Case Letter

To the Editor:

Vascular lesions associated with melanocytic nevi were first described by Ota et al¹ in 1947 and given the name phacomatosis pigmentovascularis. In 2005, Happle² reclassified phacomatosis pigmentovascularis into 3 well-defined types: (1) phacomatosis cesioflammea: blue spots (caesius means bluish gray in Latin) and nevus flammeus; (2) phacomatosis spilorosea: nevus spilus coexisting with a pale pink telangiectatic nevus; and (3) phacomatosis cesiomarmorata: blue spots and cutis marmorata telangiectatica congenita. In 2011 Joshi et al³ described a case of a 31-year-old woman who had a port-wine stain in association with neurofibromatosis type I (NF-1). We present a case of phacomatosis cesioflammea in association with NF-1.

A 20-year-old woman presented to our outpatient section with a bluish black birthmark on the left side of the face since birth with the onset of multiple painless flesh-colored nodules on the trunk and arms of 1 year’s duration. She reported having occasional pruritus over the nodular lesions. Cutaneous examination showed multiple well-defined café au lait macules (0.5–3.0 cm) with regular margins. Multiple flesh-colored nodules were evident on the upper arms (Figure 1) and trunk. The nodules were firm in consistency and showed buttonholing phenomenon with some of the lesions demonstrating bag-of-worms consistency on palpation. Both palms showed multiple brownish frecklelike macules (Figure 2). A single bluish patch extended from the left ala of the nose to the sideburns. Adjoining the bluish patch was a subtle, ill-defined, nonblanchable red patch extending from the lower margin of the bluish patch to the mandibular ridge (Figure 3). Ocular examination showed melanosis bulbi of the left sclera and a few iris hamartomas (Lisch nodules) in both eyes. A biopsy of the skin nodule was obtained under local anesthesia after obtaining the patient’s informed consent; the specimen was fixed in 10% buffered formalin. A hematoxylin and eosin–stained section showed a well-circumscribed nonencapsulated tumor in the dermis composed of loosely spaced spindle cells and wavy collagenous strands (Figure 4). Routine hemogram and blood biochemistry including urinalysis were within reference range. Radiologic examination of the long bones was unremarkable. Our patient had 3 of 6 criteria defined by the National Institutes of Health for diagnosis of NF-1.⁴ On clinicopathological correlation we made a diagnosis of phacomatosis cesioflammea in association with NF-1. We have reassured the patient about the benign nature of vascular nevus. She was informed that the skin nodules could increase in size during pregnancy and to regularly follow-up with an eye specialist if any visual abnormalities occur.

The term phacomatosis is applied to genetically determined disorders of tissue derived from ectodermal origin (eg, skin, central nervous system, eyes) and commonly includes NF-1, tuberous sclerosis, and von Hippel-Lindau syndrome. Neurofibromatosis type I was first described by German pathologist Friedrich Daniel von Recklinghausen.⁵ Phacomatosis pigmentovascularis has been defined as the association of vascular nevus with a pigmentary nevus. Its pathogenesis can be explained by the twin spotting phenomenon.⁶ Twin spots are paired patches of mutant tissue that differ from each other and from the surrounding normal background skin. They can occur as 2 clinical types: allelic and nonallelic twin spotting. Our patient had nonallelic twin spots for 2 nevoid conditions: vascular (nevus flammeus) and pigmentary (nevus of Ota). Nevus of Ota was distributed in the V2 segment (maxillary nerve) of the fifth cranial nerve along with classical melanosis bulbi, which is considered a characteristic clinical feature of nevus of Ota (nevus cesius).⁷ Nevus flammeus (port-wine stain) is a vascular malformation presenting with flat lesions that persists throughout a patient’s life. The phenomenon of twin spotting, or didymosis (didymos means twin in Greek), has been proposed for co-occurrence of vascular and pigmented nevi.⁸ The association of NF-1 along with phacomatosis cesioflammea (a twin spot) could be explained from mosaicism of tissues derived from neuroectodermal and mesenchymal elements. Neurofibromatosis type I can occur as a mosaic disorder due to either postzygotic germ line or somatic mutations in the NF1 gene located on the proximal long arm of chromosome 17.⁹ Irrespective of the mutational event, a mosaic patient has a mixture of cells, some have normal copies of a particular gene and others have an abnormal copy of the same gene. Somatic mutation can lead to segmental (localized), generalized, or gonadal mosaicism. Somatic mutations occurring early during embryonic development produce generalized mosaicism, and generalized mosaics clinically appear similar to nonmosaic NF-1 cases.^10,11 However, due to a lack of adequate facilities for mutation analysis and financial constraints, we were unable to confirm our case as generalized somatic mosaic for NF1 gene.

Several morphologic abnormalities have been reported with phacomatosis cesioflammea. Wu et al¹² reported a single case of phacomatosis cesioflammea associated with pectus excavatum in a 9-month-old infant. Shields et al¹³ suggested that a thorough ocular examination on a periodic basis is essential to rule out melanoma of ocular tissues in patients with nevus flammeus and ocular melanosis.

Phacomatosis cesioflammea can occur in association with NF-1. The exact incidence of association is not known. The nevoid condition can be treated with appropriate lasers.

To the Editor:

Vascular lesions associated with melanocytic nevi were first described by Ota et al¹ in 1947 and given the name phacomatosis pigmentovascularis. In 2005, Happle² reclassified phacomatosis pigmentovascularis into 3 well-defined types: (1) phacomatosis cesioflammea: blue spots (caesius means bluish gray in Latin) and nevus flammeus; (2) phacomatosis spilorosea: nevus spilus coexisting with a pale pink telangiectatic nevus; and (3) phacomatosis cesiomarmorata: blue spots and cutis marmorata telangiectatica congenita. In 2011 Joshi et al³ described a case of a 31-year-old woman who had a port-wine stain in association with neurofibromatosis type I (NF-1). We present a case of phacomatosis cesioflammea in association with NF-1.

A 20-year-old woman presented to our outpatient section with a bluish black birthmark on the left side of the face since birth with the onset of multiple painless flesh-colored nodules on the trunk and arms of 1 year’s duration. She reported having occasional pruritus over the nodular lesions. Cutaneous examination showed multiple well-defined café au lait macules (0.5–3.0 cm) with regular margins. Multiple flesh-colored nodules were evident on the upper arms (Figure 1) and trunk. The nodules were firm in consistency and showed buttonholing phenomenon with some of the lesions demonstrating bag-of-worms consistency on palpation. Both palms showed multiple brownish frecklelike macules (Figure 2). A single bluish patch extended from the left ala of the nose to the sideburns. Adjoining the bluish patch was a subtle, ill-defined, nonblanchable red patch extending from the lower margin of the bluish patch to the mandibular ridge (Figure 3). Ocular examination showed melanosis bulbi of the left sclera and a few iris hamartomas (Lisch nodules) in both eyes. A biopsy of the skin nodule was obtained under local anesthesia after obtaining the patient’s informed consent; the specimen was fixed in 10% buffered formalin. A hematoxylin and eosin–stained section showed a well-circumscribed nonencapsulated tumor in the dermis composed of loosely spaced spindle cells and wavy collagenous strands (Figure 4). Routine hemogram and blood biochemistry including urinalysis were within reference range. Radiologic examination of the long bones was unremarkable. Our patient had 3 of 6 criteria defined by the National Institutes of Health for diagnosis of NF-1.⁴ On clinicopathological correlation we made a diagnosis of phacomatosis cesioflammea in association with NF-1. We have reassured the patient about the benign nature of vascular nevus. She was informed that the skin nodules could increase in size during pregnancy and to regularly follow-up with an eye specialist if any visual abnormalities occur.

The term phacomatosis is applied to genetically determined disorders of tissue derived from ectodermal origin (eg, skin, central nervous system, eyes) and commonly includes NF-1, tuberous sclerosis, and von Hippel-Lindau syndrome. Neurofibromatosis type I was first described by German pathologist Friedrich Daniel von Recklinghausen.⁵ Phacomatosis pigmentovascularis has been defined as the association of vascular nevus with a pigmentary nevus. Its pathogenesis can be explained by the twin spotting phenomenon.⁶ Twin spots are paired patches of mutant tissue that differ from each other and from the surrounding normal background skin. They can occur as 2 clinical types: allelic and nonallelic twin spotting. Our patient had nonallelic twin spots for 2 nevoid conditions: vascular (nevus flammeus) and pigmentary (nevus of Ota). Nevus of Ota was distributed in the V2 segment (maxillary nerve) of the fifth cranial nerve along with classical melanosis bulbi, which is considered a characteristic clinical feature of nevus of Ota (nevus cesius).⁷ Nevus flammeus (port-wine stain) is a vascular malformation presenting with flat lesions that persists throughout a patient’s life. The phenomenon of twin spotting, or didymosis (didymos means twin in Greek), has been proposed for co-occurrence of vascular and pigmented nevi.⁸ The association of NF-1 along with phacomatosis cesioflammea (a twin spot) could be explained from mosaicism of tissues derived from neuroectodermal and mesenchymal elements. Neurofibromatosis type I can occur as a mosaic disorder due to either postzygotic germ line or somatic mutations in the NF1 gene located on the proximal long arm of chromosome 17.⁹ Irrespective of the mutational event, a mosaic patient has a mixture of cells, some have normal copies of a particular gene and others have an abnormal copy of the same gene. Somatic mutation can lead to segmental (localized), generalized, or gonadal mosaicism. Somatic mutations occurring early during embryonic development produce generalized mosaicism, and generalized mosaics clinically appear similar to nonmosaic NF-1 cases.^10,11 However, due to a lack of adequate facilities for mutation analysis and financial constraints, we were unable to confirm our case as generalized somatic mosaic for NF1 gene.

Several morphologic abnormalities have been reported with phacomatosis cesioflammea. Wu et al¹² reported a single case of phacomatosis cesioflammea associated with pectus excavatum in a 9-month-old infant. Shields et al¹³ suggested that a thorough ocular examination on a periodic basis is essential to rule out melanoma of ocular tissues in patients with nevus flammeus and ocular melanosis.

Phacomatosis cesioflammea can occur in association with NF-1. The exact incidence of association is not known. The nevoid condition can be treated with appropriate lasers.

To the Editor:

Vascular lesions associated with melanocytic nevi were first described by Ota et al¹ in 1947 and given the name phacomatosis pigmentovascularis. In 2005, Happle² reclassified phacomatosis pigmentovascularis into 3 well-defined types: (1) phacomatosis cesioflammea: blue spots (caesius means bluish gray in Latin) and nevus flammeus; (2) phacomatosis spilorosea: nevus spilus coexisting with a pale pink telangiectatic nevus; and (3) phacomatosis cesiomarmorata: blue spots and cutis marmorata telangiectatica congenita. In 2011 Joshi et al³ described a case of a 31-year-old woman who had a port-wine stain in association with neurofibromatosis type I (NF-1). We present a case of phacomatosis cesioflammea in association with NF-1.

A 20-year-old woman presented to our outpatient section with a bluish black birthmark on the left side of the face since birth with the onset of multiple painless flesh-colored nodules on the trunk and arms of 1 year’s duration. She reported having occasional pruritus over the nodular lesions. Cutaneous examination showed multiple well-defined café au lait macules (0.5–3.0 cm) with regular margins. Multiple flesh-colored nodules were evident on the upper arms (Figure 1) and trunk. The nodules were firm in consistency and showed buttonholing phenomenon with some of the lesions demonstrating bag-of-worms consistency on palpation. Both palms showed multiple brownish frecklelike macules (Figure 2). A single bluish patch extended from the left ala of the nose to the sideburns. Adjoining the bluish patch was a subtle, ill-defined, nonblanchable red patch extending from the lower margin of the bluish patch to the mandibular ridge (Figure 3). Ocular examination showed melanosis bulbi of the left sclera and a few iris hamartomas (Lisch nodules) in both eyes. A biopsy of the skin nodule was obtained under local anesthesia after obtaining the patient’s informed consent; the specimen was fixed in 10% buffered formalin. A hematoxylin and eosin–stained section showed a well-circumscribed nonencapsulated tumor in the dermis composed of loosely spaced spindle cells and wavy collagenous strands (Figure 4). Routine hemogram and blood biochemistry including urinalysis were within reference range. Radiologic examination of the long bones was unremarkable. Our patient had 3 of 6 criteria defined by the National Institutes of Health for diagnosis of NF-1.⁴ On clinicopathological correlation we made a diagnosis of phacomatosis cesioflammea in association with NF-1. We have reassured the patient about the benign nature of vascular nevus. She was informed that the skin nodules could increase in size during pregnancy and to regularly follow-up with an eye specialist if any visual abnormalities occur.

