Pigmentation Disorders

The Diagnosis: Persistent Still Disease

At the time of presentation, the patient had not taken systemic medications for a year. Laboratory studies revealed leukocytosis with neutrophilia and a serum ferritin level of 5493 ng/mL (reference range, 15-200 ng/mL). Rheumatoid factor and antinuclear antibody serologies were within reference range. Microbiologic workup was negative. Lymph node and bone marrow biopsies were negative for a lymphoproliferative disorder. Skin biopsies were performed on the back and forearm. Histologic evaluation revealed orthokeratosis, slight acanthosis, and dyskeratosis confined to the upper layers of the epidermis without evidence of interface dermatitis. There was a mixed perivascular infiltrate composed of lymphocytes and neutrophils with no attendant vasculitic change (Figure).

The patient was discharged on prednisone and seen for outpatient follow-up weeks later. Six weeks later, the cutaneous eruption remained unchanged. The patient was unable to start other systemic medications due to lack of insurance and ineligibility for the local patient-assistance program; he was subsequently lost to follow-up. 

Adult-onset Still disease is a rare, systemic, inflammatory condition with a broad spectrum of clinical presentations.^1-3 Still disease affects all age groups, and children with Still disease (<16 years) usually have a concurrent diagnosis of juvenile idiopathic arthritis (formerly known as juvenile rheumatoid arthritis).^1,2,4 Still disease preferentially affects adolescents and adults aged 16 to 35 years, with more than 75% of new cases occurring in this age range.¹ Worldwide, the incidence and prevalence of Still disease is disputed with no conclusive rates established.^1,3

Still disease is characterized by 4 cardinal signs: high spiking fevers (temperature, ≥39°C); leukocytosis with a predominance of neutrophils (≥10,000 cells/mm³ with ≥80% neutrophils); arthralgia or arthritis; and an evanescent, nonpruritic, salmon-colored morbilliform eruption of the skin, typically on the trunk or extremities.² Histologic evaluation of the classic Still disease eruption displays perivascular inflammation of the superficial dermis with infiltration by lymphocytes and histiocytes.³

In 1992, major and minor diagnostic criteria were established for adult-onset Still disease. For diagnosis, patients must meet 5 criteria, including 2 major criteria.⁵ Major criteria include arthralgia or arthritis present for more than 2 weeks, fever (temperature, >39°C) for at least 1 week, the classic Still disease morbilliform eruption (ie, salmon colored, evanescent, morbilliform), and leukocytosis with more than 80% neutrophils. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, negative rheumatoid factor and antinuclear antibody serologies, and abnormal liver function (defined as elevated transaminases).⁵ Although not included in the diagnostic criteria, there have been reports of elevated serum ferritin levels in patients with Still disease, a finding that potentially is useful in distinguishing between active and inactive rheumatic conditions.^6,7

Several case reports have described persistent Still disease, a subtype of Still disease in which patients present with brown-red, persistent, pruritic macules, papules, and plaques that are widespread and oddly shaped.^8,9 Histologically, this subtype is characterized by necrotic keratinocytes in the epidermis and dermal perivascular inflammation composed of neutrophils and lymphocytes.¹⁰ This histology differs from classic Still disease in that the latter typically does not have superficial epidermal dyskeratosis. Our case is consistent with reports of persistent Still disease.

Although the etiology of Still disease remains to be elucidated, HLA-B17, -B18, -B35, and -DR2 have been associated with the disease.³ Furthermore, helper T cell T_H1, IL-2, IFN-γ, and tumor necrosis factor α have been implicated in disease pathology, enabling the use of newer targeted pharmacologic therapies. Canakinumab, an IL-1β inhibitor, has been found to improve arthritis, fever, and rash in patients with Still disease.¹¹ These findings are particularly encouraging for patients who have not experienced improvement with traditional antirheumatic drugs, such as our patient who was not steroid responsive.³

Although a salmon-colored, evanescent, morbilliform eruption in the context of other systemic signs and symptoms readily evokes consideration of Still disease, the less common fixed cutaneous eruption seen in our case may evade accurate diagnosis. Our case aims to increase awareness of this unusual and rare subtype of the cutaneous eruption of Still disease, as a timely diagnosis may prevent potentially life-threatening sequelae including cardiopulmonary disease and respiratory failure.^3,5,9

The Diagnosis: Persistent Still Disease

At the time of presentation, the patient had not taken systemic medications for a year. Laboratory studies revealed leukocytosis with neutrophilia and a serum ferritin level of 5493 ng/mL (reference range, 15-200 ng/mL). Rheumatoid factor and antinuclear antibody serologies were within reference range. Microbiologic workup was negative. Lymph node and bone marrow biopsies were negative for a lymphoproliferative disorder. Skin biopsies were performed on the back and forearm. Histologic evaluation revealed orthokeratosis, slight acanthosis, and dyskeratosis confined to the upper layers of the epidermis without evidence of interface dermatitis. There was a mixed perivascular infiltrate composed of lymphocytes and neutrophils with no attendant vasculitic change (Figure).

The patient was discharged on prednisone and seen for outpatient follow-up weeks later. Six weeks later, the cutaneous eruption remained unchanged. The patient was unable to start other systemic medications due to lack of insurance and ineligibility for the local patient-assistance program; he was subsequently lost to follow-up. 

Adult-onset Still disease is a rare, systemic, inflammatory condition with a broad spectrum of clinical presentations.^1-3 Still disease affects all age groups, and children with Still disease (<16 years) usually have a concurrent diagnosis of juvenile idiopathic arthritis (formerly known as juvenile rheumatoid arthritis).^1,2,4 Still disease preferentially affects adolescents and adults aged 16 to 35 years, with more than 75% of new cases occurring in this age range.¹ Worldwide, the incidence and prevalence of Still disease is disputed with no conclusive rates established.^1,3

Still disease is characterized by 4 cardinal signs: high spiking fevers (temperature, ≥39°C); leukocytosis with a predominance of neutrophils (≥10,000 cells/mm³ with ≥80% neutrophils); arthralgia or arthritis; and an evanescent, nonpruritic, salmon-colored morbilliform eruption of the skin, typically on the trunk or extremities.² Histologic evaluation of the classic Still disease eruption displays perivascular inflammation of the superficial dermis with infiltration by lymphocytes and histiocytes.³

In 1992, major and minor diagnostic criteria were established for adult-onset Still disease. For diagnosis, patients must meet 5 criteria, including 2 major criteria.⁵ Major criteria include arthralgia or arthritis present for more than 2 weeks, fever (temperature, >39°C) for at least 1 week, the classic Still disease morbilliform eruption (ie, salmon colored, evanescent, morbilliform), and leukocytosis with more than 80% neutrophils. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, negative rheumatoid factor and antinuclear antibody serologies, and abnormal liver function (defined as elevated transaminases).⁵ Although not included in the diagnostic criteria, there have been reports of elevated serum ferritin levels in patients with Still disease, a finding that potentially is useful in distinguishing between active and inactive rheumatic conditions.^6,7

Several case reports have described persistent Still disease, a subtype of Still disease in which patients present with brown-red, persistent, pruritic macules, papules, and plaques that are widespread and oddly shaped.^8,9 Histologically, this subtype is characterized by necrotic keratinocytes in the epidermis and dermal perivascular inflammation composed of neutrophils and lymphocytes.¹⁰ This histology differs from classic Still disease in that the latter typically does not have superficial epidermal dyskeratosis. Our case is consistent with reports of persistent Still disease.

Although the etiology of Still disease remains to be elucidated, HLA-B17, -B18, -B35, and -DR2 have been associated with the disease.³ Furthermore, helper T cell T_H1, IL-2, IFN-γ, and tumor necrosis factor α have been implicated in disease pathology, enabling the use of newer targeted pharmacologic therapies. Canakinumab, an IL-1β inhibitor, has been found to improve arthritis, fever, and rash in patients with Still disease.¹¹ These findings are particularly encouraging for patients who have not experienced improvement with traditional antirheumatic drugs, such as our patient who was not steroid responsive.³

Although a salmon-colored, evanescent, morbilliform eruption in the context of other systemic signs and symptoms readily evokes consideration of Still disease, the less common fixed cutaneous eruption seen in our case may evade accurate diagnosis. Our case aims to increase awareness of this unusual and rare subtype of the cutaneous eruption of Still disease, as a timely diagnosis may prevent potentially life-threatening sequelae including cardiopulmonary disease and respiratory failure.^3,5,9

The Diagnosis: Persistent Still Disease

At the time of presentation, the patient had not taken systemic medications for a year. Laboratory studies revealed leukocytosis with neutrophilia and a serum ferritin level of 5493 ng/mL (reference range, 15-200 ng/mL). Rheumatoid factor and antinuclear antibody serologies were within reference range. Microbiologic workup was negative. Lymph node and bone marrow biopsies were negative for a lymphoproliferative disorder. Skin biopsies were performed on the back and forearm. Histologic evaluation revealed orthokeratosis, slight acanthosis, and dyskeratosis confined to the upper layers of the epidermis without evidence of interface dermatitis. There was a mixed perivascular infiltrate composed of lymphocytes and neutrophils with no attendant vasculitic change (Figure).

The patient was discharged on prednisone and seen for outpatient follow-up weeks later. Six weeks later, the cutaneous eruption remained unchanged. The patient was unable to start other systemic medications due to lack of insurance and ineligibility for the local patient-assistance program; he was subsequently lost to follow-up. 

Adult-onset Still disease is a rare, systemic, inflammatory condition with a broad spectrum of clinical presentations.^1-3 Still disease affects all age groups, and children with Still disease (<16 years) usually have a concurrent diagnosis of juvenile idiopathic arthritis (formerly known as juvenile rheumatoid arthritis).^1,2,4 Still disease preferentially affects adolescents and adults aged 16 to 35 years, with more than 75% of new cases occurring in this age range.¹ Worldwide, the incidence and prevalence of Still disease is disputed with no conclusive rates established.^1,3

Still disease is characterized by 4 cardinal signs: high spiking fevers (temperature, ≥39°C); leukocytosis with a predominance of neutrophils (≥10,000 cells/mm³ with ≥80% neutrophils); arthralgia or arthritis; and an evanescent, nonpruritic, salmon-colored morbilliform eruption of the skin, typically on the trunk or extremities.² Histologic evaluation of the classic Still disease eruption displays perivascular inflammation of the superficial dermis with infiltration by lymphocytes and histiocytes.³

In 1992, major and minor diagnostic criteria were established for adult-onset Still disease. For diagnosis, patients must meet 5 criteria, including 2 major criteria.⁵ Major criteria include arthralgia or arthritis present for more than 2 weeks, fever (temperature, >39°C) for at least 1 week, the classic Still disease morbilliform eruption (ie, salmon colored, evanescent, morbilliform), and leukocytosis with more than 80% neutrophils. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, negative rheumatoid factor and antinuclear antibody serologies, and abnormal liver function (defined as elevated transaminases).⁵ Although not included in the diagnostic criteria, there have been reports of elevated serum ferritin levels in patients with Still disease, a finding that potentially is useful in distinguishing between active and inactive rheumatic conditions.^6,7

Several case reports have described persistent Still disease, a subtype of Still disease in which patients present with brown-red, persistent, pruritic macules, papules, and plaques that are widespread and oddly shaped.^8,9 Histologically, this subtype is characterized by necrotic keratinocytes in the epidermis and dermal perivascular inflammation composed of neutrophils and lymphocytes.¹⁰ This histology differs from classic Still disease in that the latter typically does not have superficial epidermal dyskeratosis. Our case is consistent with reports of persistent Still disease.

Although the etiology of Still disease remains to be elucidated, HLA-B17, -B18, -B35, and -DR2 have been associated with the disease.³ Furthermore, helper T cell T_H1, IL-2, IFN-γ, and tumor necrosis factor α have been implicated in disease pathology, enabling the use of newer targeted pharmacologic therapies. Canakinumab, an IL-1β inhibitor, has been found to improve arthritis, fever, and rash in patients with Still disease.¹¹ These findings are particularly encouraging for patients who have not experienced improvement with traditional antirheumatic drugs, such as our patient who was not steroid responsive.³

Although a salmon-colored, evanescent, morbilliform eruption in the context of other systemic signs and symptoms readily evokes consideration of Still disease, the less common fixed cutaneous eruption seen in our case may evade accurate diagnosis. Our case aims to increase awareness of this unusual and rare subtype of the cutaneous eruption of Still disease, as a timely diagnosis may prevent potentially life-threatening sequelae including cardiopulmonary disease and respiratory failure.^3,5,9

To the Editor:

A 39-year-old man with a history of hypertension and vitiligo presented with a rapid-onset, generalized, pruritic rash covering the body of 4 weeks’ duration. He reported that the rash progressively worsened after developing mild sunburn. The patient stated that the rash was extremely pruritic with a burning sensation and was tender to touch. He was treated with betamethasone valerate cream 0.1% by an outside physician and an over-the-counter anti-itch lotion with no notable improvement. His only medication was telmisartan-hydrochlorothiazide (HCTZ) for hypertension. He denied any drug allergies.

Physical examination revealed multiple discrete and coalescent planar erythematous papules and plaques involving only the depigmented vitiliginous skin of the forehead, eyelids, and nape of the neck (Figure 1A), and confluent on the lateral aspect of the bilateral forearms (Figure 1B), dorsal aspect of the right hand, and bilateral dorsi of the feet. Wickham striae were noted on the lips (Figure 1C). A clinical diagnosis of lichen planus (LP) was made. The patient initially was prescribed halobetasol propionate ointment 0.05% twice daily. He reported notable relief of pruritus with reduction of overall symptoms and new lesion formation.

A 4-mm punch biopsy was performed on the left forearm. Histopathology revealed LP. Microscopic examination of the hematoxylin and eosin–stained specimen revealed a bandlike lymphohistiocytic infiltrate that extended across the papillary dermis, focally obscuring the dermoepidermal junction where there were vacuolar changes and colloid bodies. The epidermis showed sawtooth rete ridges, wedge-shaped foci of hypergranulosis, and compact hyperkeratosis (Figure 2).

On further questioning during follow-up, the patient revealed that his hypertensive medication was changed from HCTZ, which he had been taking for the last 8 years, to the combination antihypertensive medication telmisartan-HCTZ before the onset of the skin eruption. Due to the temporal relationship between the new medication and onset of the eruption, the clinical impression was highly suspicious for drug-induced eruptive LP with Köbner phenomenon caused by the recent sunburn. Systemic workup for underlying causes of LP was negative. Laboratory tests revealed normal complete blood cell counts. The hepatitis panel included hepatitis A antibodies; hepatitis B surface, e antigen, and core antibodies; hepatitis B surface antigen and e antibodies; hepatitis C antibodies; and antinuclear antibodies, which were all negative.

The patient continued to develop new pruritic papules clinically consistent with LP. He was instructed to return to his primary care physician to change the telmisartan-HCTZ to a different class of antihypertensive medication. His medication was changed to atenolol. The patient also was instructed to continue the halobetasol propionate ointment 0.05% twice daily to the affected areas.

The patient returned for a follow-up visit 1 month later and reported notable improvement in pruritus and near-complete resolution of the LP after discontinuation of telmisartan-HCTZ. He also noted some degree of perifollicular repigmentation of the vitiliginous skin that had been unresponsive to prior therapy (Figure 3).

Lichen planus is a pruritic and inflammatory papulosquamous skin condition that presents as scaly, flat-topped, violaceous, polygonal-shaped papules commonly involving the flexor surface of the arms and legs, oral mucosa, scalp, nails, and genitalia. Clinically, LP can present in various forms including actinic, annular, atrophic, erosive, follicular, hypertrophic, linear, pigmented, and vesicular/bullous types. Koebnerization is common, especially in the linear form of LP. There are no specific laboratory findings or serologic markers seen in LP.

