arch Dermatol. 2000;136:897-899.
  5. Colver GB, Ryan TJ. Acquired port-wine stain. Arch Dermatol. 1986;122:1415-1416.
  6. Nigro J, Swerlick RA, Sepp NT, et al. Angiogenesis, vascular malformations and proliferations. In: Arndt KA, LeBoit PE, Robinson JK, Wintroub BU, eds. Cutaneous Medicine and Surgery: An Integrated Program in Dermatology. Philadelphia, PA: WB Saunders Co; 1996:1492-1521.
  7. Smoller BR, Rosen S. Port-wine stains. a disease of altered neural modulation of blood vessels? Arch Dermatol. 1986;122:177-179.
  8. Chang CJ, Yu JS, Nelson JS. Confocal microscopy study of neurovascular distribution in facial port wine stains(capillary malformation). J Formos Med Assoc. 2008;107:559-666.
  9. Traub EF. Naevus flammeus appearing at the age of twenty three. Arch Dermatol. 1939;39:752.
  10. Freysz M, Cribier B, Lipsker, D. Fegelers syndrome, acquired port-wine stain or acquired capillary malformation: three cases and a literature review [article in French]. Ann Dermatol Venereol. 2013;140:341-346.
  11. Tay YK, Morelli J, Weston WL. Inflammatory nuchal-occipital port-wine stains. J Am Acad Dermatol. 1996;35:811-813.
  12. Sidwell RU, Syed S, Harper JI. Port-wine stains and eczema. Br J Dermatol. 2001;144:1269-1270.
  13. Hofer T. Meyerson phenomenon within a nevus flammeus. Dermatology. 2002;205:180-183.
  14. Raff K, Landthaler M, Hoheleutner U. Port-wine stains with eczema. Phlebologie. 2003;32:15-17.
  15. Tsuboi H, Miyata T, Katsuoka K. Eczema in a port-wine stain. Clin Exp Dermatol. 2003;28:322-323.
  16. Rajan N, Natarahan S. Impetiginized eczema arising within a port-wine stain of the arm. J Eur Acad Dermatol Venereol. 2006;20:1009-1010.
  17. Fonder MA, Mamelak AJ, Kazin RA, et al. Port-wine-stain-associated dermatitis: implications for cutaneous vascular laser therapy. Pediatr Dermatol. 2007;24:376-379.
  18. Simon V, Wolfgan H, Katharina F. Meyerson-Phenomenon hides a nevus flammeus. J Dtsch Dermatol Ges. 2011;9:305-307.
  19. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368:1971-1979.
  20. Hershkovitz D, Bercovich D, Sprecher E, et al. RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations. Br J Dermatol. 2008;158:1035-1040.
  21. Eerola I, Boon LM, Mulliken JB, et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;73:1240-1249.
  22. Henkemeyer M, Rossi DJ, Holmyard DP, et al. Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature. 1995;377:695-701.
  23. Rosen S, Smoller BR. Port-wine stains: a new hypothesis. J Am Acad Dermatol. 1987;17:164-166.
  24. Rydh M, Malm BM, Jernmeck J, et al. Ectatic blood vessels in port-wine stains lack innervation: possible role in pathogenesis. Plast Reconstr Surg. 1991;87:419-422.
  25. Tsuji T, Sawabe M. A new type of telangiectasia following trauma. J Cutan Pathol. 1988;15:22-26.
  26. Ruocco V, Ruocco E, Brunnetti G, et al. Opportunistic localization of skin lesions on vulnerable areas. Clin Dermatol. 2011;29:483-488.
  27. Thajudeheen CP, Jyothy K, Pryadarshi A. Treatment of port-wine stains with flash lamp pumped pulsed dye laser on Indian skin: a six year study. J Cutan Aesthet Surg. 2014;7:32-36.
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Acquired Port-wine Stain With Superimposed Eczema Following Penetrating Abdominal Trauma
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Practice Points

  • Port-wine stains (PWSs) most often are congenital lesions but can present later in life as acquired lesions with the same clinical and histologic findings.
  • Magnetic resonance imaging of acquired PWSs should be considered to rule out underlying vascular anomalies (eg, deeper arteriovenous malformations).
  • Pulsed dye laser therapy is safe for darker skin types and is the treatment of choice for acquired PWSs.
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Practical tips help quell pseudofolliculitis barbae

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Practical tips help quell pseudofolliculitis barbae

LAS VEGAS – Stubble is okay, and not just because it’s trendy to sport a beard. This was a key message during a presentation on pseudofolliculitis barbae at Skin Disease Education Foundation’s annual Las Vegas dermatology seminar.

Changing up personal grooming habits is an important tactic for men who are plagued with pseudofolliculitis barbae, according to Dr. Andrew F. Alexis, chair of the department of dermatology and director of The Skin of Color Center, Mount Sinai St. Luke’s and Mount Sinai Roosevelt, New York.

Dr. Andrew Alexis

This very common skin condition, affecting 45%-83% of men of African ancestry, is best managed by avoiding close shaving and preventing a sharp hair shaft tip. For those who don’t want a full beard for personal or professional reasons, using single blade razors, electric clippers, and even depilatories can help, he said.

All of these techniques prevent curly beard hairs from repenetrating or recurving before emergence – the underpinning of the pathology of pseudofolliculitis barbae. The embedded hairs eventually form a papular or pustular lesion that mimics infectious folliculitis. The inflammatory process can also prompt keloid formation in susceptible individuals.

Providing treatment options is important because the condition can be disfiguring, with such long-term physical sequelae as scarring beard alopecia and postinflammatory hyperpigmentation – changes in appearance that can have a significant psychosocial impact on affected men, Dr. Alexis said.

Therapies are centered around avoiding close shaving and/or preventing a sharp hair shaft tip.

Courtesy Dr. Andrew F. AlexisPustules and papules in pseudofolliculitis barbae.

One primary treatment is to stop shaving. “Embedded hairs spontaneously release after about one centimeter of growth,” Dr. Alexis said. This process can take up to 2 months, he said, but military studies dating back to the 1970s showed that the vast majority of pseudofolliculitis barbae cases resolved when service members stopped close shaving practices.

However, many patients want a clean-shaven appearance. “We can work with them to modify their shaving practices. Historically, we have recommended single-blade razors over multiple blade razors” because they shave less closely, he said, pointing out that razor manufacturers have funded studies that challenge this finding.

“Electric clippers are a very good alternative” to razors, Dr. Alexis said. A blade setting that allows at least 0.5-1 mm stubble is desirable.

Chemical depilatories, which act by weakening keratin disulfide bonds, can be effective, since depilated hair does not have a sharp, beveled tip on regrowth and is therefore less likely to repuncture the skin. Patients should be aware, though, that these substances can cause irritant contact dermatitis, he pointed out. Newer formulations are less caustic, but also less efficacious, he said.

In terms of practical tips, shaving technique is important. “Don’t assume the patient knows. There are all sorts of varying techniques out there,” some of which can exacerbate pseudofolliculitis barbae, Dr. Alexis said.

Before shaving, men should wash with a mild cleanser, using a gentle circular technique to free any entrapped hairs, then a moisturizing shaving cream. Razors should be changed every five to seven shaves, and shaving should always be done in the direction of beard growth without pulling on the skin.

Courtesy Dr. Andrew F. AlexisPseudofollicultis barbae, with hyperpigmentation.

Post shave, topical benzoyl peroxide 5%/clindamycin 1% can significantly reduce papules and pustules. Topical retinoids are another effective option. A low-potency steroid can be helpful for inflammatory symptoms.

For cases that just don’t respond to conservative and medical management, laser hair removal is an option. A recent military-funded split-face study found further improvement when topical eflornithine was added to long-pulse Nd:Yag laser therapy, Dr. Alexis said.

Affected individuals may find it difficult to modify shaving practices when uniformed service regulations or office dress codes require men to be close shaven; a note from a physician can be helpful. Dr. Alexis provides patients with a form letter to show their employers, explaining that the patient has a skin disorder that is exacerbated by shaving, and that the patient should be permitted to maintain a well-groomed beard. “I end up writing a lot of these for New York police officers,” he said.

Dr. Alexis disclosed that he has received grants and research support from Allergan and Novartis, and speaker honoraria from Cipla. He has received consulting fees from Aclaris, Allergan, Amgen, Anacor, Bayer, Galderma, Johnson & Johnson, Leo, L’Oreal, Roche, Schick, Suneva, and Valeant.

SDEF and this news organization are owned by the same parent company.

[email protected]

On Twitter @karioakes

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LAS VEGAS – Stubble is okay, and not just because it’s trendy to sport a beard. This was a key message during a presentation on pseudofolliculitis barbae at Skin Disease Education Foundation’s annual Las Vegas dermatology seminar.

Changing up personal grooming habits is an important tactic for men who are plagued with pseudofolliculitis barbae, according to Dr. Andrew F. Alexis, chair of the department of dermatology and director of The Skin of Color Center, Mount Sinai St. Luke’s and Mount Sinai Roosevelt, New York.

Dr. Andrew Alexis

This very common skin condition, affecting 45%-83% of men of African ancestry, is best managed by avoiding close shaving and preventing a sharp hair shaft tip. For those who don’t want a full beard for personal or professional reasons, using single blade razors, electric clippers, and even depilatories can help, he said.

All of these techniques prevent curly beard hairs from repenetrating or recurving before emergence – the underpinning of the pathology of pseudofolliculitis barbae. The embedded hairs eventually form a papular or pustular lesion that mimics infectious folliculitis. The inflammatory process can also prompt keloid formation in susceptible individuals.

Providing treatment options is important because the condition can be disfiguring, with such long-term physical sequelae as scarring beard alopecia and postinflammatory hyperpigmentation – changes in appearance that can have a significant psychosocial impact on affected men, Dr. Alexis said.

Therapies are centered around avoiding close shaving and/or preventing a sharp hair shaft tip.

Courtesy Dr. Andrew F. AlexisPustules and papules in pseudofolliculitis barbae.

One primary treatment is to stop shaving. “Embedded hairs spontaneously release after about one centimeter of growth,” Dr. Alexis said. This process can take up to 2 months, he said, but military studies dating back to the 1970s showed that the vast majority of pseudofolliculitis barbae cases resolved when service members stopped close shaving practices.

However, many patients want a clean-shaven appearance. “We can work with them to modify their shaving practices. Historically, we have recommended single-blade razors over multiple blade razors” because they shave less closely, he said, pointing out that razor manufacturers have funded studies that challenge this finding.

“Electric clippers are a very good alternative” to razors, Dr. Alexis said. A blade setting that allows at least 0.5-1 mm stubble is desirable.

Chemical depilatories, which act by weakening keratin disulfide bonds, can be effective, since depilated hair does not have a sharp, beveled tip on regrowth and is therefore less likely to repuncture the skin. Patients should be aware, though, that these substances can cause irritant contact dermatitis, he pointed out. Newer formulations are less caustic, but also less efficacious, he said.

In terms of practical tips, shaving technique is important. “Don’t assume the patient knows. There are all sorts of varying techniques out there,” some of which can exacerbate pseudofolliculitis barbae, Dr. Alexis said.

Before shaving, men should wash with a mild cleanser, using a gentle circular technique to free any entrapped hairs, then a moisturizing shaving cream. Razors should be changed every five to seven shaves, and shaving should always be done in the direction of beard growth without pulling on the skin.

Courtesy Dr. Andrew F. AlexisPseudofollicultis barbae, with hyperpigmentation.

Post shave, topical benzoyl peroxide 5%/clindamycin 1% can significantly reduce papules and pustules. Topical retinoids are another effective option. A low-potency steroid can be helpful for inflammatory symptoms.