The term phacomatosis is applied to genetically determined disorders of tissue derived from ectodermal origin (eg, skin, central nervous system, eyes) and commonly includes NF-1, tuberous sclerosis, and von Hippel-Lindau syndrome. Neurofibromatosis type I was first described by German pathologist Friedrich Daniel von Recklinghausen.⁵ Phacomatosis pigmentovascularis has been defined as the association of vascular nevus with a pigmentary nevus. Its pathogenesis can be explained by the twin spotting phenomenon.⁶ Twin spots are paired patches of mutant tissue that differ from each other and from the surrounding normal background skin. They can occur as 2 clinical types: allelic and nonallelic twin spotting. Our patient had nonallelic twin spots for 2 nevoid conditions: vascular (nevus flammeus) and pigmentary (nevus of Ota). Nevus of Ota was distributed in the V2 segment (maxillary nerve) of the fifth cranial nerve along with classical melanosis bulbi, which is considered a characteristic clinical feature of nevus of Ota (nevus cesius).⁷ Nevus flammeus (port-wine stain) is a vascular malformation presenting with flat lesions that persists throughout a patient’s life. The phenomenon of twin spotting, or didymosis (didymos means twin in Greek), has been proposed for co-occurrence of vascular and pigmented nevi.⁸ The association of NF-1 along with phacomatosis cesioflammea (a twin spot) could be explained from mosaicism of tissues derived from neuroectodermal and mesenchymal elements. Neurofibromatosis type I can occur as a mosaic disorder due to either postzygotic germ line or somatic mutations in the NF1 gene located on the proximal long arm of chromosome 17.⁹ Irrespective of the mutational event, a mosaic patient has a mixture of cells, some have normal copies of a particular gene and others have an abnormal copy of the same gene. Somatic mutation can lead to segmental (localized), generalized, or gonadal mosaicism. Somatic mutations occurring early during embryonic development produce generalized mosaicism, and generalized mosaics clinically appear similar to nonmosaic NF-1 cases.^10,11 However, due to a lack of adequate facilities for mutation analysis and financial constraints, we were unable to confirm our case as generalized somatic mosaic for NF1 gene.

Several morphologic abnormalities have been reported with phacomatosis cesioflammea. Wu et al¹² reported a single case of phacomatosis cesioflammea associated with pectus excavatum in a 9-month-old infant. Shields et al¹³ suggested that a thorough ocular examination on a periodic basis is essential to rule out melanoma of ocular tissues in patients with nevus flammeus and ocular melanosis.

Phacomatosis cesioflammea can occur in association with NF-1. The exact incidence of association is not known. The nevoid condition can be treated with appropriate lasers.

To the Editor:

Verrucous carcinoma is an uncommon type of squamous cell carcinoma (SCC) and was first described by Ackerman¹ in 1948. Rock and Fisher² called this condition oral florid papillomatosis. The distinctive features of this tumor are low-grade malignancy, slow growth, local invasiveness, and rarely intraoral and extraoral metastasis. Extraorally, it can occur in any part of the body,³ a common site being the anogenital region. Depending on the area of occurrence, the condition also is known as Buschke-Lowenstein tumor⁴ or giant condyloma acuminatum (anogenital region) and carcinoma cuniculatum⁵ (plantar region). The exact etiology of the condition is unknown, though it is associated with human papillomavirus infection, traumatic scars, chronic infection, tobacco, and chemical carcinogens.³ We report a rare case of verrucous carcinoma originating from the buccal mucosa that subsequently spread to involve the lip and cheek as a large cauliflowerlike growth, which is an unusual presentation.

A 65-year-old man presented to the dermatology department with a painless growth inside the left side of the oral cavity that had developed 5 years prior as a growth on the left buccal mucosa. The lesion gradually increased in size to involve the left oral commissure including the upper and lower lips and the skin of the left cheek; it extended beyond the nasolabial fold in a cauliflowerlike pattern. The lesion was insidious in onset and was not associated with pain, itching, or bleeding. The patient chewed tobacco for the last 40 years, with no similar lesions on any part of the body. On physical examination a warty papilliform lesion was seen on the left buccal mucosa with extension to 2 cm of the upper and lower lip on the left side including the left oral commissure and the skin of the left cheek beyond the nasolabial fold where it appeared as a cauliflowerlike growth measuring 4×5 cm in size (Figure 1). No notable lymphadenopathy was present.

Digital radiographs of the skull (posteroanterior oblique view)(Figure 2) and mandible (left oblique view) showed a lobulated soft-tissue density lesion overlying the left half of the mandible (near the mandibular angle) with involvement of both the upper and lower lips on the left side. However, no obvious underlying bony erosion was noted.

Computed tomography revealed a large soft-tissue mass (41.3×35.3 mm)(Figure 3A) involving the left buccal mucosa with extension into overlying muscle, subcutaneous tissue, and skin. Externally, the lesion was exophytic, irregular, and polypoidal with surface ulceration. Medially, the lesion involved the left oral commissure and parts of the adjoining upper and lower lips. No underlying bony erosion was seen. An enlarged lymph node measuring 20×15 mm was noted in the left upper deep cervical group in the submandibular region (Figure 3B).

Our clinical differential diagnosis included verrucous carcinoma and hypertrophic variety of lupus vulgaris. A 1×2-cm diagnostic incisional biopsy was performed from the cauliflowerlike growth and ultrasound-guided fine-needle aspiration was done from the lymph node. Histopathology revealed a hyperplastic stratified squamous epithelium with upward extension of verrucous projections, which was largely superficial to the adjacent epithelium (Figure 4A). In addition to the surface verrucous projections, there was lesion extension into the subepithelial zone in the form of round club-shaped protrusions (Figure 4B). There was no loss of polarity in these downward proliferations. No horn pearl formation was present. Fine-needle aspiration revealed reactive lymphadenitis.

The final diagnosis of verrucous carcinoma was made and the patient was referred to the oncosurgery department for further management.

Verrucous carcinoma is a rare, low-grade, well-differentiated SCC of the skin or mucosa presenting with a verrucoid or cauliflowerlike appearance. It shows locally aggressive behavior and has low metastatic potential,⁶ a low degree of dysplasia, and a good prognosis. Because it is a tumor with predominantly horizontal growth, it tends to erode more than infiltrate. It does not present with remote metastasis.⁷ It has been known by several different names, usually related to anatomic sites (eg, Ackerman tumor, oral florid papillomatosis, carcinoma cuniculatum).

In the oral cavity, verrucous carcinoma constitutes 2% to 4.5% of all forms of SCC seen mainly in men older than 50 years and also is associated with a high incidence (37.7%) of a second primary tumor mainly in the oral mucosa (eg, tongue, lips, palate, salivary gland).⁸ Indudharan et al⁹ reported a case of verrucous carcinoma of the maxillary antrum in a young male patient, which also was a rare entity. Verrucous carcinoma is thought to predominantly affect elderly men. Walvekar et al¹⁰ reported a male to female ratio of 3.6 to 1 in patients with verrucous carcinoma, with a mean age of 53.9 years. According to Varshney et al,¹¹ patients may range in age from the fourth to eighth decades of life, with a mean age of 60 years; 80% are male. The etiopathogenesis of verrucous carcinoma is related to the following carcinogens: biologic (eg, human papillomavirus), chemical (eg, smoking), and physical (eg, constant trauma).

Verrucous carcinoma should be considered in the differential diagnosis of slow-growing, locally spreading tumors. Oral tumors, especially in tobacco chewers, should raise suspicion of verrucous carcinoma, which will enable prompt management of the tumor.

To the Editor:

Verrucous carcinoma is an uncommon type of squamous cell carcinoma (SCC) and was first described by Ackerman¹ in 1948. Rock and Fisher² called this condition oral florid papillomatosis. The distinctive features of this tumor are low-grade malignancy, slow growth, local invasiveness, and rarely intraoral and extraoral metastasis. Extraorally, it can occur in any part of the body,³ a common site being the anogenital region. Depending on the area of occurrence, the condition also is known as Buschke-Lowenstein tumor⁴ or giant condyloma acuminatum (anogenital region) and carcinoma cuniculatum⁵ (plantar region). The exact etiology of the condition is unknown, though it is associated with human papillomavirus infection, traumatic scars, chronic infection, tobacco, and chemical carcinogens.³ We report a rare case of verrucous carcinoma originating from the buccal mucosa that subsequently spread to involve the lip and cheek as a large cauliflowerlike growth, which is an unusual presentation.

A 65-year-old man presented to the dermatology department with a painless growth inside the left side of the oral cavity that had developed 5 years prior as a growth on the left buccal mucosa. The lesion gradually increased in size to involve the left oral commissure including the upper and lower lips and the skin of the left cheek; it extended beyond the nasolabial fold in a cauliflowerlike pattern. The lesion was insidious in onset and was not associated with pain, itching, or bleeding. The patient chewed tobacco for the last 40 years, with no similar lesions on any part of the body. On physical examination a warty papilliform lesion was seen on the left buccal mucosa with extension to 2 cm of the upper and lower lip on the left side including the left oral commissure and the skin of the left cheek beyond the nasolabial fold where it appeared as a cauliflowerlike growth measuring 4×5 cm in size (Figure 1). No notable lymphadenopathy was present.

Digital radiographs of the skull (posteroanterior oblique view)(Figure 2) and mandible (left oblique view) showed a lobulated soft-tissue density lesion overlying the left half of the mandible (near the mandibular angle) with involvement of both the upper and lower lips on the left side. However, no obvious underlying bony erosion was noted.

Computed tomography revealed a large soft-tissue mass (41.3×35.3 mm)(Figure 3A) involving the left buccal mucosa with extension into overlying muscle, subcutaneous tissue, and skin. Externally, the lesion was exophytic, irregular, and polypoidal with surface ulceration. Medially, the lesion involved the left oral commissure and parts of the adjoining upper and lower lips. No underlying bony erosion was seen. An enlarged lymph node measuring 20×15 mm was noted in the left upper deep cervical group in the submandibular region (Figure 3B).

Our clinical differential diagnosis included verrucous carcinoma and hypertrophic variety of lupus vulgaris. A 1×2-cm diagnostic incisional biopsy was performed from the cauliflowerlike growth and ultrasound-guided fine-needle aspiration was done from the lymph node. Histopathology revealed a hyperplastic stratified squamous epithelium with upward extension of verrucous projections, which was largely superficial to the adjacent epithelium (Figure 4A). In addition to the surface verrucous projections, there was lesion extension into the subepithelial zone in the form of round club-shaped protrusions (Figure 4B). There was no loss of polarity in these downward proliferations. No horn pearl formation was present. Fine-needle aspiration revealed reactive lymphadenitis.

The final diagnosis of verrucous carcinoma was made and the patient was referred to the oncosurgery department for further management.

Verrucous carcinoma is a rare, low-grade, well-differentiated SCC of the skin or mucosa presenting with a verrucoid or cauliflowerlike appearance. It shows locally aggressive behavior and has low metastatic potential,⁶ a low degree of dysplasia, and a good prognosis. Because it is a tumor with predominantly horizontal growth, it tends to erode more than infiltrate. It does not present with remote metastasis.⁷ It has been known by several different names, usually related to anatomic sites (eg, Ackerman tumor, oral florid papillomatosis, carcinoma cuniculatum).

In the oral cavity, verrucous carcinoma constitutes 2% to 4.5% of all forms of SCC seen mainly in men older than 50 years and also is associated with a high incidence (37.7%) of a second primary tumor mainly in the oral mucosa (eg, tongue, lips, palate, salivary gland).⁸ Indudharan et al⁹ reported a case of verrucous carcinoma of the maxillary antrum in a young male patient, which also was a rare entity. Verrucous carcinoma is thought to predominantly affect elderly men. Walvekar et al¹⁰ reported a male to female ratio of 3.6 to 1 in patients with verrucous carcinoma, with a mean age of 53.9 years. According to Varshney et al,¹¹ patients may range in age from the fourth to eighth decades of life, with a mean age of 60 years; 80% are male. The etiopathogenesis of verrucous carcinoma is related to the following carcinogens: biologic (eg, human papillomavirus), chemical (eg, smoking), and physical (eg, constant trauma).