The exact cause of LP remains unknown. Clinical observations and anecdotal evidence have directed the cell-mediated immune response to insulting agents such as medications or contact allergy to metals triggering an abnormal cellular immune response. Various viral agents have been reported including hepatitis C virus, human herpesvirus, herpes simplex virus, and varicella-zoster virus.^1-5 Other factors such as seasonal change and the environment may contribute to the development of LP and an increase in the incidence of LP eruption has been observed from January to July throughout the United States.⁶ Lichen planus also has been associated with other altered immune-related disease such as ulcerative colitis, alopecia areata, vitiligo, dermatomyositis, morphea, lichen sclerosis, and myasthenia gravis.⁷ Increased levels of emotional stress, particularly related to family members, often is related to the onset or aggravation of symptoms.^8,9

Many drug-related LP-like and lichenoid eruptions have been reported with antihypertensive drugs, antimalarial drugs, diuretics, antidepressants, nonsteroidal anti-inflammatory drugs, antimicrobial drugs, and metals. In particular, medications such as captopril, enalapril, labetalol, propranolol, chlorothiazide, HCTZ, methyldopa, chloroquine, hydroxychloroquine, quinacrine, gold salts, penicillamine, and quinidine commonly are reported to induce lichenoid drug eruption.¹⁰

Several inflammatory papulosquamous skin conditions should be considered in the differential diagnosis before confirming the diagnosis of LP. It is important to rule out lupus erythematosus, especially if the oral mucosa and scalp are involved. In addition, erosive paraneoplastic pemphigus involving primarily the oral mucosa can resemble oral LP. Nail diseases such as psoriasis, onychomycosis, and alopecia areata should be considered as the differential diagnosis of nail disease. Genital involvement also can be seen in psoriasis and lichen sclerosus.

Treatment of LP is mainly symptomatic because of the benign nature of the disease and the high spontaneous remission rate with varying amount of time. If drugs, dental/metal implants, or underlying viral infections are the identifiable triggering factors of LP, the offending agents should be discontinued or removed. Additionally, topical or systemic treatments can be given depending on the severity of the disease, focusing mainly on symptomatic relief as well as the balance of risks and benefits associated with treatment.

Treatment options include topical and intralesional corticosteroids. Systemic medications such as oral corticosteroids and/or acitretin commonly are used in acute, severe, and disseminated cases, though treatment duration varies depending on the clinical response. Other systemic agents used to treat LP include griseofulvin, metronidazole, sulfasalazine, cyclosporine, and mycophenolate mofetil.

Phototherapy is considered an alternative therapy, especially for recalcitrant LP. UVA1 and narrowband UVB (wavelength, 311 nm) have been reported to effectively treat long-standing and therapy-resistant LP.¹¹ In addition, a small study used the excimer laser (wavelength, 308 nm), which is well tolerated by patients, to treat focal recalcitrant oral lesions with excellent results.¹² Photochemotherapy has been used with notable improvement, but the potential of carcinogenicity, especially in patients with Fitzpatrick skin types I and II, has limited its use.¹³

Our patient developed an unusual extensive LP eruption involving only vitiliginous skin shortly after initiation of the combined antihypertensive medication telmisartan-HCTZ, an angiotensin receptor blocker with a thiazide diuretic. Telmisartan and other angiotensin receptor blockers have not been reported to trigger LP; HCTZ is listed as one of the common drugs causing photosensitivity and LP.^14,15 Although it is possible that our patient exhibited a delayed lichenoid drug eruption from the HCTZ, it is noteworthy that he did not experience a single episode of LP during his 8-year history of taking HCTZ. Instead, he developed the LP eruption shortly after the addition of telmisartan to his HCTZ antihypertensive regimen. The temporal relationship led us to direct the patient to the prescribing physician to discontinue telmisartan-HCTZ. After changing his antihypertensive medication to atenolol, the patient presented with improvement within the first month and near-complete resolution 2 months after the discontinuation of telmisartan-HCTZ.

Our patient’s LP lesions only manifested on the skin affected by vitiligo, sparing the normal-pigmented skin. Studies have demonstrated an increased ratio of CD8⁺ T cells to CD4⁺ T cells as well as increased intercellular adhesion molecule 1 at the dermal level.^10,16 Both vitiligo and LP share some common histopathologic features including highly populated CD8⁺ T cells and intercellular adhesion molecule 1. In our case, LP was triggered on the vitiliginous skin by telmisartan. Vitiligo in combination with trauma induced by sunburn may represent the trigger that altered the cellular immune response and created the telmisartan-induced LP. As a result, the LP eruption was confined to the vitiliginous skin lesions.

Perifollicular repigmentation was observed in our patient after the LP lesions resolved; the patient’s vitiligo was unresponsive to prior treatment. The inflammatory process occurring in LP may exert and interfere in the underlying autoimmune cytotoxic effect toward the melanocytes and the melanin synthesis. It may be of interest to find out if the inflammatory response of LP has a positive influence on the effect of melanogenesis pathways or on the underlying autoimmune-related inflammatory process in vitiligo. Further studies are needed to investigate the role of immunotherapy targeting specific inflammatory pathways and the impact on the repigmentation in vitiligo.

Acknowledgment—Special thanks to Paul Chu, MD (Port Chester, New York).

To the Editor:

A 39-year-old man with a history of hypertension and vitiligo presented with a rapid-onset, generalized, pruritic rash covering the body of 4 weeks’ duration. He reported that the rash progressively worsened after developing mild sunburn. The patient stated that the rash was extremely pruritic with a burning sensation and was tender to touch. He was treated with betamethasone valerate cream 0.1% by an outside physician and an over-the-counter anti-itch lotion with no notable improvement. His only medication was telmisartan-hydrochlorothiazide (HCTZ) for hypertension. He denied any drug allergies.

Physical examination revealed multiple discrete and coalescent planar erythematous papules and plaques involving only the depigmented vitiliginous skin of the forehead, eyelids, and nape of the neck (Figure 1A), and confluent on the lateral aspect of the bilateral forearms (Figure 1B), dorsal aspect of the right hand, and bilateral dorsi of the feet. Wickham striae were noted on the lips (Figure 1C). A clinical diagnosis of lichen planus (LP) was made. The patient initially was prescribed halobetasol propionate ointment 0.05% twice daily. He reported notable relief of pruritus with reduction of overall symptoms and new lesion formation.

A 4-mm punch biopsy was performed on the left forearm. Histopathology revealed LP. Microscopic examination of the hematoxylin and eosin–stained specimen revealed a bandlike lymphohistiocytic infiltrate that extended across the papillary dermis, focally obscuring the dermoepidermal junction where there were vacuolar changes and colloid bodies. The epidermis showed sawtooth rete ridges, wedge-shaped foci of hypergranulosis, and compact hyperkeratosis (Figure 2).

On further questioning during follow-up, the patient revealed that his hypertensive medication was changed from HCTZ, which he had been taking for the last 8 years, to the combination antihypertensive medication telmisartan-HCTZ before the onset of the skin eruption. Due to the temporal relationship between the new medication and onset of the eruption, the clinical impression was highly suspicious for drug-induced eruptive LP with Köbner phenomenon caused by the recent sunburn. Systemic workup for underlying causes of LP was negative. Laboratory tests revealed normal complete blood cell counts. The hepatitis panel included hepatitis A antibodies; hepatitis B surface, e antigen, and core antibodies; hepatitis B surface antigen and e antibodies; hepatitis C antibodies; and antinuclear antibodies, which were all negative.

The patient continued to develop new pruritic papules clinically consistent with LP. He was instructed to return to his primary care physician to change the telmisartan-HCTZ to a different class of antihypertensive medication. His medication was changed to atenolol. The patient also was instructed to continue the halobetasol propionate ointment 0.05% twice daily to the affected areas.

The patient returned for a follow-up visit 1 month later and reported notable improvement in pruritus and near-complete resolution of the LP after discontinuation of telmisartan-HCTZ. He also noted some degree of perifollicular repigmentation of the vitiliginous skin that had been unresponsive to prior therapy (Figure 3).

Lichen planus is a pruritic and inflammatory papulosquamous skin condition that presents as scaly, flat-topped, violaceous, polygonal-shaped papules commonly involving the flexor surface of the arms and legs, oral mucosa, scalp, nails, and genitalia. Clinically, LP can present in various forms including actinic, annular, atrophic, erosive, follicular, hypertrophic, linear, pigmented, and vesicular/bullous types. Koebnerization is common, especially in the linear form of LP. There are no specific laboratory findings or serologic markers seen in LP.

The exact cause of LP remains unknown. Clinical observations and anecdotal evidence have directed the cell-mediated immune response to insulting agents such as medications or contact allergy to metals triggering an abnormal cellular immune response. Various viral agents have been reported including hepatitis C virus, human herpesvirus, herpes simplex virus, and varicella-zoster virus.^1-5 Other factors such as seasonal change and the environment may contribute to the development of LP and an increase in the incidence of LP eruption has been observed from January to July throughout the United States.⁶ Lichen planus also has been associated with other altered immune-related disease such as ulcerative colitis, alopecia areata, vitiligo, dermatomyositis, morphea, lichen sclerosis, and myasthenia gravis.⁷ Increased levels of emotional stress, particularly related to family members, often is related to the onset or aggravation of symptoms.^8,9

Many drug-related LP-like and lichenoid eruptions have been reported with antihypertensive drugs, antimalarial drugs, diuretics, antidepressants, nonsteroidal anti-inflammatory drugs, antimicrobial drugs, and metals. In particular, medications such as captopril, enalapril, labetalol, propranolol, chlorothiazide, HCTZ, methyldopa, chloroquine, hydroxychloroquine, quinacrine, gold salts, penicillamine, and quinidine commonly are reported to induce lichenoid drug eruption.¹⁰

Several inflammatory papulosquamous skin conditions should be considered in the differential diagnosis before confirming the diagnosis of LP. It is important to rule out lupus erythematosus, especially if the oral mucosa and scalp are involved. In addition, erosive paraneoplastic pemphigus involving primarily the oral mucosa can resemble oral LP. Nail diseases such as psoriasis, onychomycosis, and alopecia areata should be considered as the differential diagnosis of nail disease. Genital involvement also can be seen in psoriasis and lichen sclerosus.

Treatment of LP is mainly symptomatic because of the benign nature of the disease and the high spontaneous remission rate with varying amount of time. If drugs, dental/metal implants, or underlying viral infections are the identifiable triggering factors of LP, the offending agents should be discontinued or removed. Additionally, topical or systemic treatments can be given depending on the severity of the disease, focusing mainly on symptomatic relief as well as the balance of risks and benefits associated with treatment.

Treatment options include topical and intralesional corticosteroids. Systemic medications such as oral corticosteroids and/or acitretin commonly are used in acute, severe, and disseminated cases, though treatment duration varies depending on the clinical response. Other systemic agents used to treat LP include griseofulvin, metronidazole, sulfasalazine, cyclosporine, and mycophenolate mofetil.

Phototherapy is considered an alternative therapy, especially for recalcitrant LP. UVA1 and narrowband UVB (wavelength, 311 nm) have been reported to effectively treat long-standing and therapy-resistant LP.¹¹ In addition, a small study used the excimer laser (wavelength, 308 nm), which is well tolerated by patients, to treat focal recalcitrant oral lesions with excellent results.¹² Photochemotherapy has been used with notable improvement, but the potential of carcinogenicity, especially in patients with Fitzpatrick skin types I and II, has limited its use.¹³

Our patient developed an unusual extensive LP eruption involving only vitiliginous skin shortly after initiation of the combined antihypertensive medication telmisartan-HCTZ, an angiotensin receptor blocker with a thiazide diuretic. Telmisartan and other angiotensin receptor blockers have not been reported to trigger LP; HCTZ is listed as one of the common drugs causing photosensitivity and LP.^14,15 Although it is possible that our patient exhibited a delayed lichenoid drug eruption from the HCTZ, it is noteworthy that he did not experience a single episode of LP during his 8-year history of taking HCTZ. Instead, he developed the LP eruption shortly after the addition of telmisartan to his HCTZ antihypertensive regimen. The temporal relationship led us to direct the patient to the prescribing physician to discontinue telmisartan-HCTZ. After changing his antihypertensive medication to atenolol, the patient presented with improvement within the first month and near-complete resolution 2 months after the discontinuation of telmisartan-HCTZ.

Our patient’s LP lesions only manifested on the skin affected by vitiligo, sparing the normal-pigmented skin. Studies have demonstrated an increased ratio of CD8⁺ T cells to CD4⁺ T cells as well as increased intercellular adhesion molecule 1 at the dermal level.^10,16 Both vitiligo and LP share some common histopathologic features including highly populated CD8⁺ T cells and intercellular adhesion molecule 1. In our case, LP was triggered on the vitiliginous skin by telmisartan. Vitiligo in combination with trauma induced by sunburn may represent the trigger that altered the cellular immune response and created the telmisartan-induced LP. As a result, the LP eruption was confined to the vitiliginous skin lesions.

Perifollicular repigmentation was observed in our patient after the LP lesions resolved; the patient’s vitiligo was unresponsive to prior treatment. The inflammatory process occurring in LP may exert and interfere in the underlying autoimmune cytotoxic effect toward the melanocytes and the melanin synthesis. It may be of interest to find out if the inflammatory response of LP has a positive influence on the effect of melanogenesis pathways or on the underlying autoimmune-related inflammatory process in vitiligo. Further studies are needed to investigate the role of immunotherapy targeting specific inflammatory pathways and the impact on the repigmentation in vitiligo.

Acknowledgment—Special thanks to Paul Chu, MD (Port Chester, New York).

To the Editor:

A 39-year-old man with a history of hypertension and vitiligo presented with a rapid-onset, generalized, pruritic rash covering the body of 4 weeks’ duration. He reported that the rash progressively worsened after developing mild sunburn. The patient stated that the rash was extremely pruritic with a burning sensation and was tender to touch. He was treated with betamethasone valerate cream 0.1% by an outside physician and an over-the-counter anti-itch lotion with no notable improvement. His only medication was telmisartan-hydrochlorothiazide (HCTZ) for hypertension. He denied any drug allergies.

Physical examination revealed multiple discrete and coalescent planar erythematous papules and plaques involving only the depigmented vitiliginous skin of the forehead, eyelids, and nape of the neck (Figure 1A), and confluent on the lateral aspect of the bilateral forearms (Figure 1B), dorsal aspect of the right hand, and bilateral dorsi of the feet. Wickham striae were noted on the lips (Figure 1C). A clinical diagnosis of lichen planus (LP) was made. The patient initially was prescribed halobetasol propionate ointment 0.05% twice daily. He reported notable relief of pruritus with reduction of overall symptoms and new lesion formation.

A 4-mm punch biopsy was performed on the left forearm. Histopathology revealed LP. Microscopic examination of the hematoxylin and eosin–stained specimen revealed a bandlike lymphohistiocytic infiltrate that extended across the papillary dermis, focally obscuring the dermoepidermal junction where there were vacuolar changes and colloid bodies. The epidermis showed sawtooth rete ridges, wedge-shaped foci of hypergranulosis, and compact hyperkeratosis (Figure 2).

On further questioning during follow-up, the patient revealed that his hypertensive medication was changed from HCTZ, which he had been taking for the last 8 years, to the combination antihypertensive medication telmisartan-HCTZ before the onset of the skin eruption. Due to the temporal relationship between the new medication and onset of the eruption, the clinical impression was highly suspicious for drug-induced eruptive LP with Köbner phenomenon caused by the recent sunburn. Systemic workup for underlying causes of LP was negative. Laboratory tests revealed normal complete blood cell counts. The hepatitis panel included hepatitis A antibodies; hepatitis B surface, e antigen, and core antibodies; hepatitis B surface antigen and e antibodies; hepatitis C antibodies; and antinuclear antibodies, which were all negative.

The patient continued to develop new pruritic papules clinically consistent with LP. He was instructed to return to his primary care physician to change the telmisartan-HCTZ to a different class of antihypertensive medication. His medication was changed to atenolol. The patient also was instructed to continue the halobetasol propionate ointment 0.05% twice daily to the affected areas.

The patient returned for a follow-up visit 1 month later and reported notable improvement in pruritus and near-complete resolution of the LP after discontinuation of telmisartan-HCTZ. He also noted some degree of perifollicular repigmentation of the vitiliginous skin that had been unresponsive to prior therapy (Figure 3).

Lichen planus is a pruritic and inflammatory papulosquamous skin condition that presents as scaly, flat-topped, violaceous, polygonal-shaped papules commonly involving the flexor surface of the arms and legs, oral mucosa, scalp, nails, and genitalia. Clinically, LP can present in various forms including actinic, annular, atrophic, erosive, follicular, hypertrophic, linear, pigmented, and vesicular/bullous types. Koebnerization is common, especially in the linear form of LP. There are no specific laboratory findings or serologic markers seen in LP.