For cases that just don’t respond to conservative and medical management, laser hair removal is an option. A recent military-funded split-face study found further improvement when topical eflornithine was added to long-pulse Nd:Yag laser therapy, Dr. Alexis said.

Affected individuals may find it difficult to modify shaving practices when uniformed service regulations or office dress codes require men to be close shaven; a note from a physician can be helpful. Dr. Alexis provides patients with a form letter to show their employers, explaining that the patient has a skin disorder that is exacerbated by shaving, and that the patient should be permitted to maintain a well-groomed beard. “I end up writing a lot of these for New York police officers,” he said.

Dr. Alexis disclosed that he has received grants and research support from Allergan and Novartis, and speaker honoraria from Cipla. He has received consulting fees from Aclaris, Allergan, Amgen, Anacor, Bayer, Galderma, Johnson & Johnson, Leo, L’Oreal, Roche, Schick, Suneva, and Valeant.

SDEF and this news organization are owned by the same parent company.

[email protected]

On Twitter @karioakes

LAS VEGAS – Stubble is okay, and not just because it’s trendy to sport a beard. This was a key message during a presentation on pseudofolliculitis barbae at Skin Disease Education Foundation’s annual Las Vegas dermatology seminar.

Changing up personal grooming habits is an important tactic for men who are plagued with pseudofolliculitis barbae, according to Dr. Andrew F. Alexis, chair of the department of dermatology and director of The Skin of Color Center, Mount Sinai St. Luke’s and Mount Sinai Roosevelt, New York.

Dr. Andrew Alexis

This very common skin condition, affecting 45%-83% of men of African ancestry, is best managed by avoiding close shaving and preventing a sharp hair shaft tip. For those who don’t want a full beard for personal or professional reasons, using single blade razors, electric clippers, and even depilatories can help, he said.

All of these techniques prevent curly beard hairs from repenetrating or recurving before emergence – the underpinning of the pathology of pseudofolliculitis barbae. The embedded hairs eventually form a papular or pustular lesion that mimics infectious folliculitis. The inflammatory process can also prompt keloid formation in susceptible individuals.

Providing treatment options is important because the condition can be disfiguring, with such long-term physical sequelae as scarring beard alopecia and postinflammatory hyperpigmentation – changes in appearance that can have a significant psychosocial impact on affected men, Dr. Alexis said.

Therapies are centered around avoiding close shaving and/or preventing a sharp hair shaft tip.

Courtesy Dr. Andrew F. AlexisPustules and papules in pseudofolliculitis barbae.

One primary treatment is to stop shaving. “Embedded hairs spontaneously release after about one centimeter of growth,” Dr. Alexis said. This process can take up to 2 months, he said, but military studies dating back to the 1970s showed that the vast majority of pseudofolliculitis barbae cases resolved when service members stopped close shaving practices.

However, many patients want a clean-shaven appearance. “We can work with them to modify their shaving practices. Historically, we have recommended single-blade razors over multiple blade razors” because they shave less closely, he said, pointing out that razor manufacturers have funded studies that challenge this finding.

“Electric clippers are a very good alternative” to razors, Dr. Alexis said. A blade setting that allows at least 0.5-1 mm stubble is desirable.

Chemical depilatories, which act by weakening keratin disulfide bonds, can be effective, since depilated hair does not have a sharp, beveled tip on regrowth and is therefore less likely to repuncture the skin. Patients should be aware, though, that these substances can cause irritant contact dermatitis, he pointed out. Newer formulations are less caustic, but also less efficacious, he said.

In terms of practical tips, shaving technique is important. “Don’t assume the patient knows. There are all sorts of varying techniques out there,” some of which can exacerbate pseudofolliculitis barbae, Dr. Alexis said.

Before shaving, men should wash with a mild cleanser, using a gentle circular technique to free any entrapped hairs, then a moisturizing shaving cream. Razors should be changed every five to seven shaves, and shaving should always be done in the direction of beard growth without pulling on the skin.

Courtesy Dr. Andrew F. AlexisPseudofollicultis barbae, with hyperpigmentation.

Post shave, topical benzoyl peroxide 5%/clindamycin 1% can significantly reduce papules and pustules. Topical retinoids are another effective option. A low-potency steroid can be helpful for inflammatory symptoms.

For cases that just don’t respond to conservative and medical management, laser hair removal is an option. A recent military-funded split-face study found further improvement when topical eflornithine was added to long-pulse Nd:Yag laser therapy, Dr. Alexis said.

Affected individuals may find it difficult to modify shaving practices when uniformed service regulations or office dress codes require men to be close shaven; a note from a physician can be helpful. Dr. Alexis provides patients with a form letter to show their employers, explaining that the patient has a skin disorder that is exacerbated by shaving, and that the patient should be permitted to maintain a well-groomed beard. “I end up writing a lot of these for New York police officers,” he said.

Dr. Alexis disclosed that he has received grants and research support from Allergan and Novartis, and speaker honoraria from Cipla. He has received consulting fees from Aclaris, Allergan, Amgen, Anacor, Bayer, Galderma, Johnson & Johnson, Leo, L’Oreal, Roche, Schick, Suneva, and Valeant.

SDEF and this news organization are owned by the same parent company.

[email protected]

On Twitter @karioakes

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EXPERT ANALYSIS FROM SDEF LAS VEGAS DERMATOLOGY SEMINAR

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A Novel Cream Formulation Containing Nicotinamide 4%, Arbutin 3%, Bisabolol 1%, and Retinaldehyde 0.05% for Treatment of Epidermal Melasma

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A Novel Cream Formulation Containing Nicotinamide 4%, Arbutin 3%, Bisabolol 1%, and Retinaldehyde 0.05% for Treatment of Epidermal Melasma

Epidermal melasma is a common hyperpigmentation disorder that can be challenging to treat. The pathogenesis of melasma is not fully understood but has been associated with increased melanin and melanocyte activity.1,2 Melasma is characterized by jagged, light- to dark-brown patches on areas of the skin most often exposed to the sun—primarily the cheeks, forehead, upper lip, nose, and chin.3 Although it can affect both sexes and all races, melasma is more common in Fitzpatrick skin types II to IV and frequently is seen in Asian or Hispanic women residing in geographic locations with high levels of sun exposure (eg, tropical areas).2 Melasma presents more frequently in adult women of childbearing age, especially during pregnancy, but also can begin postmenopause. Onset may occur as early as menarche but typically is observed between the ages of 30 and 55 years.3,4 Only 10% of melasma cases are known to occur in males4 and are influenced by such factors as ethnicity, hormones, and level of sun exposure.2

Topical therapies for melasma attempt to inhibit melanocytic activation at each level of melanin formation until the deposited pigment is removed; however, results may vary greatly, as melasma often recurs due to the migration of new melanocytes from hair follicles to the skin’s surface, leading to new development of hyperpigmentation. The current standard of treatment for melasma involves the use of hydroquinone and other bleaching agents, but long-term use of these treatments has been associated with concerns regarding unstable preparations (which may lose their therapeutic properties) and adverse effects (eg, ochronosis, depigmentation).5 Cosmetic agents that recently have been evaluated for melasma treatment include nicotinamide (a form of vitamin B3), which inhibits the transfer of melanosomes from melanocytes to keratinocytes; arbutin, which inhibits melanin synthesis by inhibiting tyrosinase activity6; bisabolol, which prevents anti-inflammatory activity7; and retinaldehyde (RAL), a precursor of retinoic acid (RA) that has powerful bleaching action and low levels of cutaneous irritability.8

This prospective, single-arm, open-label study, evaluated the efficacy and safety of a novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05% in the treatment of epidermal melasma.

Study Product Ingredients and Background

Nicotinamide

Nicotinamide is a water-soluble amide of nicotinic acid (niacin) and one of the 2 principal forms of vitamin B3. It is a component of the coenzymes nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate. Nicotinamide essentially acts as an antioxidant, with most of its effects exerted through poly(adenosine diphosphate–ribose) polymerase inhibition. Interest has increased in the role of nicotinamide in the prevention and treatment of several skin diseases, such as acne and UV radiation–induced deleterious molecular and immunological events. Nicotinamide also has gained consideration as a potential agent in sunscreen preparations due to its possible skin-lightening effects, stimulation of DNA repair, suppression of UV photocarcinogenesis, and other antiaging effects.9

Arbutin

Arbutin is a molecule that has proven effective in treating melasma.10 Its pigment-lightening ingredients include botanicals that are structurally similar to hydroquinone. Arbutin is obtained from the leaves of the bearberry plant but also is found in lesser quantities in cranberry and blueberry leaves. A naturally occurring gluconopyranoside, arbutin reduces tyrosinase activity without affecting messenger RNA expression.11 Arbutin also inhibits melanosome maturation, is nontoxic to melanocytes, and is used in Japan in a variety of pigment-lightening preparations at 3% concentrations.12

Bisabolol

Bisabolol is a natural monocyclic sesquiterpene alcohol found in the oils of chamomile and other plants. Bisabolol often is included in cosmetics due to its favorable anti-inflammatory and depigmentation properties. Its downregulation of inducible nitric oxide synthase and cyclooxygenase-2 suggests that it may have anti-inflammatory effects.7

Retinaldehyde

Retinaldehyde is an RA precursor that forms as an intermediate metabolite in the transformation of retinol to RA in human keratinocytes. Topical RAL is well tolerated by human skin, and several of its biologic effects are identical to those of RA. Using the tails of C57BL/6 mouse models, RAL 0.05% has been found to have significantly more potent depigmenting effects than RA 0.05% (P<.001 vs P<.01, respectively) when compared to vehicle.13

Although combination therapy with RAL and arbutin could potentially cause skin irritation, the addition of bisabolol to the combination cream used in this study is believed to have conferred anti-inflammatory properties because it inhibits the release of histamine and relieves irritation.

Methods

This single-center, single-arm, prospective, open-label study evaluated the efficacy and safety of a novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05% in treating epidermal melasma. Clinical evaluation included assessment of Melasma Area and Severity Index (MASI) score, photographic analysis, and in vivo reflectance confocal microscopy (RCM) analysis.

 

 

The study population included women aged 18 to 50 years with Fitzpatrick skin types I through V who had clinically diagnosed epidermal melasma on the face. Eligibility requirements included confirmation of epidermal pigmentation on Wood lamp examination and RCM analysis and a MASI score of less than 10.5. A total of 35 participants were enrolled in the study (intention to treat [ITT] population). Thirty-three participants were included in the analysis of treatment effectiveness (ITTe population), as 2 were excluded due to lack of follow-up postbaseline. Four participants were prematurely withdrawn from the study—3 due to loss to follow-up and 1 due to treatment discontinuation following an adverse event (AE). The last observation carried forward method was used to input missing data from these 4 participants excluding repeated measure analysis that used the generalized estimated equation method.

At baseline, a 25-g tube of the study cream containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05% was distributed to all participants for once-daily application to the entire face for 30 days. Participants were instructed to apply the product in the evening after using a gentle cleanser, which also was to be used in the morning to remove the product residue. Additionally, participants were given a sunscreen with a sun protection factor of 30 to apply daily on the entire face in the morning, after lunch, and midafternoon. During the 30-day treatment period, treatment interruption of up to 5 consecutive days or 10 nonconsecutive days in total was permitted. At day 30, participants received another 30-day supply of the study product and sunscreen to be applied according to the same regimen for an additional 30-day treatment period.