Verrucous carcinoma should be considered in the differential diagnosis of slow-growing, locally spreading tumors. Oral tumors, especially in tobacco chewers, should raise suspicion of verrucous carcinoma, which will enable prompt management of the tumor.

To the Editor:

Verrucous carcinoma is an uncommon type of squamous cell carcinoma (SCC) and was first described by Ackerman¹ in 1948. Rock and Fisher² called this condition oral florid papillomatosis. The distinctive features of this tumor are low-grade malignancy, slow growth, local invasiveness, and rarely intraoral and extraoral metastasis. Extraorally, it can occur in any part of the body,³ a common site being the anogenital region. Depending on the area of occurrence, the condition also is known as Buschke-Lowenstein tumor⁴ or giant condyloma acuminatum (anogenital region) and carcinoma cuniculatum⁵ (plantar region). The exact etiology of the condition is unknown, though it is associated with human papillomavirus infection, traumatic scars, chronic infection, tobacco, and chemical carcinogens.³ We report a rare case of verrucous carcinoma originating from the buccal mucosa that subsequently spread to involve the lip and cheek as a large cauliflowerlike growth, which is an unusual presentation.

A 65-year-old man presented to the dermatology department with a painless growth inside the left side of the oral cavity that had developed 5 years prior as a growth on the left buccal mucosa. The lesion gradually increased in size to involve the left oral commissure including the upper and lower lips and the skin of the left cheek; it extended beyond the nasolabial fold in a cauliflowerlike pattern. The lesion was insidious in onset and was not associated with pain, itching, or bleeding. The patient chewed tobacco for the last 40 years, with no similar lesions on any part of the body. On physical examination a warty papilliform lesion was seen on the left buccal mucosa with extension to 2 cm of the upper and lower lip on the left side including the left oral commissure and the skin of the left cheek beyond the nasolabial fold where it appeared as a cauliflowerlike growth measuring 4×5 cm in size (Figure 1). No notable lymphadenopathy was present.

Digital radiographs of the skull (posteroanterior oblique view)(Figure 2) and mandible (left oblique view) showed a lobulated soft-tissue density lesion overlying the left half of the mandible (near the mandibular angle) with involvement of both the upper and lower lips on the left side. However, no obvious underlying bony erosion was noted.

Computed tomography revealed a large soft-tissue mass (41.3×35.3 mm)(Figure 3A) involving the left buccal mucosa with extension into overlying muscle, subcutaneous tissue, and skin. Externally, the lesion was exophytic, irregular, and polypoidal with surface ulceration. Medially, the lesion involved the left oral commissure and parts of the adjoining upper and lower lips. No underlying bony erosion was seen. An enlarged lymph node measuring 20×15 mm was noted in the left upper deep cervical group in the submandibular region (Figure 3B).

Our clinical differential diagnosis included verrucous carcinoma and hypertrophic variety of lupus vulgaris. A 1×2-cm diagnostic incisional biopsy was performed from the cauliflowerlike growth and ultrasound-guided fine-needle aspiration was done from the lymph node. Histopathology revealed a hyperplastic stratified squamous epithelium with upward extension of verrucous projections, which was largely superficial to the adjacent epithelium (Figure 4A). In addition to the surface verrucous projections, there was lesion extension into the subepithelial zone in the form of round club-shaped protrusions (Figure 4B). There was no loss of polarity in these downward proliferations. No horn pearl formation was present. Fine-needle aspiration revealed reactive lymphadenitis.

The final diagnosis of verrucous carcinoma was made and the patient was referred to the oncosurgery department for further management.

Verrucous carcinoma is a rare, low-grade, well-differentiated SCC of the skin or mucosa presenting with a verrucoid or cauliflowerlike appearance. It shows locally aggressive behavior and has low metastatic potential,⁶ a low degree of dysplasia, and a good prognosis. Because it is a tumor with predominantly horizontal growth, it tends to erode more than infiltrate. It does not present with remote metastasis.⁷ It has been known by several different names, usually related to anatomic sites (eg, Ackerman tumor, oral florid papillomatosis, carcinoma cuniculatum).

In the oral cavity, verrucous carcinoma constitutes 2% to 4.5% of all forms of SCC seen mainly in men older than 50 years and also is associated with a high incidence (37.7%) of a second primary tumor mainly in the oral mucosa (eg, tongue, lips, palate, salivary gland).⁸ Indudharan et al⁹ reported a case of verrucous carcinoma of the maxillary antrum in a young male patient, which also was a rare entity. Verrucous carcinoma is thought to predominantly affect elderly men. Walvekar et al¹⁰ reported a male to female ratio of 3.6 to 1 in patients with verrucous carcinoma, with a mean age of 53.9 years. According to Varshney et al,¹¹ patients may range in age from the fourth to eighth decades of life, with a mean age of 60 years; 80% are male. The etiopathogenesis of verrucous carcinoma is related to the following carcinogens: biologic (eg, human papillomavirus), chemical (eg, smoking), and physical (eg, constant trauma).

Verrucous carcinoma should be considered in the differential diagnosis of slow-growing, locally spreading tumors. Oral tumors, especially in tobacco chewers, should raise suspicion of verrucous carcinoma, which will enable prompt management of the tumor.

To the Editor:

Dermatomyositis represents a rare idiopathic inflammatory process presenting with cutaneous lesions and muscular weakness. It often represents a paraneoplastic syndrome. We report the case of a 62-year-old man with a history of total-body poikiloderma and a recent diagnosis of chronic lymphocytic leukemia (CLL). Despite lacking typical features of the disease, a diagnosis of dermatomyositis was made. Our patient may represent a distinct poikilodermatous variant of dermatomyositis, sharing the generalized distribution of the erythrodermic subtype.

A 62-year-old man presented with pruritic poikiloderma involving the neck, arms, legs, abdomen, chest, and back of 2 years’ duration (Figure). He also experienced dysphagia and weakness of the legs. The rash was previously treated by other dermatologists with a combination of high-potency topical steroids and topical tacrolimus 0.1% without success. His history was notable for CLL, which had been diagnosed by a dermatologist 6 months prior to the current presentation. Prior to his visit to the dermatologist, the patient had received 6 chemotherapeutic sessions with a combination of rituximab and cyclophosphamide for the treatment of CLL. The rash did not improve with chemotherapy.

Repeat biopsies of affected regions only demonstrated features of mild interface dermatitis. Direct immunofluorescence studies showed scattered colloid body fluorescence for IgM. Because of bilateral weakness of the legs, a muscle biopsy was taken, which demonstrated severe atrophy and interstitial fibrosis, with neurogenic abnormalities detected in areas of lesser atrophy via abnormal muscle fiber–type grouping. Metabolic panel showed elevated muscle enzymes in the blood: creatine kinase, 243 U/L (reference range, 10–225 U/L); serum aldolase, 16 U/L (reference range, ≤8.1 U/L); lactate dehydrogenase, 314 U/L (reference range, 60–200 U/L). An autoimmune panel was negative for Jo-1, Scl-70, U1 ribonucleoprotein, DNA, desmoglein 1 and 3, and antiacetylcholine receptor antibodies. An elevated erythrocyte sedimentation rate was measured at 16 mm/h (reference range, 0–10 mm/h). Given these findings, the lesions were confirmed as a widespread poikilodermatous variant of dermatomyositis.

The patient was placed on a daily 50-mg dose of prednisone, which produced rapid improvement in scaling and erythema. Creatine kinase and serum aldolase levels normalized and motor strength increased. After 1 week the prednisone dosage was reduced to a daily 30-mg dose, and then 20 mg a week later. The skin lesions completely resolved within 4 to 5 months and the patient is currently on a prednisone dose of 5 mg, alternating with 2.5 mg of prednisone and rituximab infusion every 2 months.

Dermatomyositis is a rare entity with an incidence of approximately 0.5 to 1 per 100,000 individuals.¹ It presents with a characteristic rash composed of Gottron papules; pathognomonic flat violaceous papules on the dorsal interphalangeal joints, elbows, or knees; and a heliotrope rash, a violaceous erythema involving the eyelids. Poikiloderma frequently is reported to present in a shawl-like distribution, encompassing the shoulders, arms, and upper back.^1,2 Dermatomyositis of the poikilodermatous type can present in nonphotoexposed areas and photoexposed areas. The unusual feature is the total-body involvement, which is analogous to erythroderma.³

Our case may represent a distinct poikilodermatous manifestation sharing the distribution of the erythrodermic subtype. We believe that the skin lesions may have represented a paraneoplastic event presenting prior to diagnosis with CLL. Dermatomyositis has a strong association with cancer, with patients 3 times more likely to develop internal malignancy.⁴ Association is strongest for non-Hodgkin lymphoma, as well as ovarian, lung, colorectal, pancreatic, and gastric cancer. When associated with malignancy, symptoms of dermatomyositis or myositis typically precede the discovery of malignancy by an average of 1.9 years.⁵ Dermatomyositis has been previously reported to present as a paraneoplastic manifestation of CLL.⁶ One case has been reported of a patient with CLL who developed leukemia cutis presenting with poikiloderma in the characteristic dermatomyositis shawl-like distribution.⁷ The lack of dermal infiltration with leukemic cells in our patient, however, makes a paraneoplastic etiology much more likely.

Our patient’s rash did not initially improve with treatment of CLL, but dermatomyositis associated with hematological malignancy may precede, occur simultaneously, or follow the diagnosis of malignancy.⁸ Additionally, symptoms of dermatomyositis do not always parallel the course of hematological malignancy outcome. However, rituximab has been used as a treatment of dermatomyositis and may have contributed some synergistic effect in combination with prednisone in our patient.⁹

To the Editor:

Dermatomyositis represents a rare idiopathic inflammatory process presenting with cutaneous lesions and muscular weakness. It often represents a paraneoplastic syndrome. We report the case of a 62-year-old man with a history of total-body poikiloderma and a recent diagnosis of chronic lymphocytic leukemia (CLL). Despite lacking typical features of the disease, a diagnosis of dermatomyositis was made. Our patient may represent a distinct poikilodermatous variant of dermatomyositis, sharing the generalized distribution of the erythrodermic subtype.

A 62-year-old man presented with pruritic poikiloderma involving the neck, arms, legs, abdomen, chest, and back of 2 years’ duration (Figure). He also experienced dysphagia and weakness of the legs. The rash was previously treated by other dermatologists with a combination of high-potency topical steroids and topical tacrolimus 0.1% without success. His history was notable for CLL, which had been diagnosed by a dermatologist 6 months prior to the current presentation. Prior to his visit to the dermatologist, the patient had received 6 chemotherapeutic sessions with a combination of rituximab and cyclophosphamide for the treatment of CLL. The rash did not improve with chemotherapy.

Repeat biopsies of affected regions only demonstrated features of mild interface dermatitis. Direct immunofluorescence studies showed scattered colloid body fluorescence for IgM. Because of bilateral weakness of the legs, a muscle biopsy was taken, which demonstrated severe atrophy and interstitial fibrosis, with neurogenic abnormalities detected in areas of lesser atrophy via abnormal muscle fiber–type grouping. Metabolic panel showed elevated muscle enzymes in the blood: creatine kinase, 243 U/L (reference range, 10–225 U/L); serum aldolase, 16 U/L (reference range, ≤8.1 U/L); lactate dehydrogenase, 314 U/L (reference range, 60–200 U/L). An autoimmune panel was negative for Jo-1, Scl-70, U1 ribonucleoprotein, DNA, desmoglein 1 and 3, and antiacetylcholine receptor antibodies. An elevated erythrocyte sedimentation rate was measured at 16 mm/h (reference range, 0–10 mm/h). Given these findings, the lesions were confirmed as a widespread poikilodermatous variant of dermatomyositis.

The patient was placed on a daily 50-mg dose of prednisone, which produced rapid improvement in scaling and erythema. Creatine kinase and serum aldolase levels normalized and motor strength increased. After 1 week the prednisone dosage was reduced to a daily 30-mg dose, and then 20 mg a week later. The skin lesions completely resolved within 4 to 5 months and the patient is currently on a prednisone dose of 5 mg, alternating with 2.5 mg of prednisone and rituximab infusion every 2 months.