The exact cause of LP remains unknown. Clinical observations and anecdotal evidence have directed the cell-mediated immune response to insulting agents such as medications or contact allergy to metals triggering an abnormal cellular immune response. Various viral agents have been reported including hepatitis C virus, human herpesvirus, herpes simplex virus, and varicella-zoster virus.^1-5 Other factors such as seasonal change and the environment may contribute to the development of LP and an increase in the incidence of LP eruption has been observed from January to July throughout the United States.⁶ Lichen planus also has been associated with other altered immune-related disease such as ulcerative colitis, alopecia areata, vitiligo, dermatomyositis, morphea, lichen sclerosis, and myasthenia gravis.⁷ Increased levels of emotional stress, particularly related to family members, often is related to the onset or aggravation of symptoms.^8,9

Many drug-related LP-like and lichenoid eruptions have been reported with antihypertensive drugs, antimalarial drugs, diuretics, antidepressants, nonsteroidal anti-inflammatory drugs, antimicrobial drugs, and metals. In particular, medications such as captopril, enalapril, labetalol, propranolol, chlorothiazide, HCTZ, methyldopa, chloroquine, hydroxychloroquine, quinacrine, gold salts, penicillamine, and quinidine commonly are reported to induce lichenoid drug eruption.¹⁰

Several inflammatory papulosquamous skin conditions should be considered in the differential diagnosis before confirming the diagnosis of LP. It is important to rule out lupus erythematosus, especially if the oral mucosa and scalp are involved. In addition, erosive paraneoplastic pemphigus involving primarily the oral mucosa can resemble oral LP. Nail diseases such as psoriasis, onychomycosis, and alopecia areata should be considered as the differential diagnosis of nail disease. Genital involvement also can be seen in psoriasis and lichen sclerosus.

Treatment of LP is mainly symptomatic because of the benign nature of the disease and the high spontaneous remission rate with varying amount of time. If drugs, dental/metal implants, or underlying viral infections are the identifiable triggering factors of LP, the offending agents should be discontinued or removed. Additionally, topical or systemic treatments can be given depending on the severity of the disease, focusing mainly on symptomatic relief as well as the balance of risks and benefits associated with treatment.

Treatment options include topical and intralesional corticosteroids. Systemic medications such as oral corticosteroids and/or acitretin commonly are used in acute, severe, and disseminated cases, though treatment duration varies depending on the clinical response. Other systemic agents used to treat LP include griseofulvin, metronidazole, sulfasalazine, cyclosporine, and mycophenolate mofetil.

Phototherapy is considered an alternative therapy, especially for recalcitrant LP. UVA1 and narrowband UVB (wavelength, 311 nm) have been reported to effectively treat long-standing and therapy-resistant LP.¹¹ In addition, a small study used the excimer laser (wavelength, 308 nm), which is well tolerated by patients, to treat focal recalcitrant oral lesions with excellent results.¹² Photochemotherapy has been used with notable improvement, but the potential of carcinogenicity, especially in patients with Fitzpatrick skin types I and II, has limited its use.¹³

Our patient developed an unusual extensive LP eruption involving only vitiliginous skin shortly after initiation of the combined antihypertensive medication telmisartan-HCTZ, an angiotensin receptor blocker with a thiazide diuretic. Telmisartan and other angiotensin receptor blockers have not been reported to trigger LP; HCTZ is listed as one of the common drugs causing photosensitivity and LP.^14,15 Although it is possible that our patient exhibited a delayed lichenoid drug eruption from the HCTZ, it is noteworthy that he did not experience a single episode of LP during his 8-year history of taking HCTZ. Instead, he developed the LP eruption shortly after the addition of telmisartan to his HCTZ antihypertensive regimen. The temporal relationship led us to direct the patient to the prescribing physician to discontinue telmisartan-HCTZ. After changing his antihypertensive medication to atenolol, the patient presented with improvement within the first month and near-complete resolution 2 months after the discontinuation of telmisartan-HCTZ.

Our patient’s LP lesions only manifested on the skin affected by vitiligo, sparing the normal-pigmented skin. Studies have demonstrated an increased ratio of CD8⁺ T cells to CD4⁺ T cells as well as increased intercellular adhesion molecule 1 at the dermal level.^10,16 Both vitiligo and LP share some common histopathologic features including highly populated CD8⁺ T cells and intercellular adhesion molecule 1. In our case, LP was triggered on the vitiliginous skin by telmisartan. Vitiligo in combination with trauma induced by sunburn may represent the trigger that altered the cellular immune response and created the telmisartan-induced LP. As a result, the LP eruption was confined to the vitiliginous skin lesions.

Perifollicular repigmentation was observed in our patient after the LP lesions resolved; the patient’s vitiligo was unresponsive to prior treatment. The inflammatory process occurring in LP may exert and interfere in the underlying autoimmune cytotoxic effect toward the melanocytes and the melanin synthesis. It may be of interest to find out if the inflammatory response of LP has a positive influence on the effect of melanogenesis pathways or on the underlying autoimmune-related inflammatory process in vitiligo. Further studies are needed to investigate the role of immunotherapy targeting specific inflammatory pathways and the impact on the repigmentation in vitiligo.

Acknowledgment—Special thanks to Paul Chu, MD (Port Chester, New York).

For Beth Drolet, MD, a pediatric dermatologist in Wisconsin, the tremendous impact oral propranolol has had on the treatment of severe infantile hemangioma is written on the faces of children diagnosed with the condition in recent years.

“You can tell which drugs the kids were on by their age,” said Dr. Drolet, professor of dermatology and pediatrics at the Medical College of Wisconsin, Milwaukee. “If they were born before 2008, before we used this medication, those kids have had multiple surgeries and are still not looking that good. But we rarely see that in the kids born after.”

• Caution parents about side effects. Cardiac side effects have been “extraordinarily rare,” Dr. Drolet said. “We have seen problems with wheezing and, very rarely, severe hypoglycemia,” which can be prevented by educating the family. While it’s uncommon for the medication alone to produce wheezing, this may occur when a respiratory infection and propranolol combine to stress the body, she noted.

In some cases, physicians prescribe albuterol for wheezing without realizing that it will interact with propranolol, she added. “One is a beta-blocker, and the other is a beta-antagonist. They completely cancel each other out.”

To prevent hypoglycemia, Dr. Frieden said she recommends that children be fed every 6 hours if they’re under 6 months old or every 8 hours if they’re over 6 months of age. And Dr. Drolet said she advises parents to stop propranolol when their infants are sick.

A major focus of an educational video provided by Dr. Drolet’s clinic is advising parents “to stop the medication if the infant is not eating regularly, vomiting, or has diarrhea. It interferes with how you respond to low blood sugar if you’re not eating,” she said. “That surprised us. Now that we’ve been teaching parents about when to call us, that’s been pretty preventable.”

Minor side effects include cold hands and feet and sleep disturbances such as sleepiness and apparent nightmares, Dr. Frieden pointed out.

• Monitor guidelines regarding safety and protocols. “Over time, we’re getting more and more expertise,” Dr. Drolet said. For example, her clinic no longer performs ECGs on babies who take the medication because research has suggested they are not needed.

• Spend time developing an education program for parents. Dr. Drolet’s clinic provides the educational video to teach parents about how oral propranolol is used. “We haven’t done that for any other drugs,” she said. “But we want to make sure we aren’t overdosing it. We’ve been very careful about our parent education to prevent that.”

Guidelines on the diagnosis and management of infantile hemangioma were published in 2015 in Pediatrics (2015 Oct;136[4]:e1060-104).

Dr. Frieden has consulted for Pierre Fabre Dermatologie, the manufacturer of the oral propranolol product, marketed as Hemangeol. Dr. Drolet has received an investigator-initiated grant from the company.

For Beth Drolet, MD, a pediatric dermatologist in Wisconsin, the tremendous impact oral propranolol has had on the treatment of severe infantile hemangioma is written on the faces of children diagnosed with the condition in recent years.

“You can tell which drugs the kids were on by their age,” said Dr. Drolet, professor of dermatology and pediatrics at the Medical College of Wisconsin, Milwaukee. “If they were born before 2008, before we used this medication, those kids have had multiple surgeries and are still not looking that good. But we rarely see that in the kids born after.”

• Caution parents about side effects. Cardiac side effects have been “extraordinarily rare,” Dr. Drolet said. “We have seen problems with wheezing and, very rarely, severe hypoglycemia,” which can be prevented by educating the family. While it’s uncommon for the medication alone to produce wheezing, this may occur when a respiratory infection and propranolol combine to stress the body, she noted.

In some cases, physicians prescribe albuterol for wheezing without realizing that it will interact with propranolol, she added. “One is a beta-blocker, and the other is a beta-antagonist. They completely cancel each other out.”

To prevent hypoglycemia, Dr. Frieden said she recommends that children be fed every 6 hours if they’re under 6 months old or every 8 hours if they’re over 6 months of age. And Dr. Drolet said she advises parents to stop propranolol when their infants are sick.

A major focus of an educational video provided by Dr. Drolet’s clinic is advising parents “to stop the medication if the infant is not eating regularly, vomiting, or has diarrhea. It interferes with how you respond to low blood sugar if you’re not eating,” she said. “That surprised us. Now that we’ve been teaching parents about when to call us, that’s been pretty preventable.”

Minor side effects include cold hands and feet and sleep disturbances such as sleepiness and apparent nightmares, Dr. Frieden pointed out.

• Monitor guidelines regarding safety and protocols. “Over time, we’re getting more and more expertise,” Dr. Drolet said. For example, her clinic no longer performs ECGs on babies who take the medication because research has suggested they are not needed.

• Spend time developing an education program for parents. Dr. Drolet’s clinic provides the educational video to teach parents about how oral propranolol is used. “We haven’t done that for any other drugs,” she said. “But we want to make sure we aren’t overdosing it. We’ve been very careful about our parent education to prevent that.”

Guidelines on the diagnosis and management of infantile hemangioma were published in 2015 in Pediatrics (2015 Oct;136[4]:e1060-104).

Dr. Frieden has consulted for Pierre Fabre Dermatologie, the manufacturer of the oral propranolol product, marketed as Hemangeol. Dr. Drolet has received an investigator-initiated grant from the company.

For Beth Drolet, MD, a pediatric dermatologist in Wisconsin, the tremendous impact oral propranolol has had on the treatment of severe infantile hemangioma is written on the faces of children diagnosed with the condition in recent years.

“You can tell which drugs the kids were on by their age,” said Dr. Drolet, professor of dermatology and pediatrics at the Medical College of Wisconsin, Milwaukee. “If they were born before 2008, before we used this medication, those kids have had multiple surgeries and are still not looking that good. But we rarely see that in the kids born after.”

• Caution parents about side effects. Cardiac side effects have been “extraordinarily rare,” Dr. Drolet said. “We have seen problems with wheezing and, very rarely, severe hypoglycemia,” which can be prevented by educating the family. While it’s uncommon for the medication alone to produce wheezing, this may occur when a respiratory infection and propranolol combine to stress the body, she noted.

In some cases, physicians prescribe albuterol for wheezing without realizing that it will interact with propranolol, she added. “One is a beta-blocker, and the other is a beta-antagonist. They completely cancel each other out.”

To prevent hypoglycemia, Dr. Frieden said she recommends that children be fed every 6 hours if they’re under 6 months old or every 8 hours if they’re over 6 months of age. And Dr. Drolet said she advises parents to stop propranolol when their infants are sick.

A major focus of an educational video provided by Dr. Drolet’s clinic is advising parents “to stop the medication if the infant is not eating regularly, vomiting, or has diarrhea. It interferes with how you respond to low blood sugar if you’re not eating,” she said. “That surprised us. Now that we’ve been teaching parents about when to call us, that’s been pretty preventable.”

Minor side effects include cold hands and feet and sleep disturbances such as sleepiness and apparent nightmares, Dr. Frieden pointed out.

• Monitor guidelines regarding safety and protocols. “Over time, we’re getting more and more expertise,” Dr. Drolet said. For example, her clinic no longer performs ECGs on babies who take the medication because research has suggested they are not needed.

• Spend time developing an education program for parents. Dr. Drolet’s clinic provides the educational video to teach parents about how oral propranolol is used. “We haven’t done that for any other drugs,” she said. “But we want to make sure we aren’t overdosing it. We’ve been very careful about our parent education to prevent that.”

Guidelines on the diagnosis and management of infantile hemangioma were published in 2015 in Pediatrics (2015 Oct;136[4]:e1060-104).

Dr. Frieden has consulted for Pierre Fabre Dermatologie, the manufacturer of the oral propranolol product, marketed as Hemangeol. Dr. Drolet has received an investigator-initiated grant from the company.

Routine ECG screening in infants before they receive propranolol for hemangiomas is “not likely to be an effective screening tool in patients with otherwise normal physical examination and family history” and may even cause harmful delays in treatment, study authors concluded.

“As previously published guidelines suggest, it is likely that an indication-driven ECG strategy is a better approach, because there is a low incidence of ECG abnormalities that would limit propranolol use in children,” wrote Kevin B. Yarbrough, MD, a dermatologist at Phoenix Children’s Hospital, and his associates. The results “support published guidelines for propranolol initiation and are congruent with findings from other investigators” (Pediatr Dermatol. 2016 Nov;33[6]:615-20).

In the retrospective study, Dr. Yarbrough and his associates tracked 162 patients (median age, 5.2 months) who underwent routine ECG screening at several clinics before propranolol treatment for hemangiomas from 2008 to 2013. The ECGs were read as abnormal in 69 cases (43%); the most common abnormality was left ventricular hypertrophy (16 patients), followed by right ventricular hypertrophy (8), sinus bradycardia (6), and sinus tachycardia (5).

Cardiologists cleared all 69 patients for propranolol treatment, which they received. “No patients in our cohort experienced an adverse effect during treatment that could have been predicted or prevented by ECG before initiation of the propranolol,” the authors wrote.

“Routine ECG adds to the cost of treating hemangiomas and leads to unnecessary consultations and testing. Even more importantly, abnormalities detected on ECG can lead to delays in treatment initiation, which in turn can lead to greater patient morbidity, as seen in the case of our patient whose hemangioma ulcerated while awaiting cardiology consultation,” they added.

Still, they noted that ECG tests should still be performed on “infants with bradycardia or cardiac arrhythmia found during initial physical examination, a family history of congenital heart disease or arrhythmias, and a maternal history of connective tissue disease.”

Study funding information was not provided. One of the study authors reported that he was a clinical investigator for Pierre Fabre Dermatologie, the manufacturer of the oral propranolol product Hemangeol.

Routine ECG screening in infants before they receive propranolol for hemangiomas is “not likely to be an effective screening tool in patients with otherwise normal physical examination and family history” and may even cause harmful delays in treatment, study authors concluded.

“As previously published guidelines suggest, it is likely that an indication-driven ECG strategy is a better approach, because there is a low incidence of ECG abnormalities that would limit propranolol use in children,” wrote Kevin B. Yarbrough, MD, a dermatologist at Phoenix Children’s Hospital, and his associates. The results “support published guidelines for propranolol initiation and are congruent with findings from other investigators” (Pediatr Dermatol. 2016 Nov;33[6]:615-20).

In the retrospective study, Dr. Yarbrough and his associates tracked 162 patients (median age, 5.2 months) who underwent routine ECG screening at several clinics before propranolol treatment for hemangiomas from 2008 to 2013. The ECGs were read as abnormal in 69 cases (43%); the most common abnormality was left ventricular hypertrophy (16 patients), followed by right ventricular hypertrophy (8), sinus bradycardia (6), and sinus tachycardia (5).

Cardiologists cleared all 69 patients for propranolol treatment, which they received. “No patients in our cohort experienced an adverse effect during treatment that could have been predicted or prevented by ECG before initiation of the propranolol,” the authors wrote.

“Routine ECG adds to the cost of treating hemangiomas and leads to unnecessary consultations and testing. Even more importantly, abnormalities detected on ECG can lead to delays in treatment initiation, which in turn can lead to greater patient morbidity, as seen in the case of our patient whose hemangioma ulcerated while awaiting cardiology consultation,” they added.

Still, they noted that ECG tests should still be performed on “infants with bradycardia or cardiac arrhythmia found during initial physical examination, a family history of congenital heart disease or arrhythmias, and a maternal history of connective tissue disease.”