Clinical Evaluation

At baseline, demographic data and medical history was recorded for all participants and dermatologic and physical examination was performed documenting weight, height, blood pressure, heart rate, and baseline MASI score. Following Wood lamp examination, participants’ faces were photographed and catalogued using medical imaging software that allowed for measurement of the total melasma surface area (Figure 1A). The photographs also were cross-polarized for further analysis of the pigmentation (Figure 1B).

    

Figure 1. Clinical (A) and cross-polarized (B) photographs of a patient before treatment with the novel compound containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05%.

A questionnaire evaluating treatment satisfaction was administered to participants (ITTe population [n=33]) at baseline and days 30 and 60. Questionnaire items pertained to skin blemishes, signs of facial aging, overall appearance, texture, oiliness, brightness, and hydration. Participants were instructed to rate their satisfaction for each item on a scale of 1 to 10 (1=bad, 10=excellent). For investigator analysis, scores of 1 to 4 were classified as “dissatisfied,” scores of 5 to 6 were classified as “satisfied,” and scores of 7 to 10 were classified as “completely satisfied.” A questionnaire evaluating product appreciation was administered at day 60 to participants who completed the study (n=29). Questionnaire items asked participants to rate the study cream’s ease of application, consistency, smell, absorption, and overall satisfaction using ratings of “bad,” “regular,” “good,” “very good,” or “excellent.”

Treatment efficacy in all participants was assessed by the investigators at days 30 and 60. Investigators evaluated reductions in pigmentation and total melasma surface area using ratings of “none,” “regular,” “good,” “very good,” or “excellent.” Local tolerance also was evaluated at both time points, and AEs were recorded and analyzed with respect to their duration, intensity, frequency, and severity.

Targeted hyperpigmented skin was selected for in vivo RCM analysis. At each time point, a sequence of block images was acquired at 4 levels of skin: (1) superficial dermis, (2) suprabasal layer/ dermoepidermal junction, (3) spinous layer, and (4) superficial granular layer. Blind evaluation of these images to assess the reduction in melanin quantity was conducted by a dermatopathologist at baseline and days 30 and 60. Melanin quantity present in each layer was graded according to 4 categories (0%–25%, 25.1%–50%, 50.1%–75%, 75.1%–100%). The mean value was used for statistical evaluation.

Results

Efficacy evaluation

The primary efficacy variable was the mean reduction in MASI score from baseline to the end of treatment (day 60), which was 2.25 ± 1.87 (P<.0001). The reduction in mean MASI score was significant from baseline to day 30 (P<.0001) and from day 30 to day 60 (P<.0001). The least root-mean-square error estimates of MASI score variation at days 30 and 60 were 1.40 and 2.25, respectively.

The mean total melasma surface area (as measured in analysis of clinical photographs using medical imaging software) was significantly reduced from 1398.5 mm2 at baseline to 1116.9 mm2 at day 30 (P<.0001) and 923.4 at day 60 (P<.0001). From baseline to end of treatment, the overall reduction in mean total melasma surface area was 475.1 mm2 (P<.0001)(Figure 2). Clinical and cross-polarized photographs taken at day 60 demonstrated a visible reduction in melasma surface area (Figure 3), which was confirmed using medical imaging software.

 

 

Figure 2. Mean surface area of melasma measured at baseline (1398.5 mm2), day 30 (1116.9 mm2), and day 60 (923.4 mm2), showing a mean total reduction of 475.1 mm2 from baseline to day 60.

  

Figure 3. Clinical (A) and cross-polarized (B) photographs of a patient after 60 days of treatment with the novel compound containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05%.

In vivo RCM analyses at each time point showed reduction in pigmentation in the 4 levels of the skin that were evaluated, but the results were not statistically significant.

Participant satisfaction

There was strong statistical evidence of patient satisfaction with the treatment results at the end of the study period (P<.0001). At baseline, 75.8% (25/33) of participants were dissatisfied with the appearance of their skin as compared with 15.2% (5/33) at day 60. Additionally, 18.1% (6/33) and 6.1% (2/33) of the participants were satisfied and completely satisfied at baseline compared with 33.3% (11/33) and 51.5% (17/33) at day 60, respectively. Participant satisfaction with signs of facial aging also increased over the study period (P=.0104). At baseline, 60.6% (20/33) were dissatisfied, 12.1% (4/33) were satisfied, and 27.3% (9/33) were completely satisfied; at the end of treatment, 30.3% (10/33) were dissatisfied, 36.4% (12/33) were satisfied, and 33.3% (11/33) were completely satisfied with the improvement in signs of facial aging.

Increased patient satisfaction with facial skin texture at baseline compared to day 60 also was statistically significant (P=.0157). At baseline, 39.4% (13/33) of the participants were dissatisfied, 30.3% (10/33) were satisfied, and 30.3% (10/33) were completely satisfied with facial texture; at day 60, 15.1% (5/33) were dissatisfied, 30.3% (10/33) were satisfied, and 54.6% (18/33) were completely satisfied. Significant improvement from baseline to day 60 also was observed in participant assessment of skin oiliness (P=.0210), brightness (P=.0003), overall appearance (P<.0001), and hydration (P<.0001).

Product appreciation

At day 60, 89.7% (26/29) of the participants who completed the study rated the product’s ease of application as being at least “good,” with more than half of participants (55.2% [16/29]) rating it as “very good” or “excellent.” Overall satisfaction with the product was rated as “very good” or “excellent” by 48.3% (14/29) of the participants. Similar results were observed in participant assessments of consistency, smell, and absorption (Figure 4).

Figure 4. Participant responses to product appreciation questionnaire.

Safety evaluation

A total of 52 AEs were observed in 23 (69.7%) participants, which were recorded by participants in diary entries throughout treatment and evaluated by investigators at each time point. Among these AEs, 48 (92.3%) were considered possibly, probably, or conditionally related to treatment by the investigators based on clinical observation. The most common presumed treatment-related AE was a burning sensation on the skin, reported by 30.3% (10/33) of the participants at day 30 and 13.8% (4/29) at day 60. Of the reported AEs related to treatment, 91.7% (44/48) were of mild intensity and 93.8% (45/48) required no treatment or other action. There were no reported serious AEs related to the investigational product. Blood pressure, heart rate, and weight remained stable among all participants throughout the study.

The intensity of the AEs was described as “light” in 91.7% (44/48) of cases and “moderate” in 8.3% (4/48) of cases. The frequency of AEs was classified as “unique,” “intermittent,” or “continuous” in 45.8% (22/48), 39.6% (19/48), and14.6% (7/48) of cases, respectively. Of the 48 AEs, 3 (6.3%) occurred in 1 participant, necessitating interruption of treatment, application of the topical corticosteroid cream mometasone, and removal from the study.

Comment

Following treatment with the study cream containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05%, the mean reduction in MASI score (P<.0001) and the mean reduction in total melasma surface area from baseline to end of treatment were statistically significant (P<.0001). The study product was associated with strong statistical evidence of patient satisfaction (P<.0001) regarding improvement in facial skin texture, skin oiliness, brightness, overall appearance, and hydration. Participants also responded favorably to the product and considered it safe and effective. In vivo RCM analysis demonstrated a reduction in the amount of melanin in 4 levels of the skin (superficial dermis, suprabasal layer/dermoepidermal junction, spinous layer, superficial granular layer) following treatment with the study cream; however, over the course of the 60-day treatment period, it did not reveal statistically significant reductions. This finding likely is due to the large ranges used to classify the amount of melanin present in each layer of the skin. These limitations suggest that scales used in future in vivo RCM analyses of melasma should be narrower.

 

 

Epidermal melasma is one of the most difficult dermatologic diseases to treat and control. Maintenance of clear, undamaged skin remains a treatment target for all dermatologists. This novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05% has proven to be an effective, safe, and tolerable treatment option for patients with epidermal melasma.

References

1. Grimes PE, Yamada N, Bhawan J. Light microscopic, immunohistochemical, and ultrastructural alterations in patients with melasma. Am J Dermatopathol. 2005;27:96-101.

2. Kang WH, Yoon KH, Lee ES, et al. Melasma: histopathological characteristics in 56 Korean patients. Br J Dermatol. 2002;146:228-237.

3. Cestari T, Arellano I, Hexsel D, et al. Melasma in Latin America: options the therapy and treatment algorithm. JEADV. 2009;23:760-772.

4. Miot LDB, Miot HA, Silva MG, et al. Fisiopatologia do Melasma. An Bras Dermatol. 2009;84:623-635.

5. Draelos Z. Skin lightening preparations and the hydroquinone controversy. Dermatol Ther. 2007;20:308-313.

6. Parvez S, Kang M, Chung HS, et al. Survey and mechanism of skin depigmenting and lightening agents. Phytoter Res. 2006;20:921-934.

7. Kim S, Jung E, Kim JH, et al. Inhibitory effects of (-)-α-bisabolol on LPS-induced inflammatory response in RAW264.7 macrophages. Food Chem Toxicol. 2011;49:2580-2585.

8. Ortonne JP. Retinoid therapy of pigmentary disorders. Dermatol Ther. 2006;19:280-288.

9. Namazi MR. Nicotinamide-containing sunscreens for use in Australasian countries and cancer-provoking conditions. Med Hypotheses. 2003;60:544-545.

10. Ertam I, Mutlu B, Unal I, et al. Efficiency of ellagic acid and arbutin in melasma: a randomized, prospective, open-label study. J Dermatol. 2008;35:570-574.

11. Hori I, Nihei K, Kubo I. Structural criteria for depigmenting mechanism of arbutin. Phytother Res. 2004;18:475-469.

12. Ethnic skin and pigmentation. In: Draelos ZD. Cosmetics and Dermatologic Problems and Solutions. 3rd ed. Boca Raton, FL: CRC Press; 2011:52-55.

13. Kasraee B, Tran C, Sorg O, et al. The depigmenting effect of RALGA in C57BL/6 mice. Dermatology. 2005;210(suppl 1):30-34.

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Author and Disclosure Information

Elisete I. Crocco, MD; John Verrinder Veasey, MD; Maria Fernanda Feitosa de Camargo Boin, MD; Rute Facchini Lellis, MD; Renata Oliveira Alves, MD

From Santa Casa de São Paulo Hospital and Medical School, Brazil. Drs. Crocco, Veasey, Boin, and Alves are from the Dermatology Clinic and Dr. Lellis is from the Department of Pathology.

This study was supported by TheraSkin Farmacêutica LTDA. Drs. Crocco, Veasey, Boin, Lellis, and Alves received a research grant from TheraSkin Farmacêutica LTDA for this study.

Correspondence: Elisete Crocco, MD, Avenida Macuco, 726/cj 2001, Moema, 04523-001, São Paulo-SP, Brazil ([email protected]).

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Cutis - 96(5)
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337-342
Legacy Keywords
melasma, topical treatment, cosmetic, hydroquinone, skin lightening, pigmentation, melanin, pigmentation disorder
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Author and Disclosure Information

Elisete I. Crocco, MD; John Verrinder Veasey, MD; Maria Fernanda Feitosa de Camargo Boin, MD; Rute Facchini Lellis, MD; Renata Oliveira Alves, MD

From Santa Casa de São Paulo Hospital and Medical School, Brazil. Drs. Crocco, Veasey, Boin, and Alves are from the Dermatology Clinic and Dr. Lellis is from the Department of Pathology.

This study was supported by TheraSkin Farmacêutica LTDA. Drs. Crocco, Veasey, Boin, Lellis, and Alves received a research grant from TheraSkin Farmacêutica LTDA for this study.

Correspondence: Elisete Crocco, MD, Avenida Macuco, 726/cj 2001, Moema, 04523-001, São Paulo-SP, Brazil ([email protected]).