Dermatomyositis is a rare entity with an incidence of approximately 0.5 to 1 per 100,000 individuals.¹ It presents with a characteristic rash composed of Gottron papules; pathognomonic flat violaceous papules on the dorsal interphalangeal joints, elbows, or knees; and a heliotrope rash, a violaceous erythema involving the eyelids. Poikiloderma frequently is reported to present in a shawl-like distribution, encompassing the shoulders, arms, and upper back.^1,2 Dermatomyositis of the poikilodermatous type can present in nonphotoexposed areas and photoexposed areas. The unusual feature is the total-body involvement, which is analogous to erythroderma.³

Our case may represent a distinct poikilodermatous manifestation sharing the distribution of the erythrodermic subtype. We believe that the skin lesions may have represented a paraneoplastic event presenting prior to diagnosis with CLL. Dermatomyositis has a strong association with cancer, with patients 3 times more likely to develop internal malignancy.⁴ Association is strongest for non-Hodgkin lymphoma, as well as ovarian, lung, colorectal, pancreatic, and gastric cancer. When associated with malignancy, symptoms of dermatomyositis or myositis typically precede the discovery of malignancy by an average of 1.9 years.⁵ Dermatomyositis has been previously reported to present as a paraneoplastic manifestation of CLL.⁶ One case has been reported of a patient with CLL who developed leukemia cutis presenting with poikiloderma in the characteristic dermatomyositis shawl-like distribution.⁷ The lack of dermal infiltration with leukemic cells in our patient, however, makes a paraneoplastic etiology much more likely.

Our patient’s rash did not initially improve with treatment of CLL, but dermatomyositis associated with hematological malignancy may precede, occur simultaneously, or follow the diagnosis of malignancy.⁸ Additionally, symptoms of dermatomyositis do not always parallel the course of hematological malignancy outcome. However, rituximab has been used as a treatment of dermatomyositis and may have contributed some synergistic effect in combination with prednisone in our patient.⁹

To the Editor:

Dermatomyositis represents a rare idiopathic inflammatory process presenting with cutaneous lesions and muscular weakness. It often represents a paraneoplastic syndrome. We report the case of a 62-year-old man with a history of total-body poikiloderma and a recent diagnosis of chronic lymphocytic leukemia (CLL). Despite lacking typical features of the disease, a diagnosis of dermatomyositis was made. Our patient may represent a distinct poikilodermatous variant of dermatomyositis, sharing the generalized distribution of the erythrodermic subtype.

A 62-year-old man presented with pruritic poikiloderma involving the neck, arms, legs, abdomen, chest, and back of 2 years’ duration (Figure). He also experienced dysphagia and weakness of the legs. The rash was previously treated by other dermatologists with a combination of high-potency topical steroids and topical tacrolimus 0.1% without success. His history was notable for CLL, which had been diagnosed by a dermatologist 6 months prior to the current presentation. Prior to his visit to the dermatologist, the patient had received 6 chemotherapeutic sessions with a combination of rituximab and cyclophosphamide for the treatment of CLL. The rash did not improve with chemotherapy.

Repeat biopsies of affected regions only demonstrated features of mild interface dermatitis. Direct immunofluorescence studies showed scattered colloid body fluorescence for IgM. Because of bilateral weakness of the legs, a muscle biopsy was taken, which demonstrated severe atrophy and interstitial fibrosis, with neurogenic abnormalities detected in areas of lesser atrophy via abnormal muscle fiber–type grouping. Metabolic panel showed elevated muscle enzymes in the blood: creatine kinase, 243 U/L (reference range, 10–225 U/L); serum aldolase, 16 U/L (reference range, ≤8.1 U/L); lactate dehydrogenase, 314 U/L (reference range, 60–200 U/L). An autoimmune panel was negative for Jo-1, Scl-70, U1 ribonucleoprotein, DNA, desmoglein 1 and 3, and antiacetylcholine receptor antibodies. An elevated erythrocyte sedimentation rate was measured at 16 mm/h (reference range, 0–10 mm/h). Given these findings, the lesions were confirmed as a widespread poikilodermatous variant of dermatomyositis.

The patient was placed on a daily 50-mg dose of prednisone, which produced rapid improvement in scaling and erythema. Creatine kinase and serum aldolase levels normalized and motor strength increased. After 1 week the prednisone dosage was reduced to a daily 30-mg dose, and then 20 mg a week later. The skin lesions completely resolved within 4 to 5 months and the patient is currently on a prednisone dose of 5 mg, alternating with 2.5 mg of prednisone and rituximab infusion every 2 months.

Dermatomyositis is a rare entity with an incidence of approximately 0.5 to 1 per 100,000 individuals.¹ It presents with a characteristic rash composed of Gottron papules; pathognomonic flat violaceous papules on the dorsal interphalangeal joints, elbows, or knees; and a heliotrope rash, a violaceous erythema involving the eyelids. Poikiloderma frequently is reported to present in a shawl-like distribution, encompassing the shoulders, arms, and upper back.^1,2 Dermatomyositis of the poikilodermatous type can present in nonphotoexposed areas and photoexposed areas. The unusual feature is the total-body involvement, which is analogous to erythroderma.³

Our case may represent a distinct poikilodermatous manifestation sharing the distribution of the erythrodermic subtype. We believe that the skin lesions may have represented a paraneoplastic event presenting prior to diagnosis with CLL. Dermatomyositis has a strong association with cancer, with patients 3 times more likely to develop internal malignancy.⁴ Association is strongest for non-Hodgkin lymphoma, as well as ovarian, lung, colorectal, pancreatic, and gastric cancer. When associated with malignancy, symptoms of dermatomyositis or myositis typically precede the discovery of malignancy by an average of 1.9 years.⁵ Dermatomyositis has been previously reported to present as a paraneoplastic manifestation of CLL.⁶ One case has been reported of a patient with CLL who developed leukemia cutis presenting with poikiloderma in the characteristic dermatomyositis shawl-like distribution.⁷ The lack of dermal infiltration with leukemic cells in our patient, however, makes a paraneoplastic etiology much more likely.

Our patient’s rash did not initially improve with treatment of CLL, but dermatomyositis associated with hematological malignancy may precede, occur simultaneously, or follow the diagnosis of malignancy.⁸ Additionally, symptoms of dermatomyositis do not always parallel the course of hematological malignancy outcome. However, rituximab has been used as a treatment of dermatomyositis and may have contributed some synergistic effect in combination with prednisone in our patient.⁹

To the Editor:

A 43-year-old woman with recently diagnosed diabetes mellitus and a history of thrombotic thrombocytopenic purpura on chronic oral steroids presented with a several-year history of small bumps and bilateral hyperpigmentation on the feet. On physical examination 2- to 3-mm dark brown, hyperkeratotic, firm papules were present on the medial aspects of the feet as well as the dorsal and medial aspects of the thumbs (Figure 1). There also were brown thickened firm plaques on the heels and soles of the feet. 

A punch biopsy of the medial aspect of the right foot was performed (Figure 2). Microscopic examination revealed acral skin with hyperkeratosis, parakeratosis, mild hypergranulosis, mild basilar pigmentation, and mild dermal fibrosis (Figure 2A). A periodic acid–Schiff stain for fungus was negative. An elastic van Gieson stain showed fragmentation of the dermal elastic fibers (Figure 2B). The patient was diagnosed with acrokeratoelastoidosis (AKE).

Acrokeratoelastoidosis is a rare autosomal-dominant genodermatosis characterized by firm yellow papules and plaques that appear along the margins of the hands and feet and increase in number over time.¹ Histopathologically, hyperkeratosis with hypergranulosis and acanthosis can be seen. Elastorrhexis, resulting in fragmentation of elastic fibers within the dermis, typically is present, a feature that distinguishes AKE from focal acral hyperkeratosis.² Also, the dermis may be normal with hematoxylin and eosin stain or slightly thickened with mild depression and thin elastic fibers. There is no reported racial or sex predilection, but rapid progression of the disease during pregnancy has been observed.³

The pathogenesis of AKE is not completely understood. However, it has been implicated that abnormalities in the secretion of elastic fibers from fibroblasts may be involved in disease pathogenesis.^4,5 Electron microscopy has demonstrated fibroblasts with dense granules at the periphery of their cytoplasm and an absence of surrounding elastic fibers. Genetic studies have linked underlying mutations in chromosome 2 to the disease.⁶ Defects in keratinization and overproduction of filaggrin also may be involved in the disease process.⁷

Most therapies generally are ineffective but have included urea, salicylic acid, prednisone, and tretinoin.⁸ Six-month treatment with etretinate 25 to 50 mg has shown promising results, though recurrences occurred with dosage reduction or discontinuation.⁹ Our patient demonstrated mild improvement with urea cream 30%.

To the Editor:

A 43-year-old woman with recently diagnosed diabetes mellitus and a history of thrombotic thrombocytopenic purpura on chronic oral steroids presented with a several-year history of small bumps and bilateral hyperpigmentation on the feet. On physical examination 2- to 3-mm dark brown, hyperkeratotic, firm papules were present on the medial aspects of the feet as well as the dorsal and medial aspects of the thumbs (Figure 1). There also were brown thickened firm plaques on the heels and soles of the feet. 

A punch biopsy of the medial aspect of the right foot was performed (Figure 2). Microscopic examination revealed acral skin with hyperkeratosis, parakeratosis, mild hypergranulosis, mild basilar pigmentation, and mild dermal fibrosis (Figure 2A). A periodic acid–Schiff stain for fungus was negative. An elastic van Gieson stain showed fragmentation of the dermal elastic fibers (Figure 2B). The patient was diagnosed with acrokeratoelastoidosis (AKE).

Acrokeratoelastoidosis is a rare autosomal-dominant genodermatosis characterized by firm yellow papules and plaques that appear along the margins of the hands and feet and increase in number over time.¹ Histopathologically, hyperkeratosis with hypergranulosis and acanthosis can be seen. Elastorrhexis, resulting in fragmentation of elastic fibers within the dermis, typically is present, a feature that distinguishes AKE from focal acral hyperkeratosis.² Also, the dermis may be normal with hematoxylin and eosin stain or slightly thickened with mild depression and thin elastic fibers. There is no reported racial or sex predilection, but rapid progression of the disease during pregnancy has been observed.³

The pathogenesis of AKE is not completely understood. However, it has been implicated that abnormalities in the secretion of elastic fibers from fibroblasts may be involved in disease pathogenesis.^4,5 Electron microscopy has demonstrated fibroblasts with dense granules at the periphery of their cytoplasm and an absence of surrounding elastic fibers. Genetic studies have linked underlying mutations in chromosome 2 to the disease.⁶ Defects in keratinization and overproduction of filaggrin also may be involved in the disease process.⁷

Most therapies generally are ineffective but have included urea, salicylic acid, prednisone, and tretinoin.⁸ Six-month treatment with etretinate 25 to 50 mg has shown promising results, though recurrences occurred with dosage reduction or discontinuation.⁹ Our patient demonstrated mild improvement with urea cream 30%.

To the Editor:

A 43-year-old woman with recently diagnosed diabetes mellitus and a history of thrombotic thrombocytopenic purpura on chronic oral steroids presented with a several-year history of small bumps and bilateral hyperpigmentation on the feet. On physical examination 2- to 3-mm dark brown, hyperkeratotic, firm papules were present on the medial aspects of the feet as well as the dorsal and medial aspects of the thumbs (Figure 1). There also were brown thickened firm plaques on the heels and soles of the feet. 

A punch biopsy of the medial aspect of the right foot was performed (Figure 2). Microscopic examination revealed acral skin with hyperkeratosis, parakeratosis, mild hypergranulosis, mild basilar pigmentation, and mild dermal fibrosis (Figure 2A). A periodic acid–Schiff stain for fungus was negative. An elastic van Gieson stain showed fragmentation of the dermal elastic fibers (Figure 2B). The patient was diagnosed with acrokeratoelastoidosis (AKE).