Study funding information was not provided. One of the study authors reported that he was a clinical investigator for Pierre Fabre Dermatologie, the manufacturer of the oral propranolol product Hemangeol.

Routine ECG screening in infants before they receive propranolol for hemangiomas is “not likely to be an effective screening tool in patients with otherwise normal physical examination and family history” and may even cause harmful delays in treatment, study authors concluded.

“As previously published guidelines suggest, it is likely that an indication-driven ECG strategy is a better approach, because there is a low incidence of ECG abnormalities that would limit propranolol use in children,” wrote Kevin B. Yarbrough, MD, a dermatologist at Phoenix Children’s Hospital, and his associates. The results “support published guidelines for propranolol initiation and are congruent with findings from other investigators” (Pediatr Dermatol. 2016 Nov;33[6]:615-20).

In the retrospective study, Dr. Yarbrough and his associates tracked 162 patients (median age, 5.2 months) who underwent routine ECG screening at several clinics before propranolol treatment for hemangiomas from 2008 to 2013. The ECGs were read as abnormal in 69 cases (43%); the most common abnormality was left ventricular hypertrophy (16 patients), followed by right ventricular hypertrophy (8), sinus bradycardia (6), and sinus tachycardia (5).

Cardiologists cleared all 69 patients for propranolol treatment, which they received. “No patients in our cohort experienced an adverse effect during treatment that could have been predicted or prevented by ECG before initiation of the propranolol,” the authors wrote.

“Routine ECG adds to the cost of treating hemangiomas and leads to unnecessary consultations and testing. Even more importantly, abnormalities detected on ECG can lead to delays in treatment initiation, which in turn can lead to greater patient morbidity, as seen in the case of our patient whose hemangioma ulcerated while awaiting cardiology consultation,” they added.

Still, they noted that ECG tests should still be performed on “infants with bradycardia or cardiac arrhythmia found during initial physical examination, a family history of congenital heart disease or arrhythmias, and a maternal history of connective tissue disease.”

Study funding information was not provided. One of the study authors reported that he was a clinical investigator for Pierre Fabre Dermatologie, the manufacturer of the oral propranolol product Hemangeol.

Infantile hemangiomas of the nose develop more complications than those at all other body sites combined, according to a report published in Pediatric Dermatology.

In what they described as the largest study to date to assess nasal infantile hemangiomas, researchers assessed which traits are associated with complications and predict residual skin changes at the age of 5 years. “Nasal infantile hemangiomas pose an immediate risk of airway obstruction because infants are obligate nasal breathers, and may have long-term functional and psychosocial consequences if involution is incomplete or development of surrounding structures, such as nasal cartilage, is compromised,” said Maria S. Kryatova of the departments of pediatrics and dermatology, Johns Hopkins University, Baltimore, and her associates.

The investigators identified all patients younger than 18 years who had been treated at their academic referral center for nasal infantile hemangiomas between 2001 and 2014. They performed retrospective chart reviews, which included photographs, for 89 participants. The parents of 63 of these children were interviewed when the participants reached a median age of 5 years and provided comparison photographs taken at their entry into kindergarten.

Thirty-five children (39%) developed one or more complications at some time during follow-up, including airway compromise, compression, or functional impairment; ulceration; visual obstruction or ocular compression; and infection. In comparison, the Hemangioma Investigator Group has previously reported a 24% overall rate of complications at all body sites. Similarly, the proportion of study participants who received at least one type of treatment (propranolol, oral steroids, pulsed dye laser, surgery, topical timolol, intralesional corticosteroids, yttrium-aluminum-garnet laser, carbon dioxide laser, or fraxel laser) was markedly higher (80%) than that reported previously by the Hemangioma Investigator Group for all body sites (38%).

“Our study is the first to report a significant association between [the hemangioma’s location on the nose] and depth. Lesions on the nasal dorsum are unlikely to be deep, whereas nasal tip lesions are unlikely to be superficial. Deep vertical growth may be limited by underlying nasal bone in the dorsum but less so by the soft tissue of the nasal tip.” Alternatively, as suggested by other investigators, an embryologic explanation is also possible – “the fusion lines between neural crest–derived mesenchyme and ectoderm-derived nasal placodes may have different properties in the vicinity of the nasal dorsum and nasal tip that predispose them to the development of superficial and deep hemangiomas, respectively,” Ms. Kryatova and her associates reported (Ped Dermatol. 2016;33[6]:652-8).

Segmental- and indeterminate-type lesions were more likely than focal-type lesions to develop ulceration, compression, or functional obstruction, and mixed-depth hemangiomas were more likely than deep or superficial hemangiomas to ulcerate. Overall, the lesions had involuted by kindergarten age in 70% of the study participants but persisted in 30%, and most of the children with involution showed residual skin changes such as telangiectasia (14 children), fibrofatty tissue (11 children), and scarring (9 children).

These findings show that a multicenter study to expand on these conclusions and to determine the best treatment algorithm for nasal infantile hemangiomas is warranted, the investigators added.

[email protected]

Infantile hemangiomas of the nose develop more complications than those at all other body sites combined, according to a report published in Pediatric Dermatology.

In what they described as the largest study to date to assess nasal infantile hemangiomas, researchers assessed which traits are associated with complications and predict residual skin changes at the age of 5 years. “Nasal infantile hemangiomas pose an immediate risk of airway obstruction because infants are obligate nasal breathers, and may have long-term functional and psychosocial consequences if involution is incomplete or development of surrounding structures, such as nasal cartilage, is compromised,” said Maria S. Kryatova of the departments of pediatrics and dermatology, Johns Hopkins University, Baltimore, and her associates.

The investigators identified all patients younger than 18 years who had been treated at their academic referral center for nasal infantile hemangiomas between 2001 and 2014. They performed retrospective chart reviews, which included photographs, for 89 participants. The parents of 63 of these children were interviewed when the participants reached a median age of 5 years and provided comparison photographs taken at their entry into kindergarten.

Thirty-five children (39%) developed one or more complications at some time during follow-up, including airway compromise, compression, or functional impairment; ulceration; visual obstruction or ocular compression; and infection. In comparison, the Hemangioma Investigator Group has previously reported a 24% overall rate of complications at all body sites. Similarly, the proportion of study participants who received at least one type of treatment (propranolol, oral steroids, pulsed dye laser, surgery, topical timolol, intralesional corticosteroids, yttrium-aluminum-garnet laser, carbon dioxide laser, or fraxel laser) was markedly higher (80%) than that reported previously by the Hemangioma Investigator Group for all body sites (38%).

“Our study is the first to report a significant association between [the hemangioma’s location on the nose] and depth. Lesions on the nasal dorsum are unlikely to be deep, whereas nasal tip lesions are unlikely to be superficial. Deep vertical growth may be limited by underlying nasal bone in the dorsum but less so by the soft tissue of the nasal tip.” Alternatively, as suggested by other investigators, an embryologic explanation is also possible – “the fusion lines between neural crest–derived mesenchyme and ectoderm-derived nasal placodes may have different properties in the vicinity of the nasal dorsum and nasal tip that predispose them to the development of superficial and deep hemangiomas, respectively,” Ms. Kryatova and her associates reported (Ped Dermatol. 2016;33[6]:652-8).

Segmental- and indeterminate-type lesions were more likely than focal-type lesions to develop ulceration, compression, or functional obstruction, and mixed-depth hemangiomas were more likely than deep or superficial hemangiomas to ulcerate. Overall, the lesions had involuted by kindergarten age in 70% of the study participants but persisted in 30%, and most of the children with involution showed residual skin changes such as telangiectasia (14 children), fibrofatty tissue (11 children), and scarring (9 children).

These findings show that a multicenter study to expand on these conclusions and to determine the best treatment algorithm for nasal infantile hemangiomas is warranted, the investigators added.

[email protected]

Infantile hemangiomas of the nose develop more complications than those at all other body sites combined, according to a report published in Pediatric Dermatology.

In what they described as the largest study to date to assess nasal infantile hemangiomas, researchers assessed which traits are associated with complications and predict residual skin changes at the age of 5 years. “Nasal infantile hemangiomas pose an immediate risk of airway obstruction because infants are obligate nasal breathers, and may have long-term functional and psychosocial consequences if involution is incomplete or development of surrounding structures, such as nasal cartilage, is compromised,” said Maria S. Kryatova of the departments of pediatrics and dermatology, Johns Hopkins University, Baltimore, and her associates.

The investigators identified all patients younger than 18 years who had been treated at their academic referral center for nasal infantile hemangiomas between 2001 and 2014. They performed retrospective chart reviews, which included photographs, for 89 participants. The parents of 63 of these children were interviewed when the participants reached a median age of 5 years and provided comparison photographs taken at their entry into kindergarten.

Thirty-five children (39%) developed one or more complications at some time during follow-up, including airway compromise, compression, or functional impairment; ulceration; visual obstruction or ocular compression; and infection. In comparison, the Hemangioma Investigator Group has previously reported a 24% overall rate of complications at all body sites. Similarly, the proportion of study participants who received at least one type of treatment (propranolol, oral steroids, pulsed dye laser, surgery, topical timolol, intralesional corticosteroids, yttrium-aluminum-garnet laser, carbon dioxide laser, or fraxel laser) was markedly higher (80%) than that reported previously by the Hemangioma Investigator Group for all body sites (38%).

“Our study is the first to report a significant association between [the hemangioma’s location on the nose] and depth. Lesions on the nasal dorsum are unlikely to be deep, whereas nasal tip lesions are unlikely to be superficial. Deep vertical growth may be limited by underlying nasal bone in the dorsum but less so by the soft tissue of the nasal tip.” Alternatively, as suggested by other investigators, an embryologic explanation is also possible – “the fusion lines between neural crest–derived mesenchyme and ectoderm-derived nasal placodes may have different properties in the vicinity of the nasal dorsum and nasal tip that predispose them to the development of superficial and deep hemangiomas, respectively,” Ms. Kryatova and her associates reported (Ped Dermatol. 2016;33[6]:652-8).

Segmental- and indeterminate-type lesions were more likely than focal-type lesions to develop ulceration, compression, or functional obstruction, and mixed-depth hemangiomas were more likely than deep or superficial hemangiomas to ulcerate. Overall, the lesions had involuted by kindergarten age in 70% of the study participants but persisted in 30%, and most of the children with involution showed residual skin changes such as telangiectasia (14 children), fibrofatty tissue (11 children), and scarring (9 children).

These findings show that a multicenter study to expand on these conclusions and to determine the best treatment algorithm for nasal infantile hemangiomas is warranted, the investigators added.

[email protected]

Vitiligo is a disorder typified by loss of pigmentation. Worldwide estimates of disease demonstrate 0.4% to 2% prevalence.¹ Vitiligo generally is felt to be an autoimmune disorder with a complex multifactorial inheritance.² Therapeutic options for vitiligo are largely off label and include topical corticosteroids, topical calcineurin inhibitors, narrowband UVB (NB-UVB) light phototherapy, and excimer (308 nm) laser therapy.^3,4 Therapies for vitiligo are time consuming, as most topical therapies require twice-daily application. Additionally, many patients require 2 or more topical therapies due to involvement of both the head and neck as well as other body sites.^3,4 Generalized disease often is treated with NB-UVB therapy 3 times weekly in-office visits, while excimer laser therapy is used for limited disease resistant to topical agents.^3,4

Many barriers to good outcomes and care exist for patients with vitiligo.⁵ Patients may experience reduced quality of life and/or sexual dysfunction because of vitiligo lesions. The purpose of this pilot study was to identify barriers to access of care in vitiligo patients.

Methods

A survey was designed and then reviewed for unclear wording by members of the local vitiligo support group at Mount Sinai St. Luke’s-Roosevelt Hospital and Beth Israel Medical Centers (New York, New York). Linguistic revision and clarifications were added to the survey to correct identified communication problems. The survey was then posted using an Internet-based survey software. Links to the survey were sent via email to 107 individuals in a LISTSERV comprising Vitiligo Support International members who participated in a New York City support group (led by C.G. and N.B.S.). Only 1 email was used per household and only individuals 18 years or older could participate. These individuals were asked to complete a deidentified, 82-question, institutional review board–reviewed and exempted survey addressing issues affecting delivery and receipt of medical care for vitiligo.

Data were analyzed using the χ² test, analysis of variance, or Student t test depending on the type of variable (categorical vs continuous). Fisher exact or Wilcoxon-Mann-Whitney tests were used when distributional assumptions were not met. A type I error rate (α=.05) was used to determine statistical significance. All analyses were performed using SAS 9.3 software.

Results

Respondents

The survey was completed by 81% (n=87) of individuals. The mean (SD) age of the treated patients about whom the respondents communicated was 33 (16) years and 71% (n=62) were women. The majority of respondents (64 [74%]) reported their race as white, followed by African American/black (12 [14%]), Hispanic (7 [8%]), and Asian (4 [5%]). Twenty-nine percent (22/76) of respondents reported a family income of less than $50,000 per year, 34% (26/76) reported an income of $50,000 to $100,000, and 37% (28/76) reported an income greater than $100,000, while 11 respondents did not report income.

Number of Physicians Seen

Respondents had reportedly seen an average (SD) number of 2 (1) physicians in the past/present before being offered any therapy for vitiligo and only 37% (32/87) of respondents reported being offered therapy by the first physician they saw. The number of physicians seen did not have a statistical relationship with years with vitiligo (ie, disease duration), sex, race, age of onset, income level, or number of sites affected.

Number of Sites Affected

The survey identified the following 23 sites affected by vitiligo: scalp, forehead, eyelids, lips, nose, cheeks, chin, neck, chest, stomach, back, upper arms, forearms, hands, wrists, fingers, genitalia, buttocks, thighs, calves/shins, ankles, feet, and toes. The average (SD) number of sites affected was 12 (6). The number of sites affected was correlated to the recommendation for phototherapy, while the recommendation for excimer laser therapy was inversely associated with the number of sites affected. The median number of sites affected for those who were not prescribed phototherapy was 10 (interquartile range [IQR]=9; P=.05); the median number of sites affected for those who were prescribed phototherapy was 15 (IQR=11). The association between the number of sites affected and whether the patient proceeded with phototherapy was not statistically significant. The need for phototherapy was not related to years with vitiligo (ie, disease duration), sex, or race.

Excimer laser therapy was prescribed more often to patients with fewer sites affected (median of 9 [IQR=3] vs median of 15 [IQR=9]; P=.04). Respondents who had fewer sites affected were on average more likely to proceed with excimer laser therapy (median of 8 [IQR=4] vs median of 11 [IQR=5]). The association between the number of sites affected and whether the patient proceeded with excimer laser therapy was not statistically significant.

Access to Topical Medications

Forty-one percent (36/87) of respondents reported difficulty accessing 1 or more topical therapies. Of 52 respondents who were prescribed a topical corticosteroid, 12 (23%) reported difficulty accessing therapy. Of 67 respondents who were prescribed a topical calcineurin inhibitor, 27 (40%) reported difficulty accessing medication (tacrolimus, n=17; pimecrolimus, n=10). Calcipotriene prescription coverage was not specifically addressed in this survey, as it usually is a second-line or adjunctive medication. Difficulty getting topical tacrolimus but not topical corticosteroids was associated with female sex (P=.03) but was not associated with race, income level, or level of education. Difficulty obtaining medication was not related to race, sex, level of education, or income level.

Consequences of Phototherapy

Twenty-three of 34 respondents (68%) who were told they required phototherapy actually received phototherapy and reported paying $38 weekly (IQR=$75). The majority of patients who proceeded with phototherapy lived (17/23 [74%]) or worked (16/23 [70%]) within 20 minutes of the therapy center. Self-reported response to phototherapy was good to very good in 65% (15/23) of respondents and no response in 30% (7/23); only 1 respondent reported worsening vitiligo. Sixty percent (15/25) of respondents said they were not satisfied with phototherapy. Respondents who were satisfied with the outcome of phototherapy had on average fewer sites affected by vitiligo (mean [SD], 10 [8]; P=.05). The association with other demographic and economic parameters (eg, sex, race, level of education, income level) was not statistically significant. Proceeding with phototherapy was not related to race, sex, level of education, or income level.