Author and Disclosure Information

Elisete I. Crocco, MD; John Verrinder Veasey, MD; Maria Fernanda Feitosa de Camargo Boin, MD; Rute Facchini Lellis, MD; Renata Oliveira Alves, MD

From Santa Casa de São Paulo Hospital and Medical School, Brazil. Drs. Crocco, Veasey, Boin, and Alves are from the Dermatology Clinic and Dr. Lellis is from the Department of Pathology.

This study was supported by TheraSkin Farmacêutica LTDA. Drs. Crocco, Veasey, Boin, Lellis, and Alves received a research grant from TheraSkin Farmacêutica LTDA for this study.

Correspondence: Elisete Crocco, MD, Avenida Macuco, 726/cj 2001, Moema, 04523-001, São Paulo-SP, Brazil ([email protected]).

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Related Articles

Epidermal melasma is a common hyperpigmentation disorder that can be challenging to treat. The pathogenesis of melasma is not fully understood but has been associated with increased melanin and melanocyte activity.1,2 Melasma is characterized by jagged, light- to dark-brown patches on areas of the skin most often exposed to the sun—primarily the cheeks, forehead, upper lip, nose, and chin.3 Although it can affect both sexes and all races, melasma is more common in Fitzpatrick skin types II to IV and frequently is seen in Asian or Hispanic women residing in geographic locations with high levels of sun exposure (eg, tropical areas).2 Melasma presents more frequently in adult women of childbearing age, especially during pregnancy, but also can begin postmenopause. Onset may occur as early as menarche but typically is observed between the ages of 30 and 55 years.3,4 Only 10% of melasma cases are known to occur in males4 and are influenced by such factors as ethnicity, hormones, and level of sun exposure.2

Topical therapies for melasma attempt to inhibit melanocytic activation at each level of melanin formation until the deposited pigment is removed; however, results may vary greatly, as melasma often recurs due to the migration of new melanocytes from hair follicles to the skin’s surface, leading to new development of hyperpigmentation. The current standard of treatment for melasma involves the use of hydroquinone and other bleaching agents, but long-term use of these treatments has been associated with concerns regarding unstable preparations (which may lose their therapeutic properties) and adverse effects (eg, ochronosis, depigmentation).5 Cosmetic agents that recently have been evaluated for melasma treatment include nicotinamide (a form of vitamin B3), which inhibits the transfer of melanosomes from melanocytes to keratinocytes; arbutin, which inhibits melanin synthesis by inhibiting tyrosinase activity6; bisabolol, which prevents anti-inflammatory activity7; and retinaldehyde (RAL), a precursor of retinoic acid (RA) that has powerful bleaching action and low levels of cutaneous irritability.8

This prospective, single-arm, open-label study, evaluated the efficacy and safety of a novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05% in the treatment of epidermal melasma.

Study Product Ingredients and Background

Nicotinamide

Nicotinamide is a water-soluble amide of nicotinic acid (niacin) and one of the 2 principal forms of vitamin B3. It is a component of the coenzymes nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate. Nicotinamide essentially acts as an antioxidant, with most of its effects exerted through poly(adenosine diphosphate–ribose) polymerase inhibition. Interest has increased in the role of nicotinamide in the prevention and treatment of several skin diseases, such as acne and UV radiation–induced deleterious molecular and immunological events. Nicotinamide also has gained consideration as a potential agent in sunscreen preparations due to its possible skin-lightening effects, stimulation of DNA repair, suppression of UV photocarcinogenesis, and other antiaging effects.9

Arbutin

Arbutin is a molecule that has proven effective in treating melasma.10 Its pigment-lightening ingredients include botanicals that are structurally similar to hydroquinone. Arbutin is obtained from the leaves of the bearberry plant but also is found in lesser quantities in cranberry and blueberry leaves. A naturally occurring gluconopyranoside, arbutin reduces tyrosinase activity without affecting messenger RNA expression.11 Arbutin also inhibits melanosome maturation, is nontoxic to melanocytes, and is used in Japan in a variety of pigment-lightening preparations at 3% concentrations.12

Bisabolol

Bisabolol is a natural monocyclic sesquiterpene alcohol found in the oils of chamomile and other plants. Bisabolol often is included in cosmetics due to its favorable anti-inflammatory and depigmentation properties. Its downregulation of inducible nitric oxide synthase and cyclooxygenase-2 suggests that it may have anti-inflammatory effects.7

Retinaldehyde

Retinaldehyde is an RA precursor that forms as an intermediate metabolite in the transformation of retinol to RA in human keratinocytes. Topical RAL is well tolerated by human skin, and several of its biologic effects are identical to those of RA. Using the tails of C57BL/6 mouse models, RAL 0.05% has been found to have significantly more potent depigmenting effects than RA 0.05% (P<.001 vs P<.01, respectively) when compared to vehicle.13

Although combination therapy with RAL and arbutin could potentially cause skin irritation, the addition of bisabolol to the combination cream used in this study is believed to have conferred anti-inflammatory properties because it inhibits the release of histamine and relieves irritation.

Methods

This single-center, single-arm, prospective, open-label study evaluated the efficacy and safety of a novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05% in treating epidermal melasma. Clinical evaluation included assessment of Melasma Area and Severity Index (MASI) score, photographic analysis, and in vivo reflectance confocal microscopy (RCM) analysis.

 

 

The study population included women aged 18 to 50 years with Fitzpatrick skin types I through V who had clinically diagnosed epidermal melasma on the face. Eligibility requirements included confirmation of epidermal pigmentation on Wood lamp examination and RCM analysis and a MASI score of less than 10.5. A total of 35 participants were enrolled in the study (intention to treat [ITT] population). Thirty-three participants were included in the analysis of treatment effectiveness (ITTe population), as 2 were excluded due to lack of follow-up postbaseline. Four participants were prematurely withdrawn from the study—3 due to loss to follow-up and 1 due to treatment discontinuation following an adverse event (AE). The last observation carried forward method was used to input missing data from these 4 participants excluding repeated measure analysis that used the generalized estimated equation method.

At baseline, a 25-g tube of the study cream containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05% was distributed to all participants for once-daily application to the entire face for 30 days. Participants were instructed to apply the product in the evening after using a gentle cleanser, which also was to be used in the morning to remove the product residue. Additionally, participants were given a sunscreen with a sun protection factor of 30 to apply daily on the entire face in the morning, after lunch, and midafternoon. During the 30-day treatment period, treatment interruption of up to 5 consecutive days or 10 nonconsecutive days in total was permitted. At day 30, participants received another 30-day supply of the study product and sunscreen to be applied according to the same regimen for an additional 30-day treatment period.

Clinical Evaluation

At baseline, demographic data and medical history was recorded for all participants and dermatologic and physical examination was performed documenting weight, height, blood pressure, heart rate, and baseline MASI score. Following Wood lamp examination, participants’ faces were photographed and catalogued using medical imaging software that allowed for measurement of the total melasma surface area (Figure 1A). The photographs also were cross-polarized for further analysis of the pigmentation (Figure 1B).

    

Figure 1. Clinical (A) and cross-polarized (B) photographs of a patient before treatment with the novel compound containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05%.

A questionnaire evaluating treatment satisfaction was administered to participants (ITTe population [n=33]) at baseline and days 30 and 60. Questionnaire items pertained to skin blemishes, signs of facial aging, overall appearance, texture, oiliness, brightness, and hydration. Participants were instructed to rate their satisfaction for each item on a scale of 1 to 10 (1=bad, 10=excellent). For investigator analysis, scores of 1 to 4 were classified as “dissatisfied,” scores of 5 to 6 were classified as “satisfied,” and scores of 7 to 10 were classified as “completely satisfied.” A questionnaire evaluating product appreciation was administered at day 60 to participants who completed the study (n=29). Questionnaire items asked participants to rate the study cream’s ease of application, consistency, smell, absorption, and overall satisfaction using ratings of “bad,” “regular,” “good,” “very good,” or “excellent.”

Treatment efficacy in all participants was assessed by the investigators at days 30 and 60. Investigators evaluated reductions in pigmentation and total melasma surface area using ratings of “none,” “regular,” “good,” “very good,” or “excellent.” Local tolerance also was evaluated at both time points, and AEs were recorded and analyzed with respect to their duration, intensity, frequency, and severity.

Targeted hyperpigmented skin was selected for in vivo RCM analysis. At each time point, a sequence of block images was acquired at 4 levels of skin: (1) superficial dermis, (2) suprabasal layer/ dermoepidermal junction, (3) spinous layer, and (4) superficial granular layer. Blind evaluation of these images to assess the reduction in melanin quantity was conducted by a dermatopathologist at baseline and days 30 and 60. Melanin quantity present in each layer was graded according to 4 categories (0%–25%, 25.1%–50%, 50.1%–75%, 75.1%–100%). The mean value was used for statistical evaluation.

Results

Efficacy evaluation

The primary efficacy variable was the mean reduction in MASI score from baseline to the end of treatment (day 60), which was 2.25 ± 1.87 (P<.0001). The reduction in mean MASI score was significant from baseline to day 30 (P<.0001) and from day 30 to day 60 (P<.0001). The least root-mean-square error estimates of MASI score variation at days 30 and 60 were 1.40 and 2.25, respectively.

The mean total melasma surface area (as measured in analysis of clinical photographs using medical imaging software) was significantly reduced from 1398.5 mm2 at baseline to 1116.9 mm2 at day 30 (P<.0001) and 923.4 at day 60 (P<.0001). From baseline to end of treatment, the overall reduction in mean total melasma surface area was 475.1 mm2 (P<.0001)(Figure 2). Clinical and cross-polarized photographs taken at day 60 demonstrated a visible reduction in melasma surface area (Figure 3), which was confirmed using medical imaging software.

 

 

Figure 2. Mean surface area of melasma measured at baseline (1398.5 mm2), day 30 (1116.9 mm2), and day 60 (923.4 mm2), showing a mean total reduction of 475.1 mm2 from baseline to day 60.

  

Figure 3. Clinical (A) and cross-polarized (B) photographs of a patient after 60 days of treatment with the novel compound containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05%.

In vivo RCM analyses at each time point showed reduction in pigmentation in the 4 levels of the skin that were evaluated, but the results were not statistically significant.

Participant satisfaction

There was strong statistical evidence of patient satisfaction with the treatment results at the end of the study period (P<.0001). At baseline, 75.8% (25/33) of participants were dissatisfied with the appearance of their skin as compared with 15.2% (5/33) at day 60. Additionally, 18.1% (6/33) and 6.1% (2/33) of the participants were satisfied and completely satisfied at baseline compared with 33.3% (11/33) and 51.5% (17/33) at day 60, respectively. Participant satisfaction with signs of facial aging also increased over the study period (P=.0104). At baseline, 60.6% (20/33) were dissatisfied, 12.1% (4/33) were satisfied, and 27.3% (9/33) were completely satisfied; at the end of treatment, 30.3% (10/33) were dissatisfied, 36.4% (12/33) were satisfied, and 33.3% (11/33) were completely satisfied with the improvement in signs of facial aging.

Increased patient satisfaction with facial skin texture at baseline compared to day 60 also was statistically significant (P=.0157). At baseline, 39.4% (13/33) of the participants were dissatisfied, 30.3% (10/33) were satisfied, and 30.3% (10/33) were completely satisfied with facial texture; at day 60, 15.1% (5/33) were dissatisfied, 30.3% (10/33) were satisfied, and 54.6% (18/33) were completely satisfied. Significant improvement from baseline to day 60 also was observed in participant assessment of skin oiliness (P=.0210), brightness (P=.0003), overall appearance (P<.0001), and hydration (P<.0001).