Acrokeratoelastoidosis is a rare autosomal-dominant genodermatosis characterized by firm yellow papules and plaques that appear along the margins of the hands and feet and increase in number over time.¹ Histopathologically, hyperkeratosis with hypergranulosis and acanthosis can be seen. Elastorrhexis, resulting in fragmentation of elastic fibers within the dermis, typically is present, a feature that distinguishes AKE from focal acral hyperkeratosis.² Also, the dermis may be normal with hematoxylin and eosin stain or slightly thickened with mild depression and thin elastic fibers. There is no reported racial or sex predilection, but rapid progression of the disease during pregnancy has been observed.³

The pathogenesis of AKE is not completely understood. However, it has been implicated that abnormalities in the secretion of elastic fibers from fibroblasts may be involved in disease pathogenesis.^4,5 Electron microscopy has demonstrated fibroblasts with dense granules at the periphery of their cytoplasm and an absence of surrounding elastic fibers. Genetic studies have linked underlying mutations in chromosome 2 to the disease.⁶ Defects in keratinization and overproduction of filaggrin also may be involved in the disease process.⁷

Most therapies generally are ineffective but have included urea, salicylic acid, prednisone, and tretinoin.⁸ Six-month treatment with etretinate 25 to 50 mg has shown promising results, though recurrences occurred with dosage reduction or discontinuation.⁹ Our patient demonstrated mild improvement with urea cream 30%.

To the Editor:

Pemphigus foliaceus is a rare autoimmune blistering disorder that typically presents with crusted scaly erosions in a seborrheic distribution. We describe a case of pemphigus foliaceus localized to the right cheek of 10 years’ duration that spread to other areas. With a PubMed search of articles indexed for MEDLINE yielding only 14 cases of localized pemphigus foliaceus (Table), it represents an extremely rare entity that often is a diagnostic challenge and may be a harbinger for disseminated disease months to years after the inciting lesion appears.

A 51-year-old woman presented with an asymptomatic cutaneous eruption that had remained localized to the right cheek for 10 years before it increased in size and new lesions developed on the left cheek, chest, and upper back. No inciting factors, such as contactants, insect bites, infections, medications, or recent travel were identified. On physical examination a well-demarcated, hypertrophic, verrucouslike plaque with central pink atrophy and exfoliative scale involved the right malar and submalar regions but spared the mucocutaneous junctions of the face (Figure 1). Subtle dark brown papules, some with overlying scale, speckled the left cheek, right jawline, chest, and upper back. The oral cavity was clear.

Leading differentials included hypertrophic discoid lupus erythematosus and pemphigus vegetans. Other considerations included sarcoidosis, granuloma faciale, lupus vulgaris, disseminated coccidioidomycosis or blastomycosis, and squamous cell carcinoma.

An initial biopsy revealed a lymphocytic lichenoid dermatitis with epidermal hyperplasia and scattered eosinophils for which the following differentials were provided: insect bite, hypertrophic lichen planus, prurigo nodularis superimposed on rosacea, and allergic contact dermatitis. Under these histologic diagnoses, tacrolimus ointment 0.03%, topical mid-potency corticosteroid, and a combination of oral doxycycline and metronidazole gel 1% were prescribed but failed to ameliorate her condition.

Because the clinical differentials were vast and noncorrelative with the original pathology, additional biopsies were performed: one from the edge of the large malar plaque, which was transected for hematoxylin and eosin (H&E) and tissue cultures; one perilesional to the large malar plaque for direct immunofluorescence (DIF); and one from the papule on the right jawline for H&E. Tissue cultures were negative for fungal and mycobacterial organisms. Both specimens submitted for H&E showed the prominent epidermal hyperplasia and lymphocytic dermal infiltrate noted on the original H&E but also demonstrated intragranular acantholysis (Figure 2). The DIF revealed intercellular IgG and C3 deposition throughout the epidermis (Figure 3). Indirect immunofluorescence was negative, but enzyme-linked immunosorbent assay detected circulating antidesmoglein-1 but not antidesmoglein-3 autoantibodies. Other serologies including antinuclear antibody, anti–double-stranded DNA, antihistone, anti–Sjögren syndrome A, and anti–Sjögren syndrome B antibodies were negative.

The diagnosis of localized pemphigus foliaceus was made and management with oral prednisone and mycophenolate mofetil resulted in improvement within weeks.

Localized pemphigus foliaceus is extremely rare with only 14 cases reported in the literature (Table).^1-10 Its diagnosis is challenging, as the clinical presentation simulates various entities and the histological features and serological markers are difficult to capture.

Localized pemphigus foliaceus typically presents as an isolated, erythematous, scaly, crusted plaque involving the nose, cheek, or scalp and may mimic several conditions including contact dermatitis, seborrheic dermatitis, rosacea, cutaneous sarcoidosis, discoid lupus erythematosus, lupus vulgaris, impetigo contagiosa, solar keratosis, and nonmelanoma skin cancer.^1-10

The predilection for sun-exposed areas suggests UV radiation may induce binding of antidesmoglein-1 autoantibodies with subsequent cytokine-mediated inflammation and acantholysis at these sites.^11-13 Similarly, the immunomodulatory agent imiquimod has been reported to induce pemphigus foliaceus at its application sites.⁶

When pemphigus foliaceus is clinically discernible, the histology and DIF are in accordance with the clinical diagnosis 53.8% of the time.¹³ In cases of localized pemphigus foliaceus in which the diagnosis is more elusive, many biopsies often are needed to capture the characteristic intragranular acantholysis; this feature often is so subtle that unless the diagnosis is suspected, it is underappreciated or undetectable. In chronic lesions, it may be masked by secondary changes such as acanthosis, hyperkeratosis, and parakeratosis.¹⁴

In pemphigus foliaceus, detection of circulating antidesmoglein-1 autoantibodies by enzyme-linked immunosorbent assay is slightly more sensitive and specific compared to indirect immunofluorescence, but both correlate with disease activity.^15,16 The low or absent autoantibody titers in localized pemphigus foliaceus may reflect its limited involvement, but dissemination of the disease with subsequent elevation of autoantibody titers may occur months to years after initial presentation,^1,2,9 as was the case with our patient.

The majority of localized pemphigus foliaceus cases require systemic prednisone, sometimes in conjunction with nonsteroidal immunosuppressants or topical high-potency corticosteroids.^1-3,5,6,8-10 One case was efficaciously managed with tacrolimus ointment 0.1%.⁷

Localized pemphigus foliaceus is a rare and challenging entity that must be a diagnostic consideration for any chronic focal plaque on the face or scalp, as it may herald disseminated disease.

To the Editor:

Pemphigus foliaceus is a rare autoimmune blistering disorder that typically presents with crusted scaly erosions in a seborrheic distribution. We describe a case of pemphigus foliaceus localized to the right cheek of 10 years’ duration that spread to other areas. With a PubMed search of articles indexed for MEDLINE yielding only 14 cases of localized pemphigus foliaceus (Table), it represents an extremely rare entity that often is a diagnostic challenge and may be a harbinger for disseminated disease months to years after the inciting lesion appears.

A 51-year-old woman presented with an asymptomatic cutaneous eruption that had remained localized to the right cheek for 10 years before it increased in size and new lesions developed on the left cheek, chest, and upper back. No inciting factors, such as contactants, insect bites, infections, medications, or recent travel were identified. On physical examination a well-demarcated, hypertrophic, verrucouslike plaque with central pink atrophy and exfoliative scale involved the right malar and submalar regions but spared the mucocutaneous junctions of the face (Figure 1). Subtle dark brown papules, some with overlying scale, speckled the left cheek, right jawline, chest, and upper back. The oral cavity was clear.

Leading differentials included hypertrophic discoid lupus erythematosus and pemphigus vegetans. Other considerations included sarcoidosis, granuloma faciale, lupus vulgaris, disseminated coccidioidomycosis or blastomycosis, and squamous cell carcinoma.

An initial biopsy revealed a lymphocytic lichenoid dermatitis with epidermal hyperplasia and scattered eosinophils for which the following differentials were provided: insect bite, hypertrophic lichen planus, prurigo nodularis superimposed on rosacea, and allergic contact dermatitis. Under these histologic diagnoses, tacrolimus ointment 0.03%, topical mid-potency corticosteroid, and a combination of oral doxycycline and metronidazole gel 1% were prescribed but failed to ameliorate her condition.

Because the clinical differentials were vast and noncorrelative with the original pathology, additional biopsies were performed: one from the edge of the large malar plaque, which was transected for hematoxylin and eosin (H&E) and tissue cultures; one perilesional to the large malar plaque for direct immunofluorescence (DIF); and one from the papule on the right jawline for H&E. Tissue cultures were negative for fungal and mycobacterial organisms. Both specimens submitted for H&E showed the prominent epidermal hyperplasia and lymphocytic dermal infiltrate noted on the original H&E but also demonstrated intragranular acantholysis (Figure 2). The DIF revealed intercellular IgG and C3 deposition throughout the epidermis (Figure 3). Indirect immunofluorescence was negative, but enzyme-linked immunosorbent assay detected circulating antidesmoglein-1 but not antidesmoglein-3 autoantibodies. Other serologies including antinuclear antibody, anti–double-stranded DNA, antihistone, anti–Sjögren syndrome A, and anti–Sjögren syndrome B antibodies were negative.

The diagnosis of localized pemphigus foliaceus was made and management with oral prednisone and mycophenolate mofetil resulted in improvement within weeks.

Localized pemphigus foliaceus is extremely rare with only 14 cases reported in the literature (Table).^1-10 Its diagnosis is challenging, as the clinical presentation simulates various entities and the histological features and serological markers are difficult to capture.

Localized pemphigus foliaceus typically presents as an isolated, erythematous, scaly, crusted plaque involving the nose, cheek, or scalp and may mimic several conditions including contact dermatitis, seborrheic dermatitis, rosacea, cutaneous sarcoidosis, discoid lupus erythematosus, lupus vulgaris, impetigo contagiosa, solar keratosis, and nonmelanoma skin cancer.^1-10

The predilection for sun-exposed areas suggests UV radiation may induce binding of antidesmoglein-1 autoantibodies with subsequent cytokine-mediated inflammation and acantholysis at these sites.^11-13 Similarly, the immunomodulatory agent imiquimod has been reported to induce pemphigus foliaceus at its application sites.⁶

When pemphigus foliaceus is clinically discernible, the histology and DIF are in accordance with the clinical diagnosis 53.8% of the time.¹³ In cases of localized pemphigus foliaceus in which the diagnosis is more elusive, many biopsies often are needed to capture the characteristic intragranular acantholysis; this feature often is so subtle that unless the diagnosis is suspected, it is underappreciated or undetectable. In chronic lesions, it may be masked by secondary changes such as acanthosis, hyperkeratosis, and parakeratosis.¹⁴

In pemphigus foliaceus, detection of circulating antidesmoglein-1 autoantibodies by enzyme-linked immunosorbent assay is slightly more sensitive and specific compared to indirect immunofluorescence, but both correlate with disease activity.^15,16 The low or absent autoantibody titers in localized pemphigus foliaceus may reflect its limited involvement, but dissemination of the disease with subsequent elevation of autoantibody titers may occur months to years after initial presentation,^1,2,9 as was the case with our patient.

The majority of localized pemphigus foliaceus cases require systemic prednisone, sometimes in conjunction with nonsteroidal immunosuppressants or topical high-potency corticosteroids.^1-3,5,6,8-10 One case was efficaciously managed with tacrolimus ointment 0.1%.⁷

Localized pemphigus foliaceus is a rare and challenging entity that must be a diagnostic consideration for any chronic focal plaque on the face or scalp, as it may herald disseminated disease.

To the Editor:

Pemphigus foliaceus is a rare autoimmune blistering disorder that typically presents with crusted scaly erosions in a seborrheic distribution. We describe a case of pemphigus foliaceus localized to the right cheek of 10 years’ duration that spread to other areas. With a PubMed search of articles indexed for MEDLINE yielding only 14 cases of localized pemphigus foliaceus (Table), it represents an extremely rare entity that often is a diagnostic challenge and may be a harbinger for disseminated disease months to years after the inciting lesion appears.

A 51-year-old woman presented with an asymptomatic cutaneous eruption that had remained localized to the right cheek for 10 years before it increased in size and new lesions developed on the left cheek, chest, and upper back. No inciting factors, such as contactants, insect bites, infections, medications, or recent travel were identified. On physical examination a well-demarcated, hypertrophic, verrucouslike plaque with central pink atrophy and exfoliative scale involved the right malar and submalar regions but spared the mucocutaneous junctions of the face (Figure 1). Subtle dark brown papules, some with overlying scale, speckled the left cheek, right jawline, chest, and upper back. The oral cavity was clear.