When questioned how many aspects of daily life (eg, work, home, school) were affected by phototherapy, 40% (35/87) of respondents reported that more than one life parameter was disturbed. Thirty-five percent (8/23) of respondents who received phototherapy reported that it affected their daily life “quite a bit” or “severely.” More respondents were likely to report that the therapy interfered with their life “somewhat,” “quite a bit,” or “severely” (76% [19/25]; 95% confidence interval, 55%-92%; P=.01) rather than “not at all” or “a little.”

Excimer Laser

Nine of 17 respondents (53%) who were recommended to undergo excimer laser therapy actually received therapy and reported paying $100 weekly (IQR=$60).

There was a trend toward significance of excimer usage being associated with lower age quartile (0–20 years)(P=.0553) and income more than $100,000 (P=.0788), neither of which reached statistical significance.

Insurance Coverage

Respondents were offered 7 answer options regarding the reason for noncoverage of topical calcineurin inhibitors. They were allowed to pick more than one reason where appropriate. For individuals who were prescribed topical tacrolimus but did not receive drug (n=17), the following reasons were cited: “no insurance coverage for the medication” (59% [10/17]), “your deductible was too high” (24% [4/17]), “prior authorization failed to produce coverage of the medication” (24% [4/17]), “your copay was prohibitively expensive” (24% [4/17]), “you were uncomfortable with the medication’s side effects” (18% [3/17]), “the tube was too small to cover your skin affected areas” (12% [2/17]), and “other” (29% [5/17]). Three patients selected 3 or more reasons, 8 patients selected 2 reasons, and 5 patients selected one reason.

Comment

It has been reported that patients with vitiligo may have difficulty related to treatment compliance for a variety of reasons.⁵ We identified notable barriers that arise for some, if not all, patients with vitiligo in the United States at some point in their care, including interference with other aspects of daily life, lack of coverage by current health insurance provider, and high out-of-pocket expenses, in addition to the negative effects of vitiligo on quality of life that have already been reported.^6,7 These barriers are not a function of race/ethnicity, income level, or age of onset, but they may be impacted, as in the case of tacrolimus, by female sex. It is clear that, based on this study’s numbers, many patients will be unable to receive and/or comply with recommended treatment plans.

A limitation of this analysis is the study population, a select group of patients who had not been prescribed all the therapies in question. The sample size may not be large enough to demonstrate differences between level of education, race, or income level; however, even with a sample size of 87 respondents, the barriers to access of care are prominent. Larger population-based surveys would potentially tease out patterns of barriers not apparent with a smaller sample. No data were generated specific to calcipotriene, and this medication was not specified as a write-in agent on open question by any respondents; therefore, access to topical calcipotriene cannot be projected from this study. Phototherapy was queried as a nonspecific term and the breakdown of NB-UVB versus psoralen plus UVA was not available for this survey. Data suggesting a burden of socioeconomic barriers have been reported for atopic dermatitis⁸ and psoriasis,⁹ which corroborate the need for greater research in the field of access to care in dermatology.

Despite some advancement in the care of vitiligo, patients often are unable to access preferred or recommended treatment modalities. Standard recommendations for care are initial usage of calcineurin inhibitors for facial involvement and topical high-potency corticosteroids for involvement of the body.^3,4 Based on this survey, it would seem that many patients are not able to receive the standard of care. Similarly, NB-UVB phototherapy and excimer laser therapy are recommended for widespread vitiligo and lesions unresponsive to topical care. It would seem that almost half of our respondents did not have access to one or more of the recommended therapies. Barriers to care may have substantial clinical and psychological outcomes, which were not evaluated in this study but merit future research.

Vitiligo is a disorder typified by loss of pigmentation. Worldwide estimates of disease demonstrate 0.4% to 2% prevalence.¹ Vitiligo generally is felt to be an autoimmune disorder with a complex multifactorial inheritance.² Therapeutic options for vitiligo are largely off label and include topical corticosteroids, topical calcineurin inhibitors, narrowband UVB (NB-UVB) light phototherapy, and excimer (308 nm) laser therapy.^3,4 Therapies for vitiligo are time consuming, as most topical therapies require twice-daily application. Additionally, many patients require 2 or more topical therapies due to involvement of both the head and neck as well as other body sites.^3,4 Generalized disease often is treated with NB-UVB therapy 3 times weekly in-office visits, while excimer laser therapy is used for limited disease resistant to topical agents.^3,4

Many barriers to good outcomes and care exist for patients with vitiligo.⁵ Patients may experience reduced quality of life and/or sexual dysfunction because of vitiligo lesions. The purpose of this pilot study was to identify barriers to access of care in vitiligo patients.

Methods

A survey was designed and then reviewed for unclear wording by members of the local vitiligo support group at Mount Sinai St. Luke’s-Roosevelt Hospital and Beth Israel Medical Centers (New York, New York). Linguistic revision and clarifications were added to the survey to correct identified communication problems. The survey was then posted using an Internet-based survey software. Links to the survey were sent via email to 107 individuals in a LISTSERV comprising Vitiligo Support International members who participated in a New York City support group (led by C.G. and N.B.S.). Only 1 email was used per household and only individuals 18 years or older could participate. These individuals were asked to complete a deidentified, 82-question, institutional review board–reviewed and exempted survey addressing issues affecting delivery and receipt of medical care for vitiligo.

Data were analyzed using the χ² test, analysis of variance, or Student t test depending on the type of variable (categorical vs continuous). Fisher exact or Wilcoxon-Mann-Whitney tests were used when distributional assumptions were not met. A type I error rate (α=.05) was used to determine statistical significance. All analyses were performed using SAS 9.3 software.

Results

Respondents

The survey was completed by 81% (n=87) of individuals. The mean (SD) age of the treated patients about whom the respondents communicated was 33 (16) years and 71% (n=62) were women. The majority of respondents (64 [74%]) reported their race as white, followed by African American/black (12 [14%]), Hispanic (7 [8%]), and Asian (4 [5%]). Twenty-nine percent (22/76) of respondents reported a family income of less than $50,000 per year, 34% (26/76) reported an income of $50,000 to $100,000, and 37% (28/76) reported an income greater than $100,000, while 11 respondents did not report income.

Number of Physicians Seen

Respondents had reportedly seen an average (SD) number of 2 (1) physicians in the past/present before being offered any therapy for vitiligo and only 37% (32/87) of respondents reported being offered therapy by the first physician they saw. The number of physicians seen did not have a statistical relationship with years with vitiligo (ie, disease duration), sex, race, age of onset, income level, or number of sites affected.

Number of Sites Affected

The survey identified the following 23 sites affected by vitiligo: scalp, forehead, eyelids, lips, nose, cheeks, chin, neck, chest, stomach, back, upper arms, forearms, hands, wrists, fingers, genitalia, buttocks, thighs, calves/shins, ankles, feet, and toes. The average (SD) number of sites affected was 12 (6). The number of sites affected was correlated to the recommendation for phototherapy, while the recommendation for excimer laser therapy was inversely associated with the number of sites affected. The median number of sites affected for those who were not prescribed phototherapy was 10 (interquartile range [IQR]=9; P=.05); the median number of sites affected for those who were prescribed phototherapy was 15 (IQR=11). The association between the number of sites affected and whether the patient proceeded with phototherapy was not statistically significant. The need for phototherapy was not related to years with vitiligo (ie, disease duration), sex, or race.

Excimer laser therapy was prescribed more often to patients with fewer sites affected (median of 9 [IQR=3] vs median of 15 [IQR=9]; P=.04). Respondents who had fewer sites affected were on average more likely to proceed with excimer laser therapy (median of 8 [IQR=4] vs median of 11 [IQR=5]). The association between the number of sites affected and whether the patient proceeded with excimer laser therapy was not statistically significant.

Access to Topical Medications

Forty-one percent (36/87) of respondents reported difficulty accessing 1 or more topical therapies. Of 52 respondents who were prescribed a topical corticosteroid, 12 (23%) reported difficulty accessing therapy. Of 67 respondents who were prescribed a topical calcineurin inhibitor, 27 (40%) reported difficulty accessing medication (tacrolimus, n=17; pimecrolimus, n=10). Calcipotriene prescription coverage was not specifically addressed in this survey, as it usually is a second-line or adjunctive medication. Difficulty getting topical tacrolimus but not topical corticosteroids was associated with female sex (P=.03) but was not associated with race, income level, or level of education. Difficulty obtaining medication was not related to race, sex, level of education, or income level.

Consequences of Phototherapy

Twenty-three of 34 respondents (68%) who were told they required phototherapy actually received phototherapy and reported paying $38 weekly (IQR=$75). The majority of patients who proceeded with phototherapy lived (17/23 [74%]) or worked (16/23 [70%]) within 20 minutes of the therapy center. Self-reported response to phototherapy was good to very good in 65% (15/23) of respondents and no response in 30% (7/23); only 1 respondent reported worsening vitiligo. Sixty percent (15/25) of respondents said they were not satisfied with phototherapy. Respondents who were satisfied with the outcome of phototherapy had on average fewer sites affected by vitiligo (mean [SD], 10 [8]; P=.05). The association with other demographic and economic parameters (eg, sex, race, level of education, income level) was not statistically significant. Proceeding with phototherapy was not related to race, sex, level of education, or income level.

When questioned how many aspects of daily life (eg, work, home, school) were affected by phototherapy, 40% (35/87) of respondents reported that more than one life parameter was disturbed. Thirty-five percent (8/23) of respondents who received phototherapy reported that it affected their daily life “quite a bit” or “severely.” More respondents were likely to report that the therapy interfered with their life “somewhat,” “quite a bit,” or “severely” (76% [19/25]; 95% confidence interval, 55%-92%; P=.01) rather than “not at all” or “a little.”

Excimer Laser

Nine of 17 respondents (53%) who were recommended to undergo excimer laser therapy actually received therapy and reported paying $100 weekly (IQR=$60).

There was a trend toward significance of excimer usage being associated with lower age quartile (0–20 years)(P=.0553) and income more than $100,000 (P=.0788), neither of which reached statistical significance.

Insurance Coverage

Respondents were offered 7 answer options regarding the reason for noncoverage of topical calcineurin inhibitors. They were allowed to pick more than one reason where appropriate. For individuals who were prescribed topical tacrolimus but did not receive drug (n=17), the following reasons were cited: “no insurance coverage for the medication” (59% [10/17]), “your deductible was too high” (24% [4/17]), “prior authorization failed to produce coverage of the medication” (24% [4/17]), “your copay was prohibitively expensive” (24% [4/17]), “you were uncomfortable with the medication’s side effects” (18% [3/17]), “the tube was too small to cover your skin affected areas” (12% [2/17]), and “other” (29% [5/17]). Three patients selected 3 or more reasons, 8 patients selected 2 reasons, and 5 patients selected one reason.

Comment

It has been reported that patients with vitiligo may have difficulty related to treatment compliance for a variety of reasons.⁵ We identified notable barriers that arise for some, if not all, patients with vitiligo in the United States at some point in their care, including interference with other aspects of daily life, lack of coverage by current health insurance provider, and high out-of-pocket expenses, in addition to the negative effects of vitiligo on quality of life that have already been reported.^6,7 These barriers are not a function of race/ethnicity, income level, or age of onset, but they may be impacted, as in the case of tacrolimus, by female sex. It is clear that, based on this study’s numbers, many patients will be unable to receive and/or comply with recommended treatment plans.

A limitation of this analysis is the study population, a select group of patients who had not been prescribed all the therapies in question. The sample size may not be large enough to demonstrate differences between level of education, race, or income level; however, even with a sample size of 87 respondents, the barriers to access of care are prominent. Larger population-based surveys would potentially tease out patterns of barriers not apparent with a smaller sample. No data were generated specific to calcipotriene, and this medication was not specified as a write-in agent on open question by any respondents; therefore, access to topical calcipotriene cannot be projected from this study. Phototherapy was queried as a nonspecific term and the breakdown of NB-UVB versus psoralen plus UVA was not available for this survey. Data suggesting a burden of socioeconomic barriers have been reported for atopic dermatitis⁸ and psoriasis,⁹ which corroborate the need for greater research in the field of access to care in dermatology.

Despite some advancement in the care of vitiligo, patients often are unable to access preferred or recommended treatment modalities. Standard recommendations for care are initial usage of calcineurin inhibitors for facial involvement and topical high-potency corticosteroids for involvement of the body.^3,4 Based on this survey, it would seem that many patients are not able to receive the standard of care. Similarly, NB-UVB phototherapy and excimer laser therapy are recommended for widespread vitiligo and lesions unresponsive to topical care. It would seem that almost half of our respondents did not have access to one or more of the recommended therapies. Barriers to care may have substantial clinical and psychological outcomes, which were not evaluated in this study but merit future research.

Vitiligo is a disorder typified by loss of pigmentation. Worldwide estimates of disease demonstrate 0.4% to 2% prevalence.¹ Vitiligo generally is felt to be an autoimmune disorder with a complex multifactorial inheritance.² Therapeutic options for vitiligo are largely off label and include topical corticosteroids, topical calcineurin inhibitors, narrowband UVB (NB-UVB) light phototherapy, and excimer (308 nm) laser therapy.^3,4 Therapies for vitiligo are time consuming, as most topical therapies require twice-daily application. Additionally, many patients require 2 or more topical therapies due to involvement of both the head and neck as well as other body sites.^3,4 Generalized disease often is treated with NB-UVB therapy 3 times weekly in-office visits, while excimer laser therapy is used for limited disease resistant to topical agents.^3,4

Many barriers to good outcomes and care exist for patients with vitiligo.⁵ Patients may experience reduced quality of life and/or sexual dysfunction because of vitiligo lesions. The purpose of this pilot study was to identify barriers to access of care in vitiligo patients.

Methods

A survey was designed and then reviewed for unclear wording by members of the local vitiligo support group at Mount Sinai St. Luke’s-Roosevelt Hospital and Beth Israel Medical Centers (New York, New York). Linguistic revision and clarifications were added to the survey to correct identified communication problems. The survey was then posted using an Internet-based survey software. Links to the survey were sent via email to 107 individuals in a LISTSERV comprising Vitiligo Support International members who participated in a New York City support group (led by C.G. and N.B.S.). Only 1 email was used per household and only individuals 18 years or older could participate. These individuals were asked to complete a deidentified, 82-question, institutional review board–reviewed and exempted survey addressing issues affecting delivery and receipt of medical care for vitiligo.

Data were analyzed using the χ² test, analysis of variance, or Student t test depending on the type of variable (categorical vs continuous). Fisher exact or Wilcoxon-Mann-Whitney tests were used when distributional assumptions were not met. A type I error rate (α=.05) was used to determine statistical significance. All analyses were performed using SAS 9.3 software.

Results

Respondents

The survey was completed by 81% (n=87) of individuals. The mean (SD) age of the treated patients about whom the respondents communicated was 33 (16) years and 71% (n=62) were women. The majority of respondents (64 [74%]) reported their race as white, followed by African American/black (12 [14%]), Hispanic (7 [8%]), and Asian (4 [5%]). Twenty-nine percent (22/76) of respondents reported a family income of less than $50,000 per year, 34% (26/76) reported an income of $50,000 to $100,000, and 37% (28/76) reported an income greater than $100,000, while 11 respondents did not report income.

Number of Physicians Seen

Respondents had reportedly seen an average (SD) number of 2 (1) physicians in the past/present before being offered any therapy for vitiligo and only 37% (32/87) of respondents reported being offered therapy by the first physician they saw. The number of physicians seen did not have a statistical relationship with years with vitiligo (ie, disease duration), sex, race, age of onset, income level, or number of sites affected.

Number of Sites Affected

The survey identified the following 23 sites affected by vitiligo: scalp, forehead, eyelids, lips, nose, cheeks, chin, neck, chest, stomach, back, upper arms, forearms, hands, wrists, fingers, genitalia, buttocks, thighs, calves/shins, ankles, feet, and toes. The average (SD) number of sites affected was 12 (6). The number of sites affected was correlated to the recommendation for phototherapy, while the recommendation for excimer laser therapy was inversely associated with the number of sites affected. The median number of sites affected for those who were not prescribed phototherapy was 10 (interquartile range [IQR]=9; P=.05); the median number of sites affected for those who were prescribed phototherapy was 15 (IQR=11). The association between the number of sites affected and whether the patient proceeded with phototherapy was not statistically significant. The need for phototherapy was not related to years with vitiligo (ie, disease duration), sex, or race.