Product appreciation

At day 60, 89.7% (26/29) of the participants who completed the study rated the product’s ease of application as being at least “good,” with more than half of participants (55.2% [16/29]) rating it as “very good” or “excellent.” Overall satisfaction with the product was rated as “very good” or “excellent” by 48.3% (14/29) of the participants. Similar results were observed in participant assessments of consistency, smell, and absorption (Figure 4).

Figure 4. Participant responses to product appreciation questionnaire.

Safety evaluation

A total of 52 AEs were observed in 23 (69.7%) participants, which were recorded by participants in diary entries throughout treatment and evaluated by investigators at each time point. Among these AEs, 48 (92.3%) were considered possibly, probably, or conditionally related to treatment by the investigators based on clinical observation. The most common presumed treatment-related AE was a burning sensation on the skin, reported by 30.3% (10/33) of the participants at day 30 and 13.8% (4/29) at day 60. Of the reported AEs related to treatment, 91.7% (44/48) were of mild intensity and 93.8% (45/48) required no treatment or other action. There were no reported serious AEs related to the investigational product. Blood pressure, heart rate, and weight remained stable among all participants throughout the study.

The intensity of the AEs was described as “light” in 91.7% (44/48) of cases and “moderate” in 8.3% (4/48) of cases. The frequency of AEs was classified as “unique,” “intermittent,” or “continuous” in 45.8% (22/48), 39.6% (19/48), and14.6% (7/48) of cases, respectively. Of the 48 AEs, 3 (6.3%) occurred in 1 participant, necessitating interruption of treatment, application of the topical corticosteroid cream mometasone, and removal from the study.

Comment

Following treatment with the study cream containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05%, the mean reduction in MASI score (P<.0001) and the mean reduction in total melasma surface area from baseline to end of treatment were statistically significant (P<.0001). The study product was associated with strong statistical evidence of patient satisfaction (P<.0001) regarding improvement in facial skin texture, skin oiliness, brightness, overall appearance, and hydration. Participants also responded favorably to the product and considered it safe and effective. In vivo RCM analysis demonstrated a reduction in the amount of melanin in 4 levels of the skin (superficial dermis, suprabasal layer/dermoepidermal junction, spinous layer, superficial granular layer) following treatment with the study cream; however, over the course of the 60-day treatment period, it did not reveal statistically significant reductions. This finding likely is due to the large ranges used to classify the amount of melanin present in each layer of the skin. These limitations suggest that scales used in future in vivo RCM analyses of melasma should be narrower.

 

 

Epidermal melasma is one of the most difficult dermatologic diseases to treat and control. Maintenance of clear, undamaged skin remains a treatment target for all dermatologists. This novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05% has proven to be an effective, safe, and tolerable treatment option for patients with epidermal melasma.

Epidermal melasma is a common hyperpigmentation disorder that can be challenging to treat. The pathogenesis of melasma is not fully understood but has been associated with increased melanin and melanocyte activity.1,2 Melasma is characterized by jagged, light- to dark-brown patches on areas of the skin most often exposed to the sun—primarily the cheeks, forehead, upper lip, nose, and chin.3 Although it can affect both sexes and all races, melasma is more common in Fitzpatrick skin types II to IV and frequently is seen in Asian or Hispanic women residing in geographic locations with high levels of sun exposure (eg, tropical areas).2 Melasma presents more frequently in adult women of childbearing age, especially during pregnancy, but also can begin postmenopause. Onset may occur as early as menarche but typically is observed between the ages of 30 and 55 years.3,4 Only 10% of melasma cases are known to occur in males4 and are influenced by such factors as ethnicity, hormones, and level of sun exposure.2

Topical therapies for melasma attempt to inhibit melanocytic activation at each level of melanin formation until the deposited pigment is removed; however, results may vary greatly, as melasma often recurs due to the migration of new melanocytes from hair follicles to the skin’s surface, leading to new development of hyperpigmentation. The current standard of treatment for melasma involves the use of hydroquinone and other bleaching agents, but long-term use of these treatments has been associated with concerns regarding unstable preparations (which may lose their therapeutic properties) and adverse effects (eg, ochronosis, depigmentation).5 Cosmetic agents that recently have been evaluated for melasma treatment include nicotinamide (a form of vitamin B3), which inhibits the transfer of melanosomes from melanocytes to keratinocytes; arbutin, which inhibits melanin synthesis by inhibiting tyrosinase activity6; bisabolol, which prevents anti-inflammatory activity7; and retinaldehyde (RAL), a precursor of retinoic acid (RA) that has powerful bleaching action and low levels of cutaneous irritability.8

This prospective, single-arm, open-label study, evaluated the efficacy and safety of a novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05% in the treatment of epidermal melasma.

Study Product Ingredients and Background

Nicotinamide

Nicotinamide is a water-soluble amide of nicotinic acid (niacin) and one of the 2 principal forms of vitamin B3. It is a component of the coenzymes nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate. Nicotinamide essentially acts as an antioxidant, with most of its effects exerted through poly(adenosine diphosphate–ribose) polymerase inhibition. Interest has increased in the role of nicotinamide in the prevention and treatment of several skin diseases, such as acne and UV radiation–induced deleterious molecular and immunological events. Nicotinamide also has gained consideration as a potential agent in sunscreen preparations due to its possible skin-lightening effects, stimulation of DNA repair, suppression of UV photocarcinogenesis, and other antiaging effects.9

Arbutin

Arbutin is a molecule that has proven effective in treating melasma.10 Its pigment-lightening ingredients include botanicals that are structurally similar to hydroquinone. Arbutin is obtained from the leaves of the bearberry plant but also is found in lesser quantities in cranberry and blueberry leaves. A naturally occurring gluconopyranoside, arbutin reduces tyrosinase activity without affecting messenger RNA expression.11 Arbutin also inhibits melanosome maturation, is nontoxic to melanocytes, and is used in Japan in a variety of pigment-lightening preparations at 3% concentrations.12

Bisabolol

Bisabolol is a natural monocyclic sesquiterpene alcohol found in the oils of chamomile and other plants. Bisabolol often is included in cosmetics due to its favorable anti-inflammatory and depigmentation properties. Its downregulation of inducible nitric oxide synthase and cyclooxygenase-2 suggests that it may have anti-inflammatory effects.7

Retinaldehyde

Retinaldehyde is an RA precursor that forms as an intermediate metabolite in the transformation of retinol to RA in human keratinocytes. Topical RAL is well tolerated by human skin, and several of its biologic effects are identical to those of RA. Using the tails of C57BL/6 mouse models, RAL 0.05% has been found to have significantly more potent depigmenting effects than RA 0.05% (P<.001 vs P<.01, respectively) when compared to vehicle.13

Although combination therapy with RAL and arbutin could potentially cause skin irritation, the addition of bisabolol to the combination cream used in this study is believed to have conferred anti-inflammatory properties because it inhibits the release of histamine and relieves irritation.

Methods

This single-center, single-arm, prospective, open-label study evaluated the efficacy and safety of a novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05% in treating epidermal melasma. Clinical evaluation included assessment of Melasma Area and Severity Index (MASI) score, photographic analysis, and in vivo reflectance confocal microscopy (RCM) analysis.

 

 

The study population included women aged 18 to 50 years with Fitzpatrick skin types I through V who had clinically diagnosed epidermal melasma on the face. Eligibility requirements included confirmation of epidermal pigmentation on Wood lamp examination and RCM analysis and a MASI score of less than 10.5. A total of 35 participants were enrolled in the study (intention to treat [ITT] population). Thirty-three participants were included in the analysis of treatment effectiveness (ITTe population), as 2 were excluded due to lack of follow-up postbaseline. Four participants were prematurely withdrawn from the study—3 due to loss to follow-up and 1 due to treatment discontinuation following an adverse event (AE). The last observation carried forward method was used to input missing data from these 4 participants excluding repeated measure analysis that used the generalized estimated equation method.

At baseline, a 25-g tube of the study cream containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05% was distributed to all participants for once-daily application to the entire face for 30 days. Participants were instructed to apply the product in the evening after using a gentle cleanser, which also was to be used in the morning to remove the product residue. Additionally, participants were given a sunscreen with a sun protection factor of 30 to apply daily on the entire face in the morning, after lunch, and midafternoon. During the 30-day treatment period, treatment interruption of up to 5 consecutive days or 10 nonconsecutive days in total was permitted. At day 30, participants received another 30-day supply of the study product and sunscreen to be applied according to the same regimen for an additional 30-day treatment period.

Clinical Evaluation

At baseline, demographic data and medical history was recorded for all participants and dermatologic and physical examination was performed documenting weight, height, blood pressure, heart rate, and baseline MASI score. Following Wood lamp examination, participants’ faces were photographed and catalogued using medical imaging software that allowed for measurement of the total melasma surface area (Figure 1A). The photographs also were cross-polarized for further analysis of the pigmentation (Figure 1B).

    

Figure 1. Clinical (A) and cross-polarized (B) photographs of a patient before treatment with the novel compound containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05%.

A questionnaire evaluating treatment satisfaction was administered to participants (ITTe population [n=33]) at baseline and days 30 and 60. Questionnaire items pertained to skin blemishes, signs of facial aging, overall appearance, texture, oiliness, brightness, and hydration. Participants were instructed to rate their satisfaction for each item on a scale of 1 to 10 (1=bad, 10=excellent). For investigator analysis, scores of 1 to 4 were classified as “dissatisfied,” scores of 5 to 6 were classified as “satisfied,” and scores of 7 to 10 were classified as “completely satisfied.” A questionnaire evaluating product appreciation was administered at day 60 to participants who completed the study (n=29). Questionnaire items asked participants to rate the study cream’s ease of application, consistency, smell, absorption, and overall satisfaction using ratings of “bad,” “regular,” “good,” “very good,” or “excellent.”

Treatment efficacy in all participants was assessed by the investigators at days 30 and 60. Investigators evaluated reductions in pigmentation and total melasma surface area using ratings of “none,” “regular,” “good,” “very good,” or “excellent.” Local tolerance also was evaluated at both time points, and AEs were recorded and analyzed with respect to their duration, intensity, frequency, and severity.

Targeted hyperpigmented skin was selected for in vivo RCM analysis. At each time point, a sequence of block images was acquired at 4 levels of skin: (1) superficial dermis, (2) suprabasal layer/ dermoepidermal junction, (3) spinous layer, and (4) superficial granular layer. Blind evaluation of these images to assess the reduction in melanin quantity was conducted by a dermatopathologist at baseline and days 30 and 60. Melanin quantity present in each layer was graded according to 4 categories (0%–25%, 25.1%–50%, 50.1%–75%, 75.1%–100%). The mean value was used for statistical evaluation.

Results

Efficacy evaluation

The primary efficacy variable was the mean reduction in MASI score from baseline to the end of treatment (day 60), which was 2.25 ± 1.87 (P<.0001). The reduction in mean MASI score was significant from baseline to day 30 (P<.0001) and from day 30 to day 60 (P<.0001). The least root-mean-square error estimates of MASI score variation at days 30 and 60 were 1.40 and 2.25, respectively.

The mean total melasma surface area (as measured in analysis of clinical photographs using medical imaging software) was significantly reduced from 1398.5 mm2 at baseline to 1116.9 mm2 at day 30 (P<.0001) and 923.4 at day 60 (P<.0001). From baseline to end of treatment, the overall reduction in mean total melasma surface area was 475.1 mm2 (P<.0001)(Figure 2). Clinical and cross-polarized photographs taken at day 60 demonstrated a visible reduction in melasma surface area (Figure 3), which was confirmed using medical imaging software.