Leading differentials included hypertrophic discoid lupus erythematosus and pemphigus vegetans. Other considerations included sarcoidosis, granuloma faciale, lupus vulgaris, disseminated coccidioidomycosis or blastomycosis, and squamous cell carcinoma.

An initial biopsy revealed a lymphocytic lichenoid dermatitis with epidermal hyperplasia and scattered eosinophils for which the following differentials were provided: insect bite, hypertrophic lichen planus, prurigo nodularis superimposed on rosacea, and allergic contact dermatitis. Under these histologic diagnoses, tacrolimus ointment 0.03%, topical mid-potency corticosteroid, and a combination of oral doxycycline and metronidazole gel 1% were prescribed but failed to ameliorate her condition.

Because the clinical differentials were vast and noncorrelative with the original pathology, additional biopsies were performed: one from the edge of the large malar plaque, which was transected for hematoxylin and eosin (H&E) and tissue cultures; one perilesional to the large malar plaque for direct immunofluorescence (DIF); and one from the papule on the right jawline for H&E. Tissue cultures were negative for fungal and mycobacterial organisms. Both specimens submitted for H&E showed the prominent epidermal hyperplasia and lymphocytic dermal infiltrate noted on the original H&E but also demonstrated intragranular acantholysis (Figure 2). The DIF revealed intercellular IgG and C3 deposition throughout the epidermis (Figure 3). Indirect immunofluorescence was negative, but enzyme-linked immunosorbent assay detected circulating antidesmoglein-1 but not antidesmoglein-3 autoantibodies. Other serologies including antinuclear antibody, anti–double-stranded DNA, antihistone, anti–Sjögren syndrome A, and anti–Sjögren syndrome B antibodies were negative.

The diagnosis of localized pemphigus foliaceus was made and management with oral prednisone and mycophenolate mofetil resulted in improvement within weeks.

Localized pemphigus foliaceus is extremely rare with only 14 cases reported in the literature (Table).^1-10 Its diagnosis is challenging, as the clinical presentation simulates various entities and the histological features and serological markers are difficult to capture.

Localized pemphigus foliaceus typically presents as an isolated, erythematous, scaly, crusted plaque involving the nose, cheek, or scalp and may mimic several conditions including contact dermatitis, seborrheic dermatitis, rosacea, cutaneous sarcoidosis, discoid lupus erythematosus, lupus vulgaris, impetigo contagiosa, solar keratosis, and nonmelanoma skin cancer.^1-10

The predilection for sun-exposed areas suggests UV radiation may induce binding of antidesmoglein-1 autoantibodies with subsequent cytokine-mediated inflammation and acantholysis at these sites.^11-13 Similarly, the immunomodulatory agent imiquimod has been reported to induce pemphigus foliaceus at its application sites.⁶

When pemphigus foliaceus is clinically discernible, the histology and DIF are in accordance with the clinical diagnosis 53.8% of the time.¹³ In cases of localized pemphigus foliaceus in which the diagnosis is more elusive, many biopsies often are needed to capture the characteristic intragranular acantholysis; this feature often is so subtle that unless the diagnosis is suspected, it is underappreciated or undetectable. In chronic lesions, it may be masked by secondary changes such as acanthosis, hyperkeratosis, and parakeratosis.¹⁴

In pemphigus foliaceus, detection of circulating antidesmoglein-1 autoantibodies by enzyme-linked immunosorbent assay is slightly more sensitive and specific compared to indirect immunofluorescence, but both correlate with disease activity.^15,16 The low or absent autoantibody titers in localized pemphigus foliaceus may reflect its limited involvement, but dissemination of the disease with subsequent elevation of autoantibody titers may occur months to years after initial presentation,^1,2,9 as was the case with our patient.

The majority of localized pemphigus foliaceus cases require systemic prednisone, sometimes in conjunction with nonsteroidal immunosuppressants or topical high-potency corticosteroids.^1-3,5,6,8-10 One case was efficaciously managed with tacrolimus ointment 0.1%.⁷

Localized pemphigus foliaceus is a rare and challenging entity that must be a diagnostic consideration for any chronic focal plaque on the face or scalp, as it may herald disseminated disease.

To the Editor:

Anti–tumor necrosis factor (TNF) α treatments have radically improved the management of chronic inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, and bowel diseases (eg, Crohn disease, ulcerative colitis [UC]). Because the number of patients treated with these agents has increased, uncommon adverse reactions have increasingly occurred. Cutaneous adverse reactions that have been reported with anti-TNF agents include immediate injection-site reaction, systemic infusion reactions, and delayed reactions.¹ Among the delayed adverse reactions, psoriatic and eczematous eruptions as well as cutaneous infections are the most common, while cutaneous adverse effects related to an immune imbalance syndrome including vasculitis; lupuslike, lichenlike, and granulomatous eruptions; and skin cancer rarely are observed.¹ Although most of the cutaneous adverse effects do not require anti-TNF treatment discontinuation and are resolved with symptomatic treatment, anti-TNF therapy must be stopped in more severe cases. We report the case of severe Henoch-Schönlein purpura (HSP) following treatment with infliximab.

A 46-year-old man who was a nonsmoker with quiescent UC on infliximab for 30 months presented with palpable necrotic purpura on both legs (Figure) and arms as well as the abdomen of 10 days’ duration, along with diffuse joint pain and swelling. He had no history of infectious or gastrointestinal symptoms. The last infliximab infusion was performed 6 weeks prior to developing the purpura. His UC was diagnosed 10 years prior to the current presentation and was not associated with any extragastrointestinal manifestations. Since diagnosis, UC had failed to respond to therapies such as azathioprine, cyclosporine, and purinethol. The complete blood cell count was normal. The C-reactive protein level was 18.7 mg/L (reference range, <5 mg/L) and the erythrocyte sedimentation rate was 30 mm/h (reference range, 0–20 mm/h). Electrolytes, urea, creatinine clearance, and liver function were normal, and a chest radiograph and radiographs of the swollen joints were unremarkable. The total IgA level was elevated at 4 g/L (reference range, 0.7–4 g/L), with IgG and IgM levels within reference range. There was no hematuria or proteinuria on urinalysis. Tests for antinuclear antibodies, rheumatoid factor, circulating immune complexes, and antineutrophil cytoplasmic antibody were negative. Total complement, C3, and C4 levels also were normal. A skin biopsy confirmed a leukocytoclastic vasculitis of small vessels with C3 deposition. Serologic tests for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus were negative. Based on these findings, the diagnosis of HSP was made. Systemic corticosteroids—120 mg daily of intravenous methylprednisolone for 3 days, followed by 1 mg/kg daily of oral prednisone for 2 weeks—were then introduced with rapid clinical improvement. Henoch-Schönlein purpura and joint symptoms completely resolved, but UC relapsed with bloody diarrhea and severe abdominal pain. Oral prednisone was maintained (1 mg/kg daily). Because of the severity of cutaneous vasculitis (HSP), a multidisciplinary decision was taken to definitively stop the anti-TNF agents and to first add azathioprine (2 mg/kg daily for 2 months), then subcutaneous methotrexate (25 mg weekly). Colonoscopy did not show any dysplasia or adenocarcinoma and confirmed the diagnosis of UC. After 6 months of combined therapy, UC was still active and we decided to perform a total colectomy with ileostomy formation. Complete remission of UC was obtained and maintained after 28 months of follow-up.

Henoch-Schönlein purpura is a multisystem small vessel leukocytoclastic vasculitis with the deposition of immune complexes containing IgA. Clinical manifestations may include palpable purpura, arthritis, enteritis, and nephritis. Henoch-Schönlein purpura usually affects children. Adult onset is rare but associated with more severe symptoms and a poor prognosis.² The criteria for HSP, as defined by the American College of Rheumatology,³ include palpable purpura, 20 years or younger at disease onset, bowel angina, and presence of vascular wall granulocytes on biopsy. At least 2 of these criteria are required for HSP diagnosis. Various viral or bacterial infections and drugs can trigger HSP, which also can be associated with autoinflammatory or autoimmune diseases. The association of HSP and UC is a rare event, as demonstrated by de Oliveira et al.⁴ Although only 2 cases of cutaneous vasculitis mimicking HSP have been described in UC,⁴ we cannot exclude a possible association between HSP and UC. However, our patient had UC for 10 years and never had clinical manifestations of vasculitis.

There are 5 reports of HSP following etanercept^5,6 or adalimumab^7-9 therapy and 1 following infliximab therapy.¹⁰ In all cases, HSP occurred after several months of anti-TNF therapy. However, there also are reports of cutaneous vasculitis associated with arthralgia and glomerulonephritis that resolved after withdrawal of anti-TNF agents.^11,12 It is possible that some of these reactions may have been manifestations of undiagnosed HSP. In a series of 113 patients who developed cutaneous vasculitis after anti-TNF agents, visceral vasculitis was observed in 24% of patients. Treatment of vasculitis involved withdrawal of the anti-TNF therapy in 101 cases (89%).¹³ In these UC patients with few therapeutic alternatives, the continuation of anti-TNF agents should be discussed. In the previous series,¹³ of 16 patients who were rechallenged with the same or a different TNF antagonist, 12 (75%) experienced vasculitis relapse, suggesting a class effect of TNF inhibition. Because of the severity of cutaneous vasculitis and as previously suggested in a recent analytical and comprehensive overview on paradoxical reactions under TNF blockers,¹ we decided not to re-expose our patient to infliximab or to other anti-TNF agents.

In conclusion, HSP may occur during anti-TNF therapy and physicians need to be aware of this potentially serious complication.

To the Editor:

Anti–tumor necrosis factor (TNF) α treatments have radically improved the management of chronic inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, and bowel diseases (eg, Crohn disease, ulcerative colitis [UC]). Because the number of patients treated with these agents has increased, uncommon adverse reactions have increasingly occurred. Cutaneous adverse reactions that have been reported with anti-TNF agents include immediate injection-site reaction, systemic infusion reactions, and delayed reactions.¹ Among the delayed adverse reactions, psoriatic and eczematous eruptions as well as cutaneous infections are the most common, while cutaneous adverse effects related to an immune imbalance syndrome including vasculitis; lupuslike, lichenlike, and granulomatous eruptions; and skin cancer rarely are observed.¹ Although most of the cutaneous adverse effects do not require anti-TNF treatment discontinuation and are resolved with symptomatic treatment, anti-TNF therapy must be stopped in more severe cases. We report the case of severe Henoch-Schönlein purpura (HSP) following treatment with infliximab.

A 46-year-old man who was a nonsmoker with quiescent UC on infliximab for 30 months presented with palpable necrotic purpura on both legs (Figure) and arms as well as the abdomen of 10 days’ duration, along with diffuse joint pain and swelling. He had no history of infectious or gastrointestinal symptoms. The last infliximab infusion was performed 6 weeks prior to developing the purpura. His UC was diagnosed 10 years prior to the current presentation and was not associated with any extragastrointestinal manifestations. Since diagnosis, UC had failed to respond to therapies such as azathioprine, cyclosporine, and purinethol. The complete blood cell count was normal. The C-reactive protein level was 18.7 mg/L (reference range, <5 mg/L) and the erythrocyte sedimentation rate was 30 mm/h (reference range, 0–20 mm/h). Electrolytes, urea, creatinine clearance, and liver function were normal, and a chest radiograph and radiographs of the swollen joints were unremarkable. The total IgA level was elevated at 4 g/L (reference range, 0.7–4 g/L), with IgG and IgM levels within reference range. There was no hematuria or proteinuria on urinalysis. Tests for antinuclear antibodies, rheumatoid factor, circulating immune complexes, and antineutrophil cytoplasmic antibody were negative. Total complement, C3, and C4 levels also were normal. A skin biopsy confirmed a leukocytoclastic vasculitis of small vessels with C3 deposition. Serologic tests for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus were negative. Based on these findings, the diagnosis of HSP was made. Systemic corticosteroids—120 mg daily of intravenous methylprednisolone for 3 days, followed by 1 mg/kg daily of oral prednisone for 2 weeks—were then introduced with rapid clinical improvement. Henoch-Schönlein purpura and joint symptoms completely resolved, but UC relapsed with bloody diarrhea and severe abdominal pain. Oral prednisone was maintained (1 mg/kg daily). Because of the severity of cutaneous vasculitis (HSP), a multidisciplinary decision was taken to definitively stop the anti-TNF agents and to first add azathioprine (2 mg/kg daily for 2 months), then subcutaneous methotrexate (25 mg weekly). Colonoscopy did not show any dysplasia or adenocarcinoma and confirmed the diagnosis of UC. After 6 months of combined therapy, UC was still active and we decided to perform a total colectomy with ileostomy formation. Complete remission of UC was obtained and maintained after 28 months of follow-up.