Excimer laser therapy was prescribed more often to patients with fewer sites affected (median of 9 [IQR=3] vs median of 15 [IQR=9]; P=.04). Respondents who had fewer sites affected were on average more likely to proceed with excimer laser therapy (median of 8 [IQR=4] vs median of 11 [IQR=5]). The association between the number of sites affected and whether the patient proceeded with excimer laser therapy was not statistically significant.

Access to Topical Medications

Forty-one percent (36/87) of respondents reported difficulty accessing 1 or more topical therapies. Of 52 respondents who were prescribed a topical corticosteroid, 12 (23%) reported difficulty accessing therapy. Of 67 respondents who were prescribed a topical calcineurin inhibitor, 27 (40%) reported difficulty accessing medication (tacrolimus, n=17; pimecrolimus, n=10). Calcipotriene prescription coverage was not specifically addressed in this survey, as it usually is a second-line or adjunctive medication. Difficulty getting topical tacrolimus but not topical corticosteroids was associated with female sex (P=.03) but was not associated with race, income level, or level of education. Difficulty obtaining medication was not related to race, sex, level of education, or income level.

Consequences of Phototherapy

Twenty-three of 34 respondents (68%) who were told they required phototherapy actually received phototherapy and reported paying $38 weekly (IQR=$75). The majority of patients who proceeded with phototherapy lived (17/23 [74%]) or worked (16/23 [70%]) within 20 minutes of the therapy center. Self-reported response to phototherapy was good to very good in 65% (15/23) of respondents and no response in 30% (7/23); only 1 respondent reported worsening vitiligo. Sixty percent (15/25) of respondents said they were not satisfied with phototherapy. Respondents who were satisfied with the outcome of phototherapy had on average fewer sites affected by vitiligo (mean [SD], 10 [8]; P=.05). The association with other demographic and economic parameters (eg, sex, race, level of education, income level) was not statistically significant. Proceeding with phototherapy was not related to race, sex, level of education, or income level.

When questioned how many aspects of daily life (eg, work, home, school) were affected by phototherapy, 40% (35/87) of respondents reported that more than one life parameter was disturbed. Thirty-five percent (8/23) of respondents who received phototherapy reported that it affected their daily life “quite a bit” or “severely.” More respondents were likely to report that the therapy interfered with their life “somewhat,” “quite a bit,” or “severely” (76% [19/25]; 95% confidence interval, 55%-92%; P=.01) rather than “not at all” or “a little.”

Excimer Laser

Nine of 17 respondents (53%) who were recommended to undergo excimer laser therapy actually received therapy and reported paying $100 weekly (IQR=$60).

There was a trend toward significance of excimer usage being associated with lower age quartile (0–20 years)(P=.0553) and income more than $100,000 (P=.0788), neither of which reached statistical significance.

Insurance Coverage

Respondents were offered 7 answer options regarding the reason for noncoverage of topical calcineurin inhibitors. They were allowed to pick more than one reason where appropriate. For individuals who were prescribed topical tacrolimus but did not receive drug (n=17), the following reasons were cited: “no insurance coverage for the medication” (59% [10/17]), “your deductible was too high” (24% [4/17]), “prior authorization failed to produce coverage of the medication” (24% [4/17]), “your copay was prohibitively expensive” (24% [4/17]), “you were uncomfortable with the medication’s side effects” (18% [3/17]), “the tube was too small to cover your skin affected areas” (12% [2/17]), and “other” (29% [5/17]). Three patients selected 3 or more reasons, 8 patients selected 2 reasons, and 5 patients selected one reason.

Comment

It has been reported that patients with vitiligo may have difficulty related to treatment compliance for a variety of reasons.⁵ We identified notable barriers that arise for some, if not all, patients with vitiligo in the United States at some point in their care, including interference with other aspects of daily life, lack of coverage by current health insurance provider, and high out-of-pocket expenses, in addition to the negative effects of vitiligo on quality of life that have already been reported.^6,7 These barriers are not a function of race/ethnicity, income level, or age of onset, but they may be impacted, as in the case of tacrolimus, by female sex. It is clear that, based on this study’s numbers, many patients will be unable to receive and/or comply with recommended treatment plans.

A limitation of this analysis is the study population, a select group of patients who had not been prescribed all the therapies in question. The sample size may not be large enough to demonstrate differences between level of education, race, or income level; however, even with a sample size of 87 respondents, the barriers to access of care are prominent. Larger population-based surveys would potentially tease out patterns of barriers not apparent with a smaller sample. No data were generated specific to calcipotriene, and this medication was not specified as a write-in agent on open question by any respondents; therefore, access to topical calcipotriene cannot be projected from this study. Phototherapy was queried as a nonspecific term and the breakdown of NB-UVB versus psoralen plus UVA was not available for this survey. Data suggesting a burden of socioeconomic barriers have been reported for atopic dermatitis⁸ and psoriasis,⁹ which corroborate the need for greater research in the field of access to care in dermatology.

Despite some advancement in the care of vitiligo, patients often are unable to access preferred or recommended treatment modalities. Standard recommendations for care are initial usage of calcineurin inhibitors for facial involvement and topical high-potency corticosteroids for involvement of the body.^3,4 Based on this survey, it would seem that many patients are not able to receive the standard of care. Similarly, NB-UVB phototherapy and excimer laser therapy are recommended for widespread vitiligo and lesions unresponsive to topical care. It would seem that almost half of our respondents did not have access to one or more of the recommended therapies. Barriers to care may have substantial clinical and psychological outcomes, which were not evaluated in this study but merit future research.

To the Editor:

Prior studies have assessed the quality of text-based dermatology information on the Internet using traditional search engine queries.¹ However, little is understood about the sources, accuracy, and quality of online dermatology images derived from direct image searches. Previous work has shown that direct search engine image queries were largely accurate for 3 pediatric dermatology diagnosis searches: atopic dermatitis, lichen striatus, and subcutaneous fat necrosis.² We assessed images obtained for common dermatologic conditions from a Google image search (GIS) compared to a traditional text-based Google web search (GWS).

Image results for 32 unique dermatologic search terms were analyzed (Table 1). These search terms were selected using the results of a prior study that identified the most common dermatologic diagnoses that led users to the 2 most popular dermatology-specific websites worldwide: the American Academy of Dermatology (www.aad.org) and DermNet New Zealand (www.dermnetnz.org).³ The Alexa directory (www.alexa.com), a large publicly available Internet analytics resource, was used to determine the most common dermatology search terms that led a user to either www.dermnetnz.org or www.aad.org. In addition, searches for the 3 most common types of skin cancer—melanoma, squamous cell carcinoma, and basal cell carcinoma—were included. Each term was entered into a GIS and a GWS. The first 10 results, which represent 92% of the websites ultimately visited by users,⁴ were analyzed. The source, diagnostic accuracy, and Fitzpatrick skin type of the images was determined. Website sources were organized into 11 categories. All data collection occurred within a 1-week period in August 2015.

A total of 320 images were analyzed. In the GIS, private websites (36%), dermatology association websites (28%), and general health information websites (10%) were the 3 most common sources. In the GWS, health information websites (35%), private websites (21%), and dermatology association websites (20%) accounted for the most common sources (Table 2). The majority of images were of Fitzpatrick skin types I and II (89%) and nearly all images were diagnostically accurate (98%). There was no statistically significant difference in accuracy of diagnosis between physician-associated websites (100% accuracy) versus nonphysician-associated sites (98% accuracy, P=.25).

Our results showed high diagnostic accuracy among the top GIS results for common dermatology search terms. Diagnostic accuracy did not vary between websites that were physician associated versus those that were not. Our results are comparable to the reported accuracy of online dermatologic health information.¹ In GIS results, the majority of images were provided by private websites, whereas the top websites in GWS results were health information websites.

Only 1% of images were of Fitzpatrick skin types VI and VII. Presentation of skin diseases is remarkably different based on the patient’s skin type.⁵ The shortage of readily accessible images of skin of color is in line with the lack of familiarity physicians and trainees have with dermatologic conditions in ethnic skin.⁶

Based on the results from this analysis, providers and patients searching for dermatologic conditions via a direct GIS should be cognizant of several considerations. Although our results showed that GIS was accurate, the searcher should note that image-based searches are not accompanied by relevant text that can help confirm relevancy and accuracy. Image searches depend on textual tags added by the source website. Websites that represent dermatological associations and academic centers can add an additional layer of confidence for users. Patients and clinicians also should be aware that the consideration of a patient’s Fitzpatrick skin type is critical when assessing the relevancy of a GIS result. In conclusion, search results via GIS queries are accurate for the dermatological diagnoses tested but may be lacking in skin of color variations, suggesting a potential unmet need based on our growing ethnic skin population.

To the Editor:

Prior studies have assessed the quality of text-based dermatology information on the Internet using traditional search engine queries.¹ However, little is understood about the sources, accuracy, and quality of online dermatology images derived from direct image searches. Previous work has shown that direct search engine image queries were largely accurate for 3 pediatric dermatology diagnosis searches: atopic dermatitis, lichen striatus, and subcutaneous fat necrosis.² We assessed images obtained for common dermatologic conditions from a Google image search (GIS) compared to a traditional text-based Google web search (GWS).

Image results for 32 unique dermatologic search terms were analyzed (Table 1). These search terms were selected using the results of a prior study that identified the most common dermatologic diagnoses that led users to the 2 most popular dermatology-specific websites worldwide: the American Academy of Dermatology (www.aad.org) and DermNet New Zealand (www.dermnetnz.org).³ The Alexa directory (www.alexa.com), a large publicly available Internet analytics resource, was used to determine the most common dermatology search terms that led a user to either www.dermnetnz.org or www.aad.org. In addition, searches for the 3 most common types of skin cancer—melanoma, squamous cell carcinoma, and basal cell carcinoma—were included. Each term was entered into a GIS and a GWS. The first 10 results, which represent 92% of the websites ultimately visited by users,⁴ were analyzed. The source, diagnostic accuracy, and Fitzpatrick skin type of the images was determined. Website sources were organized into 11 categories. All data collection occurred within a 1-week period in August 2015.

A total of 320 images were analyzed. In the GIS, private websites (36%), dermatology association websites (28%), and general health information websites (10%) were the 3 most common sources. In the GWS, health information websites (35%), private websites (21%), and dermatology association websites (20%) accounted for the most common sources (Table 2). The majority of images were of Fitzpatrick skin types I and II (89%) and nearly all images were diagnostically accurate (98%). There was no statistically significant difference in accuracy of diagnosis between physician-associated websites (100% accuracy) versus nonphysician-associated sites (98% accuracy, P=.25).

Our results showed high diagnostic accuracy among the top GIS results for common dermatology search terms. Diagnostic accuracy did not vary between websites that were physician associated versus those that were not. Our results are comparable to the reported accuracy of online dermatologic health information.¹ In GIS results, the majority of images were provided by private websites, whereas the top websites in GWS results were health information websites.

Only 1% of images were of Fitzpatrick skin types VI and VII. Presentation of skin diseases is remarkably different based on the patient’s skin type.⁵ The shortage of readily accessible images of skin of color is in line with the lack of familiarity physicians and trainees have with dermatologic conditions in ethnic skin.⁶

Based on the results from this analysis, providers and patients searching for dermatologic conditions via a direct GIS should be cognizant of several considerations. Although our results showed that GIS was accurate, the searcher should note that image-based searches are not accompanied by relevant text that can help confirm relevancy and accuracy. Image searches depend on textual tags added by the source website. Websites that represent dermatological associations and academic centers can add an additional layer of confidence for users. Patients and clinicians also should be aware that the consideration of a patient’s Fitzpatrick skin type is critical when assessing the relevancy of a GIS result. In conclusion, search results via GIS queries are accurate for the dermatological diagnoses tested but may be lacking in skin of color variations, suggesting a potential unmet need based on our growing ethnic skin population.

To the Editor:

Prior studies have assessed the quality of text-based dermatology information on the Internet using traditional search engine queries.¹ However, little is understood about the sources, accuracy, and quality of online dermatology images derived from direct image searches. Previous work has shown that direct search engine image queries were largely accurate for 3 pediatric dermatology diagnosis searches: atopic dermatitis, lichen striatus, and subcutaneous fat necrosis.² We assessed images obtained for common dermatologic conditions from a Google image search (GIS) compared to a traditional text-based Google web search (GWS).

Image results for 32 unique dermatologic search terms were analyzed (Table 1). These search terms were selected using the results of a prior study that identified the most common dermatologic diagnoses that led users to the 2 most popular dermatology-specific websites worldwide: the American Academy of Dermatology (www.aad.org) and DermNet New Zealand (www.dermnetnz.org).³ The Alexa directory (www.alexa.com), a large publicly available Internet analytics resource, was used to determine the most common dermatology search terms that led a user to either www.dermnetnz.org or www.aad.org. In addition, searches for the 3 most common types of skin cancer—melanoma, squamous cell carcinoma, and basal cell carcinoma—were included. Each term was entered into a GIS and a GWS. The first 10 results, which represent 92% of the websites ultimately visited by users,⁴ were analyzed. The source, diagnostic accuracy, and Fitzpatrick skin type of the images was determined. Website sources were organized into 11 categories. All data collection occurred within a 1-week period in August 2015.

A total of 320 images were analyzed. In the GIS, private websites (36%), dermatology association websites (28%), and general health information websites (10%) were the 3 most common sources. In the GWS, health information websites (35%), private websites (21%), and dermatology association websites (20%) accounted for the most common sources (Table 2). The majority of images were of Fitzpatrick skin types I and II (89%) and nearly all images were diagnostically accurate (98%). There was no statistically significant difference in accuracy of diagnosis between physician-associated websites (100% accuracy) versus nonphysician-associated sites (98% accuracy, P=.25).

Our results showed high diagnostic accuracy among the top GIS results for common dermatology search terms. Diagnostic accuracy did not vary between websites that were physician associated versus those that were not. Our results are comparable to the reported accuracy of online dermatologic health information.¹ In GIS results, the majority of images were provided by private websites, whereas the top websites in GWS results were health information websites.

Only 1% of images were of Fitzpatrick skin types VI and VII. Presentation of skin diseases is remarkably different based on the patient’s skin type.⁵ The shortage of readily accessible images of skin of color is in line with the lack of familiarity physicians and trainees have with dermatologic conditions in ethnic skin.⁶

Based on the results from this analysis, providers and patients searching for dermatologic conditions via a direct GIS should be cognizant of several considerations. Although our results showed that GIS was accurate, the searcher should note that image-based searches are not accompanied by relevant text that can help confirm relevancy and accuracy. Image searches depend on textual tags added by the source website. Websites that represent dermatological associations and academic centers can add an additional layer of confidence for users. Patients and clinicians also should be aware that the consideration of a patient’s Fitzpatrick skin type is critical when assessing the relevancy of a GIS result. In conclusion, search results via GIS queries are accurate for the dermatological diagnoses tested but may be lacking in skin of color variations, suggesting a potential unmet need based on our growing ethnic skin population.

To the Editor:

Dyschromatosis symmetrica hereditaria (DSH)(Online Mendelian Inheritance in Man 127400), also called reticulate acropigmentation of Dohi, is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules of various sizes on the dorsal aspects of the hands and feet. Linkage analysis has revealed that the DSH gene locus resides on chromosome 1q11-q21,¹ and the adenosine deaminase RNA specific gene, ADAR1 (also called DSRAD), in this region has been identified as being responsible for the development of DSH.² We report a sporadic case of severe DSH with the ADAR1 gene detected in a mutation analysis.

A 6-year-old girl presented with a mixture of hyperpigmented and hypopigmented macules on the dorsal aspects of the hands and feet and the curved side of the wrists, heels, and knees, as well as scattered frecklelike and depigmented spots on the face, ears, neck, arms, and upper back (Figure 1). Her parents noted that hyperpigmented and hypopigmented macules on the dorsal aspects of the hands developed at 5 months of age. Exacerbation after exposure to sunlight resulted in the eruption becoming remarkable in summer and fainter in winter. The skin lesions gradually became more progressive. Physical examination revealed that the patient generally was healthy.

After obtaining informed consent, we performed a mutation analysis of the ADAR1 gene in our patient and her parents. We used a kit to extract genomic DNA from peripheral blood, which was then used to amplify the exons of the ADAR1 gene with intronic flanking sequences by polymerase chain reaction with the primer.³ After amplification, polymerase chain reaction products were purified. We sequenced the ADAR1 gene. Sequence comparisons and analysis found that the patient (proband) carried a heterozygous insertional mutation c.2253insG in exon 6 of the ADAR1 gene. This mutation was not detected in the proband’s healthy parents and 100 normal individuals (Figure 2).