 

 

Figure 2. Mean surface area of melasma measured at baseline (1398.5 mm2), day 30 (1116.9 mm2), and day 60 (923.4 mm2), showing a mean total reduction of 475.1 mm2 from baseline to day 60.

  

Figure 3. Clinical (A) and cross-polarized (B) photographs of a patient after 60 days of treatment with the novel compound containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05%.

In vivo RCM analyses at each time point showed reduction in pigmentation in the 4 levels of the skin that were evaluated, but the results were not statistically significant.

Participant satisfaction

There was strong statistical evidence of patient satisfaction with the treatment results at the end of the study period (P<.0001). At baseline, 75.8% (25/33) of participants were dissatisfied with the appearance of their skin as compared with 15.2% (5/33) at day 60. Additionally, 18.1% (6/33) and 6.1% (2/33) of the participants were satisfied and completely satisfied at baseline compared with 33.3% (11/33) and 51.5% (17/33) at day 60, respectively. Participant satisfaction with signs of facial aging also increased over the study period (P=.0104). At baseline, 60.6% (20/33) were dissatisfied, 12.1% (4/33) were satisfied, and 27.3% (9/33) were completely satisfied; at the end of treatment, 30.3% (10/33) were dissatisfied, 36.4% (12/33) were satisfied, and 33.3% (11/33) were completely satisfied with the improvement in signs of facial aging.

Increased patient satisfaction with facial skin texture at baseline compared to day 60 also was statistically significant (P=.0157). At baseline, 39.4% (13/33) of the participants were dissatisfied, 30.3% (10/33) were satisfied, and 30.3% (10/33) were completely satisfied with facial texture; at day 60, 15.1% (5/33) were dissatisfied, 30.3% (10/33) were satisfied, and 54.6% (18/33) were completely satisfied. Significant improvement from baseline to day 60 also was observed in participant assessment of skin oiliness (P=.0210), brightness (P=.0003), overall appearance (P<.0001), and hydration (P<.0001).

Product appreciation

At day 60, 89.7% (26/29) of the participants who completed the study rated the product’s ease of application as being at least “good,” with more than half of participants (55.2% [16/29]) rating it as “very good” or “excellent.” Overall satisfaction with the product was rated as “very good” or “excellent” by 48.3% (14/29) of the participants. Similar results were observed in participant assessments of consistency, smell, and absorption (Figure 4).

Figure 4. Participant responses to product appreciation questionnaire.

Safety evaluation

A total of 52 AEs were observed in 23 (69.7%) participants, which were recorded by participants in diary entries throughout treatment and evaluated by investigators at each time point. Among these AEs, 48 (92.3%) were considered possibly, probably, or conditionally related to treatment by the investigators based on clinical observation. The most common presumed treatment-related AE was a burning sensation on the skin, reported by 30.3% (10/33) of the participants at day 30 and 13.8% (4/29) at day 60. Of the reported AEs related to treatment, 91.7% (44/48) were of mild intensity and 93.8% (45/48) required no treatment or other action. There were no reported serious AEs related to the investigational product. Blood pressure, heart rate, and weight remained stable among all participants throughout the study.

The intensity of the AEs was described as “light” in 91.7% (44/48) of cases and “moderate” in 8.3% (4/48) of cases. The frequency of AEs was classified as “unique,” “intermittent,” or “continuous” in 45.8% (22/48), 39.6% (19/48), and14.6% (7/48) of cases, respectively. Of the 48 AEs, 3 (6.3%) occurred in 1 participant, necessitating interruption of treatment, application of the topical corticosteroid cream mometasone, and removal from the study.

Comment

Following treatment with the study cream containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05%, the mean reduction in MASI score (P<.0001) and the mean reduction in total melasma surface area from baseline to end of treatment were statistically significant (P<.0001). The study product was associated with strong statistical evidence of patient satisfaction (P<.0001) regarding improvement in facial skin texture, skin oiliness, brightness, overall appearance, and hydration. Participants also responded favorably to the product and considered it safe and effective. In vivo RCM analysis demonstrated a reduction in the amount of melanin in 4 levels of the skin (superficial dermis, suprabasal layer/dermoepidermal junction, spinous layer, superficial granular layer) following treatment with the study cream; however, over the course of the 60-day treatment period, it did not reveal statistically significant reductions. This finding likely is due to the large ranges used to classify the amount of melanin present in each layer of the skin. These limitations suggest that scales used in future in vivo RCM analyses of melasma should be narrower.

 

 

Epidermal melasma is one of the most difficult dermatologic diseases to treat and control. Maintenance of clear, undamaged skin remains a treatment target for all dermatologists. This novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05% has proven to be an effective, safe, and tolerable treatment option for patients with epidermal melasma.

References

1. Grimes PE, Yamada N, Bhawan J. Light microscopic, immunohistochemical, and ultrastructural alterations in patients with melasma. Am J Dermatopathol. 2005;27:96-101.

2. Kang WH, Yoon KH, Lee ES, et al. Melasma: histopathological characteristics in 56 Korean patients. Br J Dermatol. 2002;146:228-237.

3. Cestari T, Arellano I, Hexsel D, et al. Melasma in Latin America: options the therapy and treatment algorithm. JEADV. 2009;23:760-772.

4. Miot LDB, Miot HA, Silva MG, et al. Fisiopatologia do Melasma. An Bras Dermatol. 2009;84:623-635.

5. Draelos Z. Skin lightening preparations and the hydroquinone controversy. Dermatol Ther. 2007;20:308-313.

6. Parvez S, Kang M, Chung HS, et al. Survey and mechanism of skin depigmenting and lightening agents. Phytoter Res. 2006;20:921-934.

7. Kim S, Jung E, Kim JH, et al. Inhibitory effects of (-)-α-bisabolol on LPS-induced inflammatory response in RAW264.7 macrophages. Food Chem Toxicol. 2011;49:2580-2585.

8. Ortonne JP. Retinoid therapy of pigmentary disorders. Dermatol Ther. 2006;19:280-288.

9. Namazi MR. Nicotinamide-containing sunscreens for use in Australasian countries and cancer-provoking conditions. Med Hypotheses. 2003;60:544-545.

10. Ertam I, Mutlu B, Unal I, et al. Efficiency of ellagic acid and arbutin in melasma: a randomized, prospective, open-label study. J Dermatol. 2008;35:570-574.

11. Hori I, Nihei K, Kubo I. Structural criteria for depigmenting mechanism of arbutin. Phytother Res. 2004;18:475-469.

12. Ethnic skin and pigmentation. In: Draelos ZD. Cosmetics and Dermatologic Problems and Solutions. 3rd ed. Boca Raton, FL: CRC Press; 2011:52-55.

13. Kasraee B, Tran C, Sorg O, et al. The depigmenting effect of RALGA in C57BL/6 mice. Dermatology. 2005;210(suppl 1):30-34.

References

1. Grimes PE, Yamada N, Bhawan J. Light microscopic, immunohistochemical, and ultrastructural alterations in patients with melasma. Am J Dermatopathol. 2005;27:96-101.

2. Kang WH, Yoon KH, Lee ES, et al. Melasma: histopathological characteristics in 56 Korean patients. Br J Dermatol. 2002;146:228-237.

3. Cestari T, Arellano I, Hexsel D, et al. Melasma in Latin America: options the therapy and treatment algorithm. JEADV. 2009;23:760-772.

4. Miot LDB, Miot HA, Silva MG, et al. Fisiopatologia do Melasma. An Bras Dermatol. 2009;84:623-635.

5. Draelos Z. Skin lightening preparations and the hydroquinone controversy. Dermatol Ther. 2007;20:308-313.

6. Parvez S, Kang M, Chung HS, et al. Survey and mechanism of skin depigmenting and lightening agents. Phytoter Res. 2006;20:921-934.

7. Kim S, Jung E, Kim JH, et al. Inhibitory effects of (-)-α-bisabolol on LPS-induced inflammatory response in RAW264.7 macrophages. Food Chem Toxicol. 2011;49:2580-2585.

8. Ortonne JP. Retinoid therapy of pigmentary disorders. Dermatol Ther. 2006;19:280-288.

9. Namazi MR. Nicotinamide-containing sunscreens for use in Australasian countries and cancer-provoking conditions. Med Hypotheses. 2003;60:544-545.

10. Ertam I, Mutlu B, Unal I, et al. Efficiency of ellagic acid and arbutin in melasma: a randomized, prospective, open-label study. J Dermatol. 2008;35:570-574.

11. Hori I, Nihei K, Kubo I. Structural criteria for depigmenting mechanism of arbutin. Phytother Res. 2004;18:475-469.

12. Ethnic skin and pigmentation. In: Draelos ZD. Cosmetics and Dermatologic Problems and Solutions. 3rd ed. Boca Raton, FL: CRC Press; 2011:52-55.

13. Kasraee B, Tran C, Sorg O, et al. The depigmenting effect of RALGA in C57BL/6 mice. Dermatology. 2005;210(suppl 1):30-34.

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A Novel Cream Formulation Containing Nicotinamide 4%, Arbutin 3%, Bisabolol 1%, and Retinaldehyde 0.05% for Treatment of Epidermal Melasma
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A Novel Cream Formulation Containing Nicotinamide 4%, Arbutin 3%, Bisabolol 1%, and Retinaldehyde 0.05% for Treatment of Epidermal Melasma
Legacy Keywords
melasma, topical treatment, cosmetic, hydroquinone, skin lightening, pigmentation, melanin, pigmentation disorder
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    Practice Points

  • Epidermal melasma is a common hyperpigmentation disorder characterized by the appearance of abnormal melanin deposits in different layers of the skin.
  • Melasma can be difficult to treat and often recurs due to the migration of new melanocytes from hair follicles to the skin’s surface.
  • A novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05% offers a safe and effective option for treatment of epidermal melasma.
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What Is Your Diagnosis? Idiopathic Guttate Hypomelanosis

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What Is Your Diagnosis? Idiopathic Guttate Hypomelanosis

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.1 Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.1 The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.2

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.1 Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.6 Shin et al1 reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.2 The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.7 Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.10-12 CO2 lasers also have demonstrated promising results.13

References
  1. Shin MK, Jeong KH, Oh IH, et al. Clinical features of idiopathic guttate hypomelanosis in 646 subjects and association with other aspects of photoaging. Int J Dermatol. 2011;50:798-805.
  2. Kim SK, Kim EH, Kang HY, et al. Comprehensive understanding of idiopathic guttate hypomelanosis: clinical 
and histopathological correlation. Int J Dermatol. 2010;49:162-166.
  3. Friedland R, David M, Feinmesser M, et al. Idiopathic guttate hypomelanosis-like lesions in patients with mycosis fungoides: a new adverse effect of phototherapy. 
J Eur Acad Dermatol Venereol. 2010;24:1026-1030.
  4. Kaya TI, Yazici AC, Tursen U, et al. Idiopathic guttate hypomelanosis: idiopathic or ultraviolet induced? 
Photodermatol Photoimmunol Photomed. 2005;21:270-271.
  5. Loquai C, Metze D, Nashan D, et al. Confetti-like lesions with hyperkeratosis: a novel ultraviolet-induced hypomelanotic disorder? Br J Dermatol. 2005;153:190-193.
  6. Arrunategui A, Trujillo RA, Marulanda MP, et al. 
HLA-DQ3 is associated with idiopathic guttate 
hypomelanosis, whereas HLA-DR8 is not, in a group 
of renal transplant patients. Int J Dermatol. 
2002;41:744-747.
  7. Wallace ML, Grichnik JM, Prieto VG, et al. Numbers and differentiation status of melanocytes in idiopathic guttate hypomelanosis. J Cutan Pathol. 1998;25:375-379.
  8. Ortonne JP, Perrot H. Idiopathic guttate hypomelanosis. ultrastructural study. Arch Dermatol. 1980;116:664-668.
  9. Rerknimitr P, Disphanurat W, Achariyakul M. 
Topical tacrolimus significantly promotes repigmentation in idiopathic guttate hypomelanosis: a double-blind, randomized, placebo-controlled study. J Eur Acad Dermatol Venereol. 2013;27:460-464.
  10. Pagnoni A, Kligman AM, Sadiq I, et al. Hypopigmented macules of photodamaged skin and their treatment with topical tretinoin. Acta Derm Venereol. 1999;79:305-310.
  11. Kumarasinghe SP. 3-5 second cryotherapy is effective 
in idiopathic guttate hypomelanosis. J Dermatol. 2004;31:457-459.
  12. Hexsel DM. Treatment of idiopathic guttate hypomelanosis by localized superficial dermabrasion. Dermatol Surg. 1999;25:917-918.
  13. Shin J, Kim M, Park SH, et al. The effect of fractional carbon dioxide lasers on idiopathic guttate hypomelanosis: a preliminary study. J Eur Acad Dermatol Venereol. 2013;27:e243-e246.
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Mr. Lal is from New York Institute of Technology College of Osteopathic Medicine, Old Westbury. Dr. Kazlouskaya is from and Dr. Elston 
was from the Ackerman Academy of Dermatopathology, New York, New York. Dr. Elston currently is from the Department of Dermatology, Medical University of South Carolina, Charleston.