Henoch-Schönlein purpura is a multisystem small vessel leukocytoclastic vasculitis with the deposition of immune complexes containing IgA. Clinical manifestations may include palpable purpura, arthritis, enteritis, and nephritis. Henoch-Schönlein purpura usually affects children. Adult onset is rare but associated with more severe symptoms and a poor prognosis.² The criteria for HSP, as defined by the American College of Rheumatology,³ include palpable purpura, 20 years or younger at disease onset, bowel angina, and presence of vascular wall granulocytes on biopsy. At least 2 of these criteria are required for HSP diagnosis. Various viral or bacterial infections and drugs can trigger HSP, which also can be associated with autoinflammatory or autoimmune diseases. The association of HSP and UC is a rare event, as demonstrated by de Oliveira et al.⁴ Although only 2 cases of cutaneous vasculitis mimicking HSP have been described in UC,⁴ we cannot exclude a possible association between HSP and UC. However, our patient had UC for 10 years and never had clinical manifestations of vasculitis.

There are 5 reports of HSP following etanercept^5,6 or adalimumab^7-9 therapy and 1 following infliximab therapy.¹⁰ In all cases, HSP occurred after several months of anti-TNF therapy. However, there also are reports of cutaneous vasculitis associated with arthralgia and glomerulonephritis that resolved after withdrawal of anti-TNF agents.^11,12 It is possible that some of these reactions may have been manifestations of undiagnosed HSP. In a series of 113 patients who developed cutaneous vasculitis after anti-TNF agents, visceral vasculitis was observed in 24% of patients. Treatment of vasculitis involved withdrawal of the anti-TNF therapy in 101 cases (89%).¹³ In these UC patients with few therapeutic alternatives, the continuation of anti-TNF agents should be discussed. In the previous series,¹³ of 16 patients who were rechallenged with the same or a different TNF antagonist, 12 (75%) experienced vasculitis relapse, suggesting a class effect of TNF inhibition. Because of the severity of cutaneous vasculitis and as previously suggested in a recent analytical and comprehensive overview on paradoxical reactions under TNF blockers,¹ we decided not to re-expose our patient to infliximab or to other anti-TNF agents.

In conclusion, HSP may occur during anti-TNF therapy and physicians need to be aware of this potentially serious complication.

To the Editor:

Anti–tumor necrosis factor (TNF) α treatments have radically improved the management of chronic inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, and bowel diseases (eg, Crohn disease, ulcerative colitis [UC]). Because the number of patients treated with these agents has increased, uncommon adverse reactions have increasingly occurred. Cutaneous adverse reactions that have been reported with anti-TNF agents include immediate injection-site reaction, systemic infusion reactions, and delayed reactions.¹ Among the delayed adverse reactions, psoriatic and eczematous eruptions as well as cutaneous infections are the most common, while cutaneous adverse effects related to an immune imbalance syndrome including vasculitis; lupuslike, lichenlike, and granulomatous eruptions; and skin cancer rarely are observed.¹ Although most of the cutaneous adverse effects do not require anti-TNF treatment discontinuation and are resolved with symptomatic treatment, anti-TNF therapy must be stopped in more severe cases. We report the case of severe Henoch-Schönlein purpura (HSP) following treatment with infliximab.

A 46-year-old man who was a nonsmoker with quiescent UC on infliximab for 30 months presented with palpable necrotic purpura on both legs (Figure) and arms as well as the abdomen of 10 days’ duration, along with diffuse joint pain and swelling. He had no history of infectious or gastrointestinal symptoms. The last infliximab infusion was performed 6 weeks prior to developing the purpura. His UC was diagnosed 10 years prior to the current presentation and was not associated with any extragastrointestinal manifestations. Since diagnosis, UC had failed to respond to therapies such as azathioprine, cyclosporine, and purinethol. The complete blood cell count was normal. The C-reactive protein level was 18.7 mg/L (reference range, <5 mg/L) and the erythrocyte sedimentation rate was 30 mm/h (reference range, 0–20 mm/h). Electrolytes, urea, creatinine clearance, and liver function were normal, and a chest radiograph and radiographs of the swollen joints were unremarkable. The total IgA level was elevated at 4 g/L (reference range, 0.7–4 g/L), with IgG and IgM levels within reference range. There was no hematuria or proteinuria on urinalysis. Tests for antinuclear antibodies, rheumatoid factor, circulating immune complexes, and antineutrophil cytoplasmic antibody were negative. Total complement, C3, and C4 levels also were normal. A skin biopsy confirmed a leukocytoclastic vasculitis of small vessels with C3 deposition. Serologic tests for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus were negative. Based on these findings, the diagnosis of HSP was made. Systemic corticosteroids—120 mg daily of intravenous methylprednisolone for 3 days, followed by 1 mg/kg daily of oral prednisone for 2 weeks—were then introduced with rapid clinical improvement. Henoch-Schönlein purpura and joint symptoms completely resolved, but UC relapsed with bloody diarrhea and severe abdominal pain. Oral prednisone was maintained (1 mg/kg daily). Because of the severity of cutaneous vasculitis (HSP), a multidisciplinary decision was taken to definitively stop the anti-TNF agents and to first add azathioprine (2 mg/kg daily for 2 months), then subcutaneous methotrexate (25 mg weekly). Colonoscopy did not show any dysplasia or adenocarcinoma and confirmed the diagnosis of UC. After 6 months of combined therapy, UC was still active and we decided to perform a total colectomy with ileostomy formation. Complete remission of UC was obtained and maintained after 28 months of follow-up.

Henoch-Schönlein purpura is a multisystem small vessel leukocytoclastic vasculitis with the deposition of immune complexes containing IgA. Clinical manifestations may include palpable purpura, arthritis, enteritis, and nephritis. Henoch-Schönlein purpura usually affects children. Adult onset is rare but associated with more severe symptoms and a poor prognosis.² The criteria for HSP, as defined by the American College of Rheumatology,³ include palpable purpura, 20 years or younger at disease onset, bowel angina, and presence of vascular wall granulocytes on biopsy. At least 2 of these criteria are required for HSP diagnosis. Various viral or bacterial infections and drugs can trigger HSP, which also can be associated with autoinflammatory or autoimmune diseases. The association of HSP and UC is a rare event, as demonstrated by de Oliveira et al.⁴ Although only 2 cases of cutaneous vasculitis mimicking HSP have been described in UC,⁴ we cannot exclude a possible association between HSP and UC. However, our patient had UC for 10 years and never had clinical manifestations of vasculitis.

There are 5 reports of HSP following etanercept^5,6 or adalimumab^7-9 therapy and 1 following infliximab therapy.¹⁰ In all cases, HSP occurred after several months of anti-TNF therapy. However, there also are reports of cutaneous vasculitis associated with arthralgia and glomerulonephritis that resolved after withdrawal of anti-TNF agents.^11,12 It is possible that some of these reactions may have been manifestations of undiagnosed HSP. In a series of 113 patients who developed cutaneous vasculitis after anti-TNF agents, visceral vasculitis was observed in 24% of patients. Treatment of vasculitis involved withdrawal of the anti-TNF therapy in 101 cases (89%).¹³ In these UC patients with few therapeutic alternatives, the continuation of anti-TNF agents should be discussed. In the previous series,¹³ of 16 patients who were rechallenged with the same or a different TNF antagonist, 12 (75%) experienced vasculitis relapse, suggesting a class effect of TNF inhibition. Because of the severity of cutaneous vasculitis and as previously suggested in a recent analytical and comprehensive overview on paradoxical reactions under TNF blockers,¹ we decided not to re-expose our patient to infliximab or to other anti-TNF agents.

In conclusion, HSP may occur during anti-TNF therapy and physicians need to be aware of this potentially serious complication.

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).

To the Editor:

A 52-year-old woman with a history of arthralgia, rhinitis, sinusitis, and episodic epistaxis was admitted to the hospital with multiple nonhealing severe leg ulcerations. She noticed subcutaneous nodules on the legs 6 months prior to the development of ulcers. The lesions progressed from subcutaneous nodules to red-black skin discoloration, blister formation, and eventually ulceration. Over a period of months, the ulcers were treated with several courses of antibiotics and wound care including a single surgical debridement of one of the ulcers on the dorsum of the right foot. These interventions did not make a remarkable impact on ulcer healing.

On physical examination, the patient had scattered 4- to 5-mm palpable purpura on the knees, elbows, and feet bilaterally. She had multiple 1- to 8-cm indurated purple ulcerations with friable surfaces and raised irregular borders on the feet, toes, and lower legs bilaterally (Figure, A–C). One notably larger ulcer was found on the anterior aspect of the left thigh (Figure, A). Scattered 5- to 15-mm eschars were present on the legs bilaterally. She also had multiple large, firm, nonerythematous dermal plaques on the thighs bilaterally that measured several centimeters. There were no oral mucosal lesions and no ulcerations above the waist.

Magnetic resonance imaging of the foot showed some surrounding cellulitis but no osteomyelitis. Chest radiograph and computed tomography revealed bilateral apical nodules. Proteinase 3–antineutrophil cytoplasmic antibody (PR3-ANCA) testing was positive. Serum complement levels were normal. An antinuclear antibody test and rheumatoid factor were both negative. Skin biopsies were obtained from the thigh ulcer, foot ulcer, and purpuric lesions on the right knee. The results demonstrated leukocytoclastic vasculitis and neutrophilic small vessel vasculitis with necrotizing neutrophilic dermatitis and panniculitis. Granulomatosis with polyangiitis (GPA) was diagnosed based on these findings.

Initial inpatient treatment included intravenous methylprednisolone (100 mg every 8 hours for 3 doses), followed by oral prednisone 60 mg daily. Two weeks later the ulcers were reevaluated and only mild improvement had occurred with the steroids. Therefore, rituximab (RTX) was initiated at 375 mg/m² (700 mg) intravenously once weekly for 4 weeks. After 3 doses of RTX, the ulcerations were healing dramatically and the treatment was well tolerated. A rapid prednisone taper was started, and the patient received her fourth and final dose of RTX. Two months after the initial infusion, the thigh ulcer and most of the ulcerations on the feet and lower legs had almost completely resolved. Photographs were taken 5 months after initial RTX infusion (Figure, D–F). A chest radiograph 4 months after initial RTX infusion showed resolution of lung nodules. Two months after RTX induction therapy, azathioprine was added for maintenance but was stopped due to poor tolerance. Oral methotrexate 17.5 mg once weekly was added 5 months after RTX for maintenance and was well tolerated. At that time the prednisone dose was 10 mg daily and was successfully tapered to 5 mg by 9 months after RTX induction therapy.

Granulomatosis with polyangiitis (Wegener granulomatosis) is a granulomatous small- and medium-sized vessel vasculitis that traditionally affects the upper and lower respiratory tract and kidneys.¹ Skin lesions also are quite common and include palpable purpura, ulcers, vesicles, papules, and subcutaneous nodules. Patients with active GPA also tend to have ANCAs directed against proteinase 3 (PR3-ANCA). Although GPA was once considered a fatal disease, treatment with cyclophosphamide combined with corticosteroids has been shown to substantially improve outcomes.¹ Rituximab, a chimeric monoclonal anti-CD20 antibody, works by depleting B lymphocytes and has been used with success to treat diseases such as lymphoma and rheumatoid arthritis.^2,3 The US Food and Drug Administration approved RTX for GPA and microscopic polyangiitis in 2011, with a number of trials supporting its efficacy.⁴

The success of RTX in treating GPA has been documented in case reports as well as several trials with extended follow-up. A single-center observational study of 53 patients showed that RTX was safe and effective for induction and maintenance of remission in patients with refractory GPA. This study also uncovered the potential for predicting relapse based on following B cell and ANCA levels and preventing relapse by initializing further treatment.⁵ Other small studies and case reports have shown similar success using RTX for refractory GPA.^6-10 These studies included various combinations of concurrent therapies and various follow-up intervals. The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared RTX versus cyclophosphamide for ANCA-positive vasculitis.¹¹ This multicenter, randomized, double-blind study found that RTX was as efficacious as cyclophosphamide for induction of remission in severe GPA.The data also suggested that RTX may be superior for relapsing disease.¹¹ Another multicenter, open-label, randomized trial (RITUXVAS) compared RTX to cyclophosphamide in ANCA-associated renal vasculitis. This trial also found the 2 treatments to be similar in both efficacy in inducing remission and adverse events.¹²

Some conflicting reports have appeared on the effectiveness of using RTX for the granulomatous versus vasculitic manifestations of GPA. Aires et al¹³ showed failure of improvement in most patients with granulomatous manifestations of GPA in a study of 8 patients. A retrospective study including 59 patients who were treated with RTX also showed that complete remission was more common in patients with primarily vasculitic manifestations, not granulomatous manifestations.¹⁴ However, some case series that included patients with refractory ophthalmic GPA, a primarily granulomatous manifestation, have found success using RTX.^15,16 More studies are needed to determine if there truly is a difference and whether this difference has an effect on when to use RTX. The skin lesions our patient demonstrated were due to the vasculitic component of the disease, and consequently, the rapid and complete response we observed would be consistent with the premise that the therapy works best for vasculitis.