Dyschromatosis symmetrica hereditaria is acquired by autosomal-dominant inheritance and is mainly reported in Asians, especially in Japan and China. Oyama et al⁴ reviewed 185 cases of DSH in Japan and found the onset of this disease usually was during infancy or childhood; 73% of patients developed the skin lesions before 6 years of age. Suzuki et al⁵ reported 10 unrelated Japanese patients and found the onset of disease ranged from 1 year of age to childhood. Zhang et al^1,6 investigated 78 Chinese patients with DSH including 8 multigenerational families and 2 sporadic patients and found the age of disease onset ranged from 6 months to 15 years of age. The age of onset in our patient (5 months) was younger than these prior reports.

Patients with DSH have a characteristic appearance including a mixture of hyperpigmented and hypopigmented macules of various sizes on the dorsal aspects of the hands and feet. Few patients have similar lesions on the knees and elbows. Many patients have frecklelike macules on the face and arms.^1-6 One patient has been described with scattered depigmented spots on the face and chest.¹ Our patient had a characteristic appearance as well as some special manifestations including skin lesions on the curved side of the wrist, ears, neck, and upper back.

The human ADAR1 gene spans 30 kilobase and contains 15 exons. It encodes RNA-specific adenosine deaminase composed of 1226 amino acid residues. This enzyme is important for various functions such as site-specific RNA editing and nuclear translation. This enzyme has 2 Z-alpha domains, 3 double-stranded RNA–binding domains, and the putative deaminase domain corresponding to exon 2, exons 2 to 7, and exons 9 to 14 of ADAR1, respectively.⁶

Mutation analysis of the ADAR1 gene in this case showed heterozygous insertion mutation c.2253insG in exon 6 of the ADAR1 gene, which changed the reading frame, and 475 amino acid residues in C-terminus are replaced by 90 amino acid residues (TSSRAQVRLPSKSWGSLVPSRLRTQQEA RQAGSSRCGSPCLDWGEREGRTHGFHRG NPSDRGQSQKNYAPPLKVPRSTAKT DTPSHWQHLP). This mutation was not detected in the proband’s healthy parents and the 100 control individuals, which indicated that it was a de novo mutation and the pathogenic mutation of DSH rather than a common polymorphism.

In conclusion, we report a novel mutation of the ADAR1 gene with a heavy clinical phenotype in DSH. This study expands the spectrum of clinical manifestations and demonstrates the ADAR1 mutation in DSH.

Acknowledgments
We are most grateful to the patient and her family for taking part in our study.

To the Editor:

Dyschromatosis symmetrica hereditaria (DSH)(Online Mendelian Inheritance in Man 127400), also called reticulate acropigmentation of Dohi, is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules of various sizes on the dorsal aspects of the hands and feet. Linkage analysis has revealed that the DSH gene locus resides on chromosome 1q11-q21,¹ and the adenosine deaminase RNA specific gene, ADAR1 (also called DSRAD), in this region has been identified as being responsible for the development of DSH.² We report a sporadic case of severe DSH with the ADAR1 gene detected in a mutation analysis.

A 6-year-old girl presented with a mixture of hyperpigmented and hypopigmented macules on the dorsal aspects of the hands and feet and the curved side of the wrists, heels, and knees, as well as scattered frecklelike and depigmented spots on the face, ears, neck, arms, and upper back (Figure 1). Her parents noted that hyperpigmented and hypopigmented macules on the dorsal aspects of the hands developed at 5 months of age. Exacerbation after exposure to sunlight resulted in the eruption becoming remarkable in summer and fainter in winter. The skin lesions gradually became more progressive. Physical examination revealed that the patient generally was healthy.

After obtaining informed consent, we performed a mutation analysis of the ADAR1 gene in our patient and her parents. We used a kit to extract genomic DNA from peripheral blood, which was then used to amplify the exons of the ADAR1 gene with intronic flanking sequences by polymerase chain reaction with the primer.³ After amplification, polymerase chain reaction products were purified. We sequenced the ADAR1 gene. Sequence comparisons and analysis found that the patient (proband) carried a heterozygous insertional mutation c.2253insG in exon 6 of the ADAR1 gene. This mutation was not detected in the proband’s healthy parents and 100 normal individuals (Figure 2).

Dyschromatosis symmetrica hereditaria is acquired by autosomal-dominant inheritance and is mainly reported in Asians, especially in Japan and China. Oyama et al⁴ reviewed 185 cases of DSH in Japan and found the onset of this disease usually was during infancy or childhood; 73% of patients developed the skin lesions before 6 years of age. Suzuki et al⁵ reported 10 unrelated Japanese patients and found the onset of disease ranged from 1 year of age to childhood. Zhang et al^1,6 investigated 78 Chinese patients with DSH including 8 multigenerational families and 2 sporadic patients and found the age of disease onset ranged from 6 months to 15 years of age. The age of onset in our patient (5 months) was younger than these prior reports.

Patients with DSH have a characteristic appearance including a mixture of hyperpigmented and hypopigmented macules of various sizes on the dorsal aspects of the hands and feet. Few patients have similar lesions on the knees and elbows. Many patients have frecklelike macules on the face and arms.^1-6 One patient has been described with scattered depigmented spots on the face and chest.¹ Our patient had a characteristic appearance as well as some special manifestations including skin lesions on the curved side of the wrist, ears, neck, and upper back.

The human ADAR1 gene spans 30 kilobase and contains 15 exons. It encodes RNA-specific adenosine deaminase composed of 1226 amino acid residues. This enzyme is important for various functions such as site-specific RNA editing and nuclear translation. This enzyme has 2 Z-alpha domains, 3 double-stranded RNA–binding domains, and the putative deaminase domain corresponding to exon 2, exons 2 to 7, and exons 9 to 14 of ADAR1, respectively.⁶

Mutation analysis of the ADAR1 gene in this case showed heterozygous insertion mutation c.2253insG in exon 6 of the ADAR1 gene, which changed the reading frame, and 475 amino acid residues in C-terminus are replaced by 90 amino acid residues (TSSRAQVRLPSKSWGSLVPSRLRTQQEA RQAGSSRCGSPCLDWGEREGRTHGFHRG NPSDRGQSQKNYAPPLKVPRSTAKT DTPSHWQHLP). This mutation was not detected in the proband’s healthy parents and the 100 control individuals, which indicated that it was a de novo mutation and the pathogenic mutation of DSH rather than a common polymorphism.

In conclusion, we report a novel mutation of the ADAR1 gene with a heavy clinical phenotype in DSH. This study expands the spectrum of clinical manifestations and demonstrates the ADAR1 mutation in DSH.

Acknowledgments
We are most grateful to the patient and her family for taking part in our study.

To the Editor:

Dyschromatosis symmetrica hereditaria (DSH)(Online Mendelian Inheritance in Man 127400), also called reticulate acropigmentation of Dohi, is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules of various sizes on the dorsal aspects of the hands and feet. Linkage analysis has revealed that the DSH gene locus resides on chromosome 1q11-q21,¹ and the adenosine deaminase RNA specific gene, ADAR1 (also called DSRAD), in this region has been identified as being responsible for the development of DSH.² We report a sporadic case of severe DSH with the ADAR1 gene detected in a mutation analysis.

A 6-year-old girl presented with a mixture of hyperpigmented and hypopigmented macules on the dorsal aspects of the hands and feet and the curved side of the wrists, heels, and knees, as well as scattered frecklelike and depigmented spots on the face, ears, neck, arms, and upper back (Figure 1). Her parents noted that hyperpigmented and hypopigmented macules on the dorsal aspects of the hands developed at 5 months of age. Exacerbation after exposure to sunlight resulted in the eruption becoming remarkable in summer and fainter in winter. The skin lesions gradually became more progressive. Physical examination revealed that the patient generally was healthy.

After obtaining informed consent, we performed a mutation analysis of the ADAR1 gene in our patient and her parents. We used a kit to extract genomic DNA from peripheral blood, which was then used to amplify the exons of the ADAR1 gene with intronic flanking sequences by polymerase chain reaction with the primer.³ After amplification, polymerase chain reaction products were purified. We sequenced the ADAR1 gene. Sequence comparisons and analysis found that the patient (proband) carried a heterozygous insertional mutation c.2253insG in exon 6 of the ADAR1 gene. This mutation was not detected in the proband’s healthy parents and 100 normal individuals (Figure 2).

Dyschromatosis symmetrica hereditaria is acquired by autosomal-dominant inheritance and is mainly reported in Asians, especially in Japan and China. Oyama et al⁴ reviewed 185 cases of DSH in Japan and found the onset of this disease usually was during infancy or childhood; 73% of patients developed the skin lesions before 6 years of age. Suzuki et al⁵ reported 10 unrelated Japanese patients and found the onset of disease ranged from 1 year of age to childhood. Zhang et al^1,6 investigated 78 Chinese patients with DSH including 8 multigenerational families and 2 sporadic patients and found the age of disease onset ranged from 6 months to 15 years of age. The age of onset in our patient (5 months) was younger than these prior reports.

Patients with DSH have a characteristic appearance including a mixture of hyperpigmented and hypopigmented macules of various sizes on the dorsal aspects of the hands and feet. Few patients have similar lesions on the knees and elbows. Many patients have frecklelike macules on the face and arms.^1-6 One patient has been described with scattered depigmented spots on the face and chest.¹ Our patient had a characteristic appearance as well as some special manifestations including skin lesions on the curved side of the wrist, ears, neck, and upper back.

The human ADAR1 gene spans 30 kilobase and contains 15 exons. It encodes RNA-specific adenosine deaminase composed of 1226 amino acid residues. This enzyme is important for various functions such as site-specific RNA editing and nuclear translation. This enzyme has 2 Z-alpha domains, 3 double-stranded RNA–binding domains, and the putative deaminase domain corresponding to exon 2, exons 2 to 7, and exons 9 to 14 of ADAR1, respectively.⁶

Mutation analysis of the ADAR1 gene in this case showed heterozygous insertion mutation c.2253insG in exon 6 of the ADAR1 gene, which changed the reading frame, and 475 amino acid residues in C-terminus are replaced by 90 amino acid residues (TSSRAQVRLPSKSWGSLVPSRLRTQQEA RQAGSSRCGSPCLDWGEREGRTHGFHRG NPSDRGQSQKNYAPPLKVPRSTAKT DTPSHWQHLP). This mutation was not detected in the proband’s healthy parents and the 100 control individuals, which indicated that it was a de novo mutation and the pathogenic mutation of DSH rather than a common polymorphism.

In conclusion, we report a novel mutation of the ADAR1 gene with a heavy clinical phenotype in DSH. This study expands the spectrum of clinical manifestations and demonstrates the ADAR1 mutation in DSH.

Acknowledgments
We are most grateful to the patient and her family for taking part in our study.

To the Editor:

We report 2 cases of desmoplastic hairless hypopigmented nevi (DHHN), which are giant congenital melanocytic nevi (GCMN) that show sclerosis with progressive loss of pigment and hair. These changes in GCMN could be considered signs of regression.

A 6-year-old boy presented in the dermatology department with an asymptomatic skin lesion on the right buttock since birth. The parents claimed that the lesion was darkly pigmented at birth and gradually increased in size, with progressive reduction in color in the last 2 years. Physical examination revealed a 10×6-cm, well-defined, raised plaque on the upper medial side of the right buttock (Figure 1). The plaque was firm with a shiny smooth surface and was devoid of hair. The surface was flesh colored with scattered pigmented spots. A punch biopsy of the lesion showed increased melanin content in the basal cell layer. The upper dermis showed small nests of epithelioid nevus cells, most of them containing melanin pigment (Figure 2). In the lower two-thirds of the dermis, nevus cells were both epithelioid and spindle shaped and were arranged in between thick sclerotic collagen bundles with an increased number of fibroblasts. There was a marked reduction in the number of hair follicles. Immunohistochemical staining results were S-100 positive and CD34 negative.

A 5-year-old boy presented in the dermatology department with a large hairy GCMN covering most of the trunk since birth. In the last 1.5 years the parents noted gradual fading of color, decreased hair density, and increased induration of the nevus. Physical examination revealed a large plaque covering the anterior aspect of the trunk (Figure 3) and the back extending down to the buttocks. The lesion formed large skin folds that were more pronounced on the back. The nevus was darkly pigmented with large areas of lighter color that were indurated, devoid of hair, and showed small spots of dark pigmentation. A punch biopsy from the lesion showed small nests of nevus cells in the upper part of the reticular dermis. In the lower part of the dermis, nevus cells were arranged in single units in between thick collagen bundles.

In 2003, Ruiz-Maldonado et al¹ described 4 cases of GCMN that showed progressive loss of pigmentation, sclerosis, and hair loss. They proposed the term desmoplastic hairless hypopigmented nevus for their cases and considered it as a variant of GCMN.¹ Prior to these reported cases, 2 similar cases were described. The first was a report by Hogan et al² in 1988 of a 7-month-old girl with a GCMN involving the occipital area and the upper back that became indurated and ulcerated with progressive involution that led to complete disappearance of the nevus. The second was a report by Pattee et al³ in 2001 of a newborn with a GCMN located on the trunk with progressive sclerodermiform reaction. After surgical excision of the nevus, the sclerotic margin disappeared.³

Following the report by Ruiz-Maldonaldo et al,¹ 5 more cases of DHHN were described.^4-8 All cases of DHHN share the same clinical and histopathological features. The clinical features include a GCMN present since birth with progressive sclerosis over time and loss of both pigmentation and hair. Histologically, DHHN shows the typical changes of a congenital melanocytic nevus with decreased numbers of nevus cells, thick sclerotic collagen bundles of the reticular dermis, increased number of fibroblasts, and decreased number of hair follicles. The progressive reduction in the number of nevus cells in melanocytic nevi is considered a sign of regression. Spontaneous regression was rarely described in GCMN, and all the reported cases of regression were associated with desmoplasia.⁴ Desmoplasia is thought to be induced by either melanocytes that function as adaptive fibroblasts or by fibroblasts themselves, as fibroblasts can show multifunctional differentiation capabilities.⁹ The direct correlation between the increased induration of DHHN and pigment depletion supports the former hypothesis. The absence of inflammatory cells within the sections of DHHN lesions is against the possibility of an immune-mediated reaction as a cause for the clinical and histological changes seen in this rare form of GCMN. The progressive hair loss in DHHN may be explained by the progressive fibrotic changes in the reticular dermis that affect the blood supply to follicles, leading to atrophy or even absence of the follicles. The progressive reduction in the number of nevus cells in DHHN reduces the potential for malignant transformation and hence following a watchful waiting strategy is a reasonable way to manage these nevi.

We present 2 patients with DHHN, which is a rare form of GCMN that shows signs of regression. The cause of these changes is still unclear.

To the Editor:

We report 2 cases of desmoplastic hairless hypopigmented nevi (DHHN), which are giant congenital melanocytic nevi (GCMN) that show sclerosis with progressive loss of pigment and hair. These changes in GCMN could be considered signs of regression.

A 6-year-old boy presented in the dermatology department with an asymptomatic skin lesion on the right buttock since birth. The parents claimed that the lesion was darkly pigmented at birth and gradually increased in size, with progressive reduction in color in the last 2 years. Physical examination revealed a 10×6-cm, well-defined, raised plaque on the upper medial side of the right buttock (Figure 1). The plaque was firm with a shiny smooth surface and was devoid of hair. The surface was flesh colored with scattered pigmented spots. A punch biopsy of the lesion showed increased melanin content in the basal cell layer. The upper dermis showed small nests of epithelioid nevus cells, most of them containing melanin pigment (Figure 2). In the lower two-thirds of the dermis, nevus cells were both epithelioid and spindle shaped and were arranged in between thick sclerotic collagen bundles with an increased number of fibroblasts. There was a marked reduction in the number of hair follicles. Immunohistochemical staining results were S-100 positive and CD34 negative.

A 5-year-old boy presented in the dermatology department with a large hairy GCMN covering most of the trunk since birth. In the last 1.5 years the parents noted gradual fading of color, decreased hair density, and increased induration of the nevus. Physical examination revealed a large plaque covering the anterior aspect of the trunk (Figure 3) and the back extending down to the buttocks. The lesion formed large skin folds that were more pronounced on the back. The nevus was darkly pigmented with large areas of lighter color that were indurated, devoid of hair, and showed small spots of dark pigmentation. A punch biopsy from the lesion showed small nests of nevus cells in the upper part of the reticular dermis. In the lower part of the dermis, nevus cells were arranged in single units in between thick collagen bundles.

In 2003, Ruiz-Maldonado et al¹ described 4 cases of GCMN that showed progressive loss of pigmentation, sclerosis, and hair loss. They proposed the term desmoplastic hairless hypopigmented nevus for their cases and considered it as a variant of GCMN.¹ Prior to these reported cases, 2 similar cases were described. The first was a report by Hogan et al² in 1988 of a 7-month-old girl with a GCMN involving the occipital area and the upper back that became indurated and ulcerated with progressive involution that led to complete disappearance of the nevus. The second was a report by Pattee et al³ in 2001 of a newborn with a GCMN located on the trunk with progressive sclerodermiform reaction. After surgical excision of the nevus, the sclerotic margin disappeared.³

Following the report by Ruiz-Maldonaldo et al,¹ 5 more cases of DHHN were described.^4-8 All cases of DHHN share the same clinical and histopathological features. The clinical features include a GCMN present since birth with progressive sclerosis over time and loss of both pigmentation and hair. Histologically, DHHN shows the typical changes of a congenital melanocytic nevus with decreased numbers of nevus cells, thick sclerotic collagen bundles of the reticular dermis, increased number of fibroblasts, and decreased number of hair follicles. The progressive reduction in the number of nevus cells in melanocytic nevi is considered a sign of regression. Spontaneous regression was rarely described in GCMN, and all the reported cases of regression were associated with desmoplasia.⁴ Desmoplasia is thought to be induced by either melanocytes that function as adaptive fibroblasts or by fibroblasts themselves, as fibroblasts can show multifunctional differentiation capabilities.⁹ The direct correlation between the increased induration of DHHN and pigment depletion supports the former hypothesis. The absence of inflammatory cells within the sections of DHHN lesions is against the possibility of an immune-mediated reaction as a cause for the clinical and histological changes seen in this rare form of GCMN. The progressive hair loss in DHHN may be explained by the progressive fibrotic changes in the reticular dermis that affect the blood supply to follicles, leading to atrophy or even absence of the follicles. The progressive reduction in the number of nevus cells in DHHN reduces the potential for malignant transformation and hence following a watchful waiting strategy is a reasonable way to manage these nevi.

We present 2 patients with DHHN, which is a rare form of GCMN that shows signs of regression. The cause of these changes is still unclear.

To the Editor:

We report 2 cases of desmoplastic hairless hypopigmented nevi (DHHN), which are giant congenital melanocytic nevi (GCMN) that show sclerosis with progressive loss of pigment and hair. These changes in GCMN could be considered signs of regression.

A 6-year-old boy presented in the dermatology department with an asymptomatic skin lesion on the right buttock since birth. The parents claimed that the lesion was darkly pigmented at birth and gradually increased in size, with progressive reduction in color in the last 2 years. Physical examination revealed a 10×6-cm, well-defined, raised plaque on the upper medial side of the right buttock (Figure 1). The plaque was firm with a shiny smooth surface and was devoid of hair. The surface was flesh colored with scattered pigmented spots. A punch biopsy of the lesion showed increased melanin content in the basal cell layer. The upper dermis showed small nests of epithelioid nevus cells, most of them containing melanin pigment (Figure 2). In the lower two-thirds of the dermis, nevus cells were both epithelioid and spindle shaped and were arranged in between thick sclerotic collagen bundles with an increased number of fibroblasts. There was a marked reduction in the number of hair follicles. Immunohistochemical staining results were S-100 positive and CD34 negative.

A 5-year-old boy presented in the dermatology department with a large hairy GCMN covering most of the trunk since birth. In the last 1.5 years the parents noted gradual fading of color, decreased hair density, and increased induration of the nevus. Physical examination revealed a large plaque covering the anterior aspect of the trunk (Figure 3) and the back extending down to the buttocks. The lesion formed large skin folds that were more pronounced on the back. The nevus was darkly pigmented with large areas of lighter color that were indurated, devoid of hair, and showed small spots of dark pigmentation. A punch biopsy from the lesion showed small nests of nevus cells in the upper part of the reticular dermis. In the lower part of the dermis, nevus cells were arranged in single units in between thick collagen bundles.

In 2003, Ruiz-Maldonado et al¹ described 4 cases of GCMN that showed progressive loss of pigmentation, sclerosis, and hair loss. They proposed the term desmoplastic hairless hypopigmented nevus for their cases and considered it as a variant of GCMN.¹ Prior to these reported cases, 2 similar cases were described. The first was a report by Hogan et al² in 1988 of a 7-month-old girl with a GCMN involving the occipital area and the upper back that became indurated and ulcerated with progressive involution that led to complete disappearance of the nevus. The second was a report by Pattee et al³ in 2001 of a newborn with a GCMN located on the trunk with progressive sclerodermiform reaction. After surgical excision of the nevus, the sclerotic margin disappeared.³

Following the report by Ruiz-Maldonaldo et al,¹ 5 more cases of DHHN were described.^4-8 All cases of DHHN share the same clinical and histopathological features. The clinical features include a GCMN present since birth with progressive sclerosis over time and loss of both pigmentation and hair. Histologically, DHHN shows the typical changes of a congenital melanocytic nevus with decreased numbers of nevus cells, thick sclerotic collagen bundles of the reticular dermis, increased number of fibroblasts, and decreased number of hair follicles. The progressive reduction in the number of nevus cells in melanocytic nevi is considered a sign of regression. Spontaneous regression was rarely described in GCMN, and all the reported cases of regression were associated with desmoplasia.⁴ Desmoplasia is thought to be induced by either melanocytes that function as adaptive fibroblasts or by fibroblasts themselves, as fibroblasts can show multifunctional differentiation capabilities.⁹ The direct correlation between the increased induration of DHHN and pigment depletion supports the former hypothesis. The absence of inflammatory cells within the sections of DHHN lesions is against the possibility of an immune-mediated reaction as a cause for the clinical and histological changes seen in this rare form of GCMN. The progressive hair loss in DHHN may be explained by the progressive fibrotic changes in the reticular dermis that affect the blood supply to follicles, leading to atrophy or even absence of the follicles. The progressive reduction in the number of nevus cells in DHHN reduces the potential for malignant transformation and hence following a watchful waiting strategy is a reasonable way to manage these nevi.

We present 2 patients with DHHN, which is a rare form of GCMN that shows signs of regression. The cause of these changes is still unclear.

The term nevus spilus (NS), also known as speckled lentiginous nevus, was first used in the 19th century to describe lesions with background café au lait–like lentiginous melanocytic hyperplasia speckled with small, 1- to 3-mm, darker foci. The dark spots reflect lentigines; junctional, compound, and intradermal nevus cell nests; and more rarely Spitz and blue nevi. Both macular and papular subtypes have been described.¹ This birthmark is quite common, occurring in 1.3% to 2.3% of the adult population worldwide.² Hypertrichosis has been described in NS.^3-9 Two subsequent cases of malignant melanoma in hairy NS suggested that lesions may be particularly prone to malignant degeneration.^4,8 We report an additional case of hairy NS that was not associated with melanoma and consider whether dermatologists should warn their patients about this association.

Case Report

A 26-year-old woman presented with a stable 7×8-cm, tan-brown, macular, pigmented birthmark studded with darker 1- to 2-mm, irregular, brown-black and blue, confettilike macules on the left proximal lateral thigh that had been present since birth (Figure 1). Dark terminal hairs were present, arising from both the darker and lighter pigmented areas but not the surrounding normal skin.

A 4-mm punch biopsy from one of the dark blue macules demonstrated uniform lentiginous melanocytic hyperplasia and nevus cell nests adjacent to the sweat glands extending into the mid dermis (Figure 2). No clinical evidence of malignant degeneration was present.

Comment

The risk for melanoma is increased in classic nonspeckled congenital nevi and the risk correlates with the size of the lesion and most probably the number of nevus cells in the lesion that increase the risk for a random mutation.^8,10,11 It is likely that NS with or without hair presages a small increased risk for melanoma,^6,9,12 which is not surprising because NS is a subtype of congenital melanocytic nevus (CMN), a condition that is present at birth and results from a proliferation of melanocytes.⁶ Nevus spilus, however, appears to have a notably lower risk for malignant degeneration than other classic CMN of the same size. The following support for this hypothesis is offered: First, CMN have nevus cells broadly filling the dermis that extend more deeply into the dermis than NS (Figure 2A).¹⁰ In our estimation, CMN have at least 100 times the number of nevus cells per square centimeter compared to NS. The potential for malignant degeneration of any one melanocyte is greater when more are present. Second, although some NS lesions evolve, classic CMN are universally more proliferative than NS.^10,13 The involved skin in CMN thickens over time with increased numbers of melanocytes and marked overgrowth of adjacent tissue. Melanocytes in a proliferative phase may be more likely to undergo malignant degeneration.¹⁰

A PubMed search of articles indexed for MEDLINE using the search term nevus spilus and melanoma yielded 2 cases^4,8 of melanoma arising among 15 cases of hairy NS in the literature, which led to the suggestion that the presence of hair could be associated with an increased risk for malignant degeneration in NS (Table). This apparent high incidence of melanoma most likely reflects referral/publication bias rather than a statistically significant association. In fact, the clinical lesion most clinically similar to hairy NS is Becker nevus, with tan macules demonstrating lentiginous melanocytic hyperplasia associated with numerous coarse terminal hairs. There is no indication that Becker nevi have a considerable premalignant potential, though one case of melanoma arising in a Becker nevus has been reported.⁹ There is no evidence to suggest that classic CMN with hypertrichosis has a greater premalignant potential than similar lesions without hypertrichosis.

The term nevus spilus (NS), also known as speckled lentiginous nevus, was first used in the 19th century to describe lesions with background café au lait–like lentiginous melanocytic hyperplasia speckled with small, 1- to 3-mm, darker foci. The dark spots reflect lentigines; junctional, compound, and intradermal nevus cell nests; and more rarely Spitz and blue nevi. Both macular and papular subtypes have been described.¹ This birthmark is quite common, occurring in 1.3% to 2.3% of the adult population worldwide.² Hypertrichosis has been described in NS.^3-9 Two subsequent cases of malignant melanoma in hairy NS suggested that lesions may be particularly prone to malignant degeneration.^4,8 We report an additional case of hairy NS that was not associated with melanoma and consider whether dermatologists should warn their patients about this association.

Case Report

A 26-year-old woman presented with a stable 7×8-cm, tan-brown, macular, pigmented birthmark studded with darker 1- to 2-mm, irregular, brown-black and blue, confettilike macules on the left proximal lateral thigh that had been present since birth (Figure 1). Dark terminal hairs were present, arising from both the darker and lighter pigmented areas but not the surrounding normal skin.

A 4-mm punch biopsy from one of the dark blue macules demonstrated uniform lentiginous melanocytic hyperplasia and nevus cell nests adjacent to the sweat glands extending into the mid dermis (Figure 2). No clinical evidence of malignant degeneration was present.

Comment

The risk for melanoma is increased in classic nonspeckled congenital nevi and the risk correlates with the size of the lesion and most probably the number of nevus cells in the lesion that increase the risk for a random mutation.^8,10,11 It is likely that NS with or without hair presages a small increased risk for melanoma,^6,9,12 which is not surprising because NS is a subtype of congenital melanocytic nevus (CMN), a condition that is present at birth and results from a proliferation of melanocytes.⁶ Nevus spilus, however, appears to have a notably lower risk for malignant degeneration than other classic CMN of the same size. The following support for this hypothesis is offered: First, CMN have nevus cells broadly filling the dermis that extend more deeply into the dermis than NS (Figure 2A).¹⁰ In our estimation, CMN have at least 100 times the number of nevus cells per square centimeter compared to NS. The potential for malignant degeneration of any one melanocyte is greater when more are present. Second, although some NS lesions evolve, classic CMN are universally more proliferative than NS.^10,13 The involved skin in CMN thickens over time with increased numbers of melanocytes and marked overgrowth of adjacent tissue. Melanocytes in a proliferative phase may be more likely to undergo malignant degeneration.¹⁰

A PubMed search of articles indexed for MEDLINE using the search term nevus spilus and melanoma yielded 2 cases^4,8 of melanoma arising among 15 cases of hairy NS in the literature, which led to the suggestion that the presence of hair could be associated with an increased risk for malignant degeneration in NS (Table). This apparent high incidence of melanoma most likely reflects referral/publication bias rather than a statistically significant association. In fact, the clinical lesion most clinically similar to hairy NS is Becker nevus, with tan macules demonstrating lentiginous melanocytic hyperplasia associated with numerous coarse terminal hairs. There is no indication that Becker nevi have a considerable premalignant potential, though one case of melanoma arising in a Becker nevus has been reported.⁹ There is no evidence to suggest that classic CMN with hypertrichosis has a greater premalignant potential than similar lesions without hypertrichosis.

The term nevus spilus (NS), also known as speckled lentiginous nevus, was first used in the 19th century to describe lesions with background café au lait–like lentiginous melanocytic hyperplasia speckled with small, 1- to 3-mm, darker foci. The dark spots reflect lentigines; junctional, compound, and intradermal nevus cell nests; and more rarely Spitz and blue nevi. Both macular and papular subtypes have been described.¹ This birthmark is quite common, occurring in 1.3% to 2.3% of the adult population worldwide.² Hypertrichosis has been described in NS.^3-9 Two subsequent cases of malignant melanoma in hairy NS suggested that lesions may be particularly prone to malignant degeneration.^4,8 We report an additional case of hairy NS that was not associated with melanoma and consider whether dermatologists should warn their patients about this association.

Case Report

A 26-year-old woman presented with a stable 7×8-cm, tan-brown, macular, pigmented birthmark studded with darker 1- to 2-mm, irregular, brown-black and blue, confettilike macules on the left proximal lateral thigh that had been present since birth (Figure 1). Dark terminal hairs were present, arising from both the darker and lighter pigmented areas but not the surrounding normal skin.

A 4-mm punch biopsy from one of the dark blue macules demonstrated uniform lentiginous melanocytic hyperplasia and nevus cell nests adjacent to the sweat glands extending into the mid dermis (Figure 2). No clinical evidence of malignant degeneration was present.

Comment

The risk for melanoma is increased in classic nonspeckled congenital nevi and the risk correlates with the size of the lesion and most probably the number of nevus cells in the lesion that increase the risk for a random mutation.^8,10,11 It is likely that NS with or without hair presages a small increased risk for melanoma,^6,9,12 which is not surprising because NS is a subtype of congenital melanocytic nevus (CMN), a condition that is present at birth and results from a proliferation of melanocytes.⁶ Nevus spilus, however, appears to have a notably lower risk for malignant degeneration than other classic CMN of the same size. The following support for this hypothesis is offered: First, CMN have nevus cells broadly filling the dermis that extend more deeply into the dermis than NS (Figure 2A).¹⁰ In our estimation, CMN have at least 100 times the number of nevus cells per square centimeter compared to NS. The potential for malignant degeneration of any one melanocyte is greater when more are present. Second, although some NS lesions evolve, classic CMN are universally more proliferative than NS.^10,13 The involved skin in CMN thickens over time with increased numbers of melanocytes and marked overgrowth of adjacent tissue. Melanocytes in a proliferative phase may be more likely to undergo malignant degeneration.¹⁰

A PubMed search of articles indexed for MEDLINE using the search term nevus spilus and melanoma yielded 2 cases^4,8 of melanoma arising among 15 cases of hairy NS in the literature, which led to the suggestion that the presence of hair could be associated with an increased risk for malignant degeneration in NS (Table). This apparent high incidence of melanoma most likely reflects referral/publication bias rather than a statistically significant association. In fact, the clinical lesion most clinically similar to hairy NS is Becker nevus, with tan macules demonstrating lentiginous melanocytic hyperplasia associated with numerous coarse terminal hairs. There is no indication that Becker nevi have a considerable premalignant potential, though one case of melanoma arising in a Becker nevus has been reported.⁹ There is no evidence to suggest that classic CMN with hypertrichosis has a greater premalignant potential than similar lesions without hypertrichosis.