The authors report no conflict of interest.

Correspondence: Karan Lal, BS, PO Box 8000, Northern Blvd, Old Westbury, NY 11568 ([email protected]).

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Mr. Lal is from New York Institute of Technology College of Osteopathic Medicine, Old Westbury. Dr. Kazlouskaya is from and Dr. Elston 
was from the Ackerman Academy of Dermatopathology, New York, New York. Dr. Elston currently is from the Department of Dermatology, Medical University of South Carolina, Charleston.

The authors report no conflict of interest.

Correspondence: Karan Lal, BS, PO Box 8000, Northern Blvd, Old Westbury, NY 11568 ([email protected]).

Author and Disclosure Information

Mr. Lal is from New York Institute of Technology College of Osteopathic Medicine, Old Westbury. Dr. Kazlouskaya is from and Dr. Elston 
was from the Ackerman Academy of Dermatopathology, New York, New York. Dr. Elston currently is from the Department of Dermatology, Medical University of South Carolina, Charleston.

The authors report no conflict of interest.

Correspondence: Karan Lal, BS, PO Box 8000, Northern Blvd, Old Westbury, NY 11568 ([email protected]).

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Related Articles

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.1 Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.1 The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.2

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.1 Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.6 Shin et al1 reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.2 The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.7 Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.10-12 CO2 lasers also have demonstrated promising results.13

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.1 Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.1 The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.2

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.1 Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.6 Shin et al1 reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.2 The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.7 Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.10-12 CO2 lasers also have demonstrated promising results.13

References
  1. Shin MK, Jeong KH, Oh IH, et al. Clinical features of idiopathic guttate hypomelanosis in 646 subjects and association with other aspects of photoaging. Int J Dermatol. 2011;50:798-805.
  2. Kim SK, Kim EH, Kang HY, et al. Comprehensive understanding of idiopathic guttate hypomelanosis: clinical 
and histopathological correlation. Int J Dermatol. 2010;49:162-166.
  3. Friedland R, David M, Feinmesser M, et al. Idiopathic guttate hypomelanosis-like lesions in patients with mycosis fungoides: a new adverse effect of phototherapy. 
J Eur Acad Dermatol Venereol. 2010;24:1026-1030.
  4. Kaya TI, Yazici AC, Tursen U, et al. Idiopathic guttate hypomelanosis: idiopathic or ultraviolet induced? 
Photodermatol Photoimmunol Photomed. 2005;21:270-271.
  5. Loquai C, Metze D, Nashan D, et al. Confetti-like lesions with hyperkeratosis: a novel ultraviolet-induced hypomelanotic disorder? Br J Dermatol. 2005;153:190-193.
  6. Arrunategui A, Trujillo RA, Marulanda MP, et al. 
HLA-DQ3 is associated with idiopathic guttate 
hypomelanosis, whereas HLA-DR8 is not, in a group 
of renal transplant patients. Int J Dermatol. 
2002;41:744-747.
  7. Wallace ML, Grichnik JM, Prieto VG, et al. Numbers and differentiation status of melanocytes in idiopathic guttate hypomelanosis. J Cutan Pathol. 1998;25:375-379.
  8. Ortonne JP, Perrot H. Idiopathic guttate hypomelanosis. ultrastructural study. Arch Dermatol. 1980;116:664-668.
  9. Rerknimitr P, Disphanurat W, Achariyakul M. 
Topical tacrolimus significantly promotes repigmentation in idiopathic guttate hypomelanosis: a double-blind, randomized, placebo-controlled study. J Eur Acad Dermatol Venereol. 2013;27:460-464.
  10. Pagnoni A, Kligman AM, Sadiq I, et al. Hypopigmented macules of photodamaged skin and their treatment with topical tretinoin. Acta Derm Venereol. 1999;79:305-310.
  11. Kumarasinghe SP. 3-5 second cryotherapy is effective 
in idiopathic guttate hypomelanosis. J Dermatol. 2004;31:457-459.
  12. Hexsel DM. Treatment of idiopathic guttate hypomelanosis by localized superficial dermabrasion. Dermatol Surg. 1999;25:917-918.
  13. Shin J, Kim M, Park SH, et al. The effect of fractional carbon dioxide lasers on idiopathic guttate hypomelanosis: a preliminary study. J Eur Acad Dermatol Venereol. 2013;27:e243-e246.
References
  1. Shin MK, Jeong KH, Oh IH, et al. Clinical features of idiopathic guttate hypomelanosis in 646 subjects and association with other aspects of photoaging. Int J Dermatol. 2011;50:798-805.
  2. Kim SK, Kim EH, Kang HY, et al. Comprehensive understanding of idiopathic guttate hypomelanosis: clinical 
and histopathological correlation. Int J Dermatol. 2010;49:162-166.
  3. Friedland R, David M, Feinmesser M, et al. Idiopathic guttate hypomelanosis-like lesions in patients with mycosis fungoides: a new adverse effect of phototherapy. 
J Eur Acad Dermatol Venereol. 2010;24:1026-1030.
  4. Kaya TI, Yazici AC, Tursen U, et al. Idiopathic guttate hypomelanosis: idiopathic or ultraviolet induced? 
Photodermatol Photoimmunol Photomed. 2005;21:270-271.
  5. Loquai C, Metze D, Nashan D, et al. Confetti-like lesions with hyperkeratosis: a novel ultraviolet-induced hypomelanotic disorder? Br J Dermatol. 2005;153:190-193.
  6. Arrunategui A, Trujillo RA, Marulanda MP, et al. 
HLA-DQ3 is associated with idiopathic guttate 
hypomelanosis, whereas HLA-DR8 is not, in a group 
of renal transplant patients. Int J Dermatol. 
2002;41:744-747.
  7. Wallace ML, Grichnik JM, Prieto VG, et al. Numbers and differentiation status of melanocytes in idiopathic guttate hypomelanosis. J Cutan Pathol. 1998;25:375-379.
  8. Ortonne JP, Perrot H. Idiopathic guttate hypomelanosis. ultrastructural study. Arch Dermatol. 1980;116:664-668.
  9. Rerknimitr P, Disphanurat W, Achariyakul M. 
Topical tacrolimus significantly promotes repigmentation in idiopathic guttate hypomelanosis: a double-blind, randomized, placebo-controlled study. J Eur Acad Dermatol Venereol. 2013;27:460-464.
  10. Pagnoni A, Kligman AM, Sadiq I, et al. Hypopigmented macules of photodamaged skin and their treatment with topical tretinoin. Acta Derm Venereol. 1999;79:305-310.
  11. Kumarasinghe SP. 3-5 second cryotherapy is effective 
in idiopathic guttate hypomelanosis. J Dermatol. 2004;31:457-459.
  12. Hexsel DM. Treatment of idiopathic guttate hypomelanosis by localized superficial dermabrasion. Dermatol Surg. 1999;25:917-918.
  13. Shin J, Kim M, Park SH, et al. The effect of fractional carbon dioxide lasers on idiopathic guttate hypomelanosis: a preliminary study. J Eur Acad Dermatol Venereol. 2013;27:e243-e246.
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A 58-year-old man presented with disseminated, hypopigmented, asymptomatic lesions on the right arm (top) and left leg (bottom) that had been present for approximately 6 years. The patient reported that the lesions had become more visible and greater in number within the last year. 
Multiple circular hypopigmented macules of various sizes ranging from 1 to 3 mm in diameter were identified. No scaling was seen. Physical examination was otherwise unremarkable.

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Top 10 treatments for vitiligo

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PARK CITY, UTAH – At the annual meeting of the Pacific Dermatologic Association, Dr. Sancy A. Leachman offered a top 10 list of new agents and technologies for the treatment of vitiligo.

No. 10: Ultraviolet A1 (UVA1) phototherapy

Dr. Harvey Lui at the University of British Columbia in Vancouver is leading a phase II trial to evaluate the potential for UVA1 to induce repigmentation within vitiligo patches and to assess the side effect profile of the treatment. “I think it might work,” said Dr. Leachman, professor and chair of dermatology at Oregon Health & Science University (OHSU), Portland.

Dr. Sancy A. Leachman

No. 9: Ginkgo biloba

The use of ginko biloba 40-60 mg 2-3 times per day, 10 minutes before a meal, was mentioned in a Cochrane Review of vitiligo treatments published on Feb. 24, 2015. “I think I’m going to give this a try in people who have failed other treatments and see if I can get some response,” Dr. Leachman said.

No. 8: Red light

Dr. Lui is leading a randomized phase II trial of low-intensity and high-intensity red light versus no treatment for vitiligo patches. Treatments will be given twice weekly for 10 weeks, with follow-up assessments at 4, 8, and 12 weeks post treatment.

No. 7: Micrografting

A novel suction blister device known as the CelluTome epidermal harvesting system uses heat and slight vacuum pressure to harvest healthy epidermal skin tissue without damaging the donor site. Dr. Leachman characterized the technology as “semiautomating the process of suction graft transplantation.”

No. 6: The ReCell device

Manufactured by Avita Medical, this investigational autologous cell harvesting device is used after CO2 abrasion and enables clinicians to create regenerative epithelial suspension with a small sample of the patient’s skin. A phase IV trial in the Netherlands is underway to assess the efficacy and safety of autologous epidermal cell suspension grafting with the ReCell device after CO2 laser abrasion, compared with CO2 laser abrasion alone and no treatment, in patients with piebaldism and stable vitiligo.

Courtesy Dr. Sancy A. Leachman
This case of vitiligo demonstrates bilaterally symmetric involvement, a stigmatizing location on the face in a patient with phototype 5 skin, and retention of pigment in the hair follicles, which is a good prognostic sign for response to therapy.

No. 5: Topical Photocil

In a pilot study sponsored by Applied Biology, researchers are enrolling patients with vitiligo to assess the safety and efficacy of Photocil. The primary outcome measure is the Vitiligo Area Severity Index (VASI). “When this cream is activated by sunlight, it degrades into narrow-band and UVB light, so you can put a topical cream on that will administer narrow-band UVB only in that spot,” said Dr. Leachman, who is also director of OHSU’s Knight Melanoma Research Program. “That’s amazing to me.”