Most of the trials assessing the efficacy of RTX utilize a tool such as the Wegener granulomatosis-specific Birmingham Vasculitis Activity Score.¹⁷ This measure of treatment response does include a skin item, but it is part of the composite response score. Consequently, a specific statement regarding skin improvement cannot be made. Additionally, little is reported pertaining to the treatment of skin-related findings in GPA. One report did specifically address the treatment of dermatologic manifestations of GPA utilizing systemic tacrolimus with oral prednisone successfully in 1 patient with GPA and a history of recurrent lower extremity nodules and ulcers.¹⁸ The efficacy of RTX in limited GPA was good in a small study of 8 patients. However, the study had only 1 patient with purpura and 1 patient with a subcutaneous nodule.¹⁹ Several other case series and studies have included patients with various cutaneous findings associated with GPA.^5-7,9,11 However, they did not comment specifically on skin response to treatment, and the focus appeared to be on other organ system involvement. One case series did report improvement of lower extremity gangrene with RTX therapy for ANCA-associated vasculitis.⁸ Our report demonstrates a case of severe skin disease that responded well to RTX. It is common to have various skin findings in GPA, and our patient presented with notable skin disease. Although skin findings may not be the more life-threatening manifestations of the disease, they can be quite debilitating, as shown in our case report.

Our patient with notable leg ulcerations required hospitalization due to GPA and received RTX in addition to corticosteroids for treatment. We observed a rapid and dramatic improvement in the skin findings, which seemed to exceed expectations from steroids alone. The other manifestations of the disease including lung nodules also improved. Although cyclophosphamide and corticosteroids have been quite successful in induction of remission, cyclophosphamide is not without serious adverse effects. There also are some patients who have contraindications to cyclophosphamide or do not see successful results. In our brief review of the literature, RTX, a B cell–depleting antibody, has shown to have success in treating refractory and severe GPA. There is little reported specifically about treating the skin manifestations of GPA. A few studies and case reports mention skin findings but do not comment on the success of RTX in treating them. Although the severity of other organ involvement in GPA may take precedence, the skin findings can be quite debilitating, as in our patient. Patients with GPA and notable skin findings may benefit from RTX, and it would be beneficial to include these results in future studies using RTX to treat GPA.

To the Editor:

A 52-year-old woman with a history of arthralgia, rhinitis, sinusitis, and episodic epistaxis was admitted to the hospital with multiple nonhealing severe leg ulcerations. She noticed subcutaneous nodules on the legs 6 months prior to the development of ulcers. The lesions progressed from subcutaneous nodules to red-black skin discoloration, blister formation, and eventually ulceration. Over a period of months, the ulcers were treated with several courses of antibiotics and wound care including a single surgical debridement of one of the ulcers on the dorsum of the right foot. These interventions did not make a remarkable impact on ulcer healing.

On physical examination, the patient had scattered 4- to 5-mm palpable purpura on the knees, elbows, and feet bilaterally. She had multiple 1- to 8-cm indurated purple ulcerations with friable surfaces and raised irregular borders on the feet, toes, and lower legs bilaterally (Figure, A–C). One notably larger ulcer was found on the anterior aspect of the left thigh (Figure, A). Scattered 5- to 15-mm eschars were present on the legs bilaterally. She also had multiple large, firm, nonerythematous dermal plaques on the thighs bilaterally that measured several centimeters. There were no oral mucosal lesions and no ulcerations above the waist.

Magnetic resonance imaging of the foot showed some surrounding cellulitis but no osteomyelitis. Chest radiograph and computed tomography revealed bilateral apical nodules. Proteinase 3–antineutrophil cytoplasmic antibody (PR3-ANCA) testing was positive. Serum complement levels were normal. An antinuclear antibody test and rheumatoid factor were both negative. Skin biopsies were obtained from the thigh ulcer, foot ulcer, and purpuric lesions on the right knee. The results demonstrated leukocytoclastic vasculitis and neutrophilic small vessel vasculitis with necrotizing neutrophilic dermatitis and panniculitis. Granulomatosis with polyangiitis (GPA) was diagnosed based on these findings.

Initial inpatient treatment included intravenous methylprednisolone (100 mg every 8 hours for 3 doses), followed by oral prednisone 60 mg daily. Two weeks later the ulcers were reevaluated and only mild improvement had occurred with the steroids. Therefore, rituximab (RTX) was initiated at 375 mg/m² (700 mg) intravenously once weekly for 4 weeks. After 3 doses of RTX, the ulcerations were healing dramatically and the treatment was well tolerated. A rapid prednisone taper was started, and the patient received her fourth and final dose of RTX. Two months after the initial infusion, the thigh ulcer and most of the ulcerations on the feet and lower legs had almost completely resolved. Photographs were taken 5 months after initial RTX infusion (Figure, D–F). A chest radiograph 4 months after initial RTX infusion showed resolution of lung nodules. Two months after RTX induction therapy, azathioprine was added for maintenance but was stopped due to poor tolerance. Oral methotrexate 17.5 mg once weekly was added 5 months after RTX for maintenance and was well tolerated. At that time the prednisone dose was 10 mg daily and was successfully tapered to 5 mg by 9 months after RTX induction therapy.

Granulomatosis with polyangiitis (Wegener granulomatosis) is a granulomatous small- and medium-sized vessel vasculitis that traditionally affects the upper and lower respiratory tract and kidneys.¹ Skin lesions also are quite common and include palpable purpura, ulcers, vesicles, papules, and subcutaneous nodules. Patients with active GPA also tend to have ANCAs directed against proteinase 3 (PR3-ANCA). Although GPA was once considered a fatal disease, treatment with cyclophosphamide combined with corticosteroids has been shown to substantially improve outcomes.¹ Rituximab, a chimeric monoclonal anti-CD20 antibody, works by depleting B lymphocytes and has been used with success to treat diseases such as lymphoma and rheumatoid arthritis.^2,3 The US Food and Drug Administration approved RTX for GPA and microscopic polyangiitis in 2011, with a number of trials supporting its efficacy.⁴

The success of RTX in treating GPA has been documented in case reports as well as several trials with extended follow-up. A single-center observational study of 53 patients showed that RTX was safe and effective for induction and maintenance of remission in patients with refractory GPA. This study also uncovered the potential for predicting relapse based on following B cell and ANCA levels and preventing relapse by initializing further treatment.⁵ Other small studies and case reports have shown similar success using RTX for refractory GPA.^6-10 These studies included various combinations of concurrent therapies and various follow-up intervals. The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared RTX versus cyclophosphamide for ANCA-positive vasculitis.¹¹ This multicenter, randomized, double-blind study found that RTX was as efficacious as cyclophosphamide for induction of remission in severe GPA.The data also suggested that RTX may be superior for relapsing disease.¹¹ Another multicenter, open-label, randomized trial (RITUXVAS) compared RTX to cyclophosphamide in ANCA-associated renal vasculitis. This trial also found the 2 treatments to be similar in both efficacy in inducing remission and adverse events.¹²

Some conflicting reports have appeared on the effectiveness of using RTX for the granulomatous versus vasculitic manifestations of GPA. Aires et al¹³ showed failure of improvement in most patients with granulomatous manifestations of GPA in a study of 8 patients. A retrospective study including 59 patients who were treated with RTX also showed that complete remission was more common in patients with primarily vasculitic manifestations, not granulomatous manifestations.¹⁴ However, some case series that included patients with refractory ophthalmic GPA, a primarily granulomatous manifestation, have found success using RTX.^15,16 More studies are needed to determine if there truly is a difference and whether this difference has an effect on when to use RTX. The skin lesions our patient demonstrated were due to the vasculitic component of the disease, and consequently, the rapid and complete response we observed would be consistent with the premise that the therapy works best for vasculitis.

Most of the trials assessing the efficacy of RTX utilize a tool such as the Wegener granulomatosis-specific Birmingham Vasculitis Activity Score.¹⁷ This measure of treatment response does include a skin item, but it is part of the composite response score. Consequently, a specific statement regarding skin improvement cannot be made. Additionally, little is reported pertaining to the treatment of skin-related findings in GPA. One report did specifically address the treatment of dermatologic manifestations of GPA utilizing systemic tacrolimus with oral prednisone successfully in 1 patient with GPA and a history of recurrent lower extremity nodules and ulcers.¹⁸ The efficacy of RTX in limited GPA was good in a small study of 8 patients. However, the study had only 1 patient with purpura and 1 patient with a subcutaneous nodule.¹⁹ Several other case series and studies have included patients with various cutaneous findings associated with GPA.^5-7,9,11 However, they did not comment specifically on skin response to treatment, and the focus appeared to be on other organ system involvement. One case series did report improvement of lower extremity gangrene with RTX therapy for ANCA-associated vasculitis.⁸ Our report demonstrates a case of severe skin disease that responded well to RTX. It is common to have various skin findings in GPA, and our patient presented with notable skin disease. Although skin findings may not be the more life-threatening manifestations of the disease, they can be quite debilitating, as shown in our case report.

Our patient with notable leg ulcerations required hospitalization due to GPA and received RTX in addition to corticosteroids for treatment. We observed a rapid and dramatic improvement in the skin findings, which seemed to exceed expectations from steroids alone. The other manifestations of the disease including lung nodules also improved. Although cyclophosphamide and corticosteroids have been quite successful in induction of remission, cyclophosphamide is not without serious adverse effects. There also are some patients who have contraindications to cyclophosphamide or do not see successful results. In our brief review of the literature, RTX, a B cell–depleting antibody, has shown to have success in treating refractory and severe GPA. There is little reported specifically about treating the skin manifestations of GPA. A few studies and case reports mention skin findings but do not comment on the success of RTX in treating them. Although the severity of other organ involvement in GPA may take precedence, the skin findings can be quite debilitating, as in our patient. Patients with GPA and notable skin findings may benefit from RTX, and it would be beneficial to include these results in future studies using RTX to treat GPA.

To the Editor:

A 52-year-old woman with a history of arthralgia, rhinitis, sinusitis, and episodic epistaxis was admitted to the hospital with multiple nonhealing severe leg ulcerations. She noticed subcutaneous nodules on the legs 6 months prior to the development of ulcers. The lesions progressed from subcutaneous nodules to red-black skin discoloration, blister formation, and eventually ulceration. Over a period of months, the ulcers were treated with several courses of antibiotics and wound care including a single surgical debridement of one of the ulcers on the dorsum of the right foot. These interventions did not make a remarkable impact on ulcer healing.

On physical examination, the patient had scattered 4- to 5-mm palpable purpura on the knees, elbows, and feet bilaterally. She had multiple 1- to 8-cm indurated purple ulcerations with friable surfaces and raised irregular borders on the feet, toes, and lower legs bilaterally (Figure, A–C). One notably larger ulcer was found on the anterior aspect of the left thigh (Figure, A). Scattered 5- to 15-mm eschars were present on the legs bilaterally. She also had multiple large, firm, nonerythematous dermal plaques on the thighs bilaterally that measured several centimeters. There were no oral mucosal lesions and no ulcerations above the waist.

Magnetic resonance imaging of the foot showed some surrounding cellulitis but no osteomyelitis. Chest radiograph and computed tomography revealed bilateral apical nodules. Proteinase