No. 4: Afamelanotide

This is an analogue of a melanocyte-stimulating hormone. A randomized study conducted at two academic medical centers found that the combination of afamelanotide implant and narrow-band UVB phototherapy resulted in statistically superior and faster repigmentation, compared with narrow-band UVB monotherapy (JAMA Dermatol. 2015 Jan;151(1):42-50).

No. 3: Abatacept (Orencia)

This is a soluble fusion protein consisting of human cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), which prevents T-cell activation. A phase I trial is underway at Brigham and Women’s Hospital in Boston to determine if weekly self-injections of the agent lead to clinical improvements of vitiligo lesions. The primary outcome measure is change in repigmentation with abatacept therapy based on the VASI score.

No. 2. Simvastatin

The notion of its use is based on STAT1 inhibition reducing interferon-gamma–dependent activation of CD8-positive T cells, according to Dr. Leachman. The concept has been successful in a mouse model, and a study in humans was recently completed by Dr. John Harris at the University of Massachusetts, Worcester. “What we have is the ability to apply an existing drug (Simvastatin) to the process and see if it works,” she said. “Wouldn’t it be cool if we could give a statin and improve vitiligo?”

No 1: Tofacitinib

This is a Janus kinase inhibitor commonly used for rheumatoid arthritis. According to Dr. Leachman, Janus kinase inhibition prevents STAT activation, “which prevents [interferon]-gamma production, which reduces activation of CD8-positive T cells via CXCL10 binding to CXCR3,” she said. A case report demonstrating its efficacy in a 53-year-old patient was recently published in JAMA Dermatology by Dr. Brett A. King and Dr. Brittany Craiglow, dermatologists at Yale School of Medicine, New Haven, Conn. “I’m hopeful that this [agent] will be made into a topical cream because these drugs do have substantial side effects,” Dr. Leachman said.

 

 

Dr. Leachman disclosed that she is a member of the medical and scientific advisory board for Myriad Genetics Laboratory. She has also participated in an advisory board meeting for Castle Biosciences and has participated in the DecisionDx registry.

[email protected]

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PARK CITY, UTAH – At the annual meeting of the Pacific Dermatologic Association, Dr. Sancy A. Leachman offered a top 10 list of new agents and technologies for the treatment of vitiligo.

No. 10: Ultraviolet A1 (UVA1) phototherapy

Dr. Harvey Lui at the University of British Columbia in Vancouver is leading a phase II trial to evaluate the potential for UVA1 to induce repigmentation within vitiligo patches and to assess the side effect profile of the treatment. “I think it might work,” said Dr. Leachman, professor and chair of dermatology at Oregon Health & Science University (OHSU), Portland.

Dr. Sancy A. Leachman

No. 9: Ginkgo biloba

The use of ginko biloba 40-60 mg 2-3 times per day, 10 minutes before a meal, was mentioned in a Cochrane Review of vitiligo treatments published on Feb. 24, 2015. “I think I’m going to give this a try in people who have failed other treatments and see if I can get some response,” Dr. Leachman said.

No. 8: Red light

Dr. Lui is leading a randomized phase II trial of low-intensity and high-intensity red light versus no treatment for vitiligo patches. Treatments will be given twice weekly for 10 weeks, with follow-up assessments at 4, 8, and 12 weeks post treatment.

No. 7: Micrografting

A novel suction blister device known as the CelluTome epidermal harvesting system uses heat and slight vacuum pressure to harvest healthy epidermal skin tissue without damaging the donor site. Dr. Leachman characterized the technology as “semiautomating the process of suction graft transplantation.”

No. 6: The ReCell device

Manufactured by Avita Medical, this investigational autologous cell harvesting device is used after CO2 abrasion and enables clinicians to create regenerative epithelial suspension with a small sample of the patient’s skin. A phase IV trial in the Netherlands is underway to assess the efficacy and safety of autologous epidermal cell suspension grafting with the ReCell device after CO2 laser abrasion, compared with CO2 laser abrasion alone and no treatment, in patients with piebaldism and stable vitiligo.

Courtesy Dr. Sancy A. Leachman
This case of vitiligo demonstrates bilaterally symmetric involvement, a stigmatizing location on the face in a patient with phototype 5 skin, and retention of pigment in the hair follicles, which is a good prognostic sign for response to therapy.

No. 5: Topical Photocil

In a pilot study sponsored by Applied Biology, researchers are enrolling patients with vitiligo to assess the safety and efficacy of Photocil. The primary outcome measure is the Vitiligo Area Severity Index (VASI). “When this cream is activated by sunlight, it degrades into narrow-band and UVB light, so you can put a topical cream on that will administer narrow-band UVB only in that spot,” said Dr. Leachman, who is also director of OHSU’s Knight Melanoma Research Program. “That’s amazing to me.”

No. 4: Afamelanotide

This is an analogue of a melanocyte-stimulating hormone. A randomized study conducted at two academic medical centers found that the combination of afamelanotide implant and narrow-band UVB phototherapy resulted in statistically superior and faster repigmentation, compared with narrow-band UVB monotherapy (JAMA Dermatol. 2015 Jan;151(1):42-50).

No. 3: Abatacept (Orencia)

This is a soluble fusion protein consisting of human cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), which prevents T-cell activation. A phase I trial is underway at Brigham and Women’s Hospital in Boston to determine if weekly self-injections of the agent lead to clinical improvements of vitiligo lesions. The primary outcome measure is change in repigmentation with abatacept therapy based on the VASI score.

No. 2. Simvastatin

The notion of its use is based on STAT1 inhibition reducing interferon-gamma–dependent activation of CD8-positive T cells, according to Dr. Leachman. The concept has been successful in a mouse model, and a study in humans was recently completed by Dr. John Harris at the University of Massachusetts, Worcester. “What we have is the ability to apply an existing drug (Simvastatin) to the process and see if it works,” she said. “Wouldn’t it be cool if we could give a statin and improve vitiligo?”

No 1: Tofacitinib

This is a Janus kinase inhibitor commonly used for rheumatoid arthritis. According to Dr. Leachman, Janus kinase inhibition prevents STAT activation, “which prevents [interferon]-gamma production, which reduces activation of CD8-positive T cells via CXCL10 binding to CXCR3,” she said. A case report demonstrating its efficacy in a 53-year-old patient was recently published in JAMA Dermatology by Dr. Brett A. King and Dr. Brittany Craiglow, dermatologists at Yale School of Medicine, New Haven, Conn. “I’m hopeful that this [agent] will be made into a topical cream because these drugs do have substantial side effects,” Dr. Leachman said.

 

 

Dr. Leachman disclosed that she is a member of the medical and scientific advisory board for Myriad Genetics Laboratory. She has also participated in an advisory board meeting for Castle Biosciences and has participated in the DecisionDx registry.

[email protected]

PARK CITY, UTAH – At the annual meeting of the Pacific Dermatologic Association, Dr. Sancy A. Leachman offered a top 10 list of new agents and technologies for the treatment of vitiligo.

No. 10: Ultraviolet A1 (UVA1) phototherapy

Dr. Harvey Lui at the University of British Columbia in Vancouver is leading a phase II trial to evaluate the potential for UVA1 to induce repigmentation within vitiligo patches and to assess the side effect profile of the treatment. “I think it might work,” said Dr. Leachman, professor and chair of dermatology at Oregon Health & Science University (OHSU), Portland.

Dr. Sancy A. Leachman

No. 9: Ginkgo biloba

The use of ginko biloba 40-60 mg 2-3 times per day, 10 minutes before a meal, was mentioned in a Cochrane Review of vitiligo treatments published on Feb. 24, 2015. “I think I’m going to give this a try in people who have failed other treatments and see if I can get some response,” Dr. Leachman said.

No. 8: Red light

Dr. Lui is leading a randomized phase II trial of low-intensity and high-intensity red light versus no treatment for vitiligo patches. Treatments will be given twice weekly for 10 weeks, with follow-up assessments at 4, 8, and 12 weeks post treatment.

No. 7: Micrografting

A novel suction blister device known as the CelluTome epidermal harvesting system uses heat and slight vacuum pressure to harvest healthy epidermal skin tissue without damaging the donor site. Dr. Leachman characterized the technology as “semiautomating the process of suction graft transplantation.”

No. 6: The ReCell device

Manufactured by Avita Medical, this investigational autologous cell harvesting device is used after CO2 abrasion and enables clinicians to create regenerative epithelial suspension with a small sample of the patient’s skin. A phase IV trial in the Netherlands is underway to assess the efficacy and safety of autologous epidermal cell suspension grafting with the ReCell device after CO2 laser abrasion, compared with CO2 laser abrasion alone and no treatment, in patients with piebaldism and stable vitiligo.

Courtesy Dr. Sancy A. Leachman
This case of vitiligo demonstrates bilaterally symmetric involvement, a stigmatizing location on the face in a patient with phototype 5 skin, and retention of pigment in the hair follicles, which is a good prognostic sign for response to therapy.

No. 5: Topical Photocil

In a pilot study sponsored by Applied Biology, researchers are enrolling patients with vitiligo to assess the safety and efficacy of Photocil. The primary outcome measure is the Vitiligo Area Severity Index (VASI). “When this cream is activated by sunlight, it degrades into narrow-band and UVB light, so you can put a topical cream on that will administer narrow-band UVB only in that spot,” said Dr. Leachman, who is also director of OHSU’s Knight Melanoma Research Program. “That’s amazing to me.”

No. 4: Afamelanotide

This is an analogue of a melanocyte-stimulating hormone. A randomized study conducted at two academic medical centers found that the combination of afamelanotide implant and narrow-band UVB phototherapy resulted in statistically superior and faster repigmentation, compared with narrow-band UVB monotherapy (JAMA Dermatol. 2015 Jan;151(1):42-50).

No. 3: Abatacept (Orencia)

This is a soluble fusion protein consisting of human cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), which prevents T-cell activation. A phase I trial is underway at Brigham and Women’s Hospital in Boston to determine if weekly self-injections of the agent lead to clinical improvements of vitiligo lesions. The primary outcome measure is change in repigmentation with abatacept therapy based on the VASI score.

No. 2. Simvastatin

The notion of its use is based on STAT1 inhibition reducing interferon-gamma–dependent activation of CD8-positive T cells, according to Dr. Leachman. The concept has been successful in a mouse model, and a study in humans was recently completed by Dr. John Harris at the University of Massachusetts, Worcester. “What we have is the ability to apply an existing drug (Simvastatin) to the process and see if it works,” she said. “Wouldn’t it be cool if we could give a statin and improve vitiligo?”

No 1: Tofacitinib

This is a Janus kinase inhibitor commonly used for rheumatoid arthritis. According to Dr. Leachman, Janus kinase inhibition prevents STAT activation, “which prevents [interferon]-gamma production, which reduces activation of CD8-positive T cells via CXCL10 binding to CXCR3,” she said. A case report demonstrating its efficacy in a 53-year-old patient was recently published in JAMA Dermatology by Dr. Brett A. King and Dr. Brittany Craiglow, dermatologists at Yale School of Medicine, New Haven, Conn. “I’m hopeful that this [agent] will be made into a topical cream because these drugs do have substantial side effects,” Dr. Leachman said.

 

 

Dr. Leachman disclosed that she is a member of the medical and scientific advisory board for Myriad Genetics Laboratory. She has also participated in an advisory board meeting for Castle Biosciences and has participated in the DecisionDx registry.

[email protected]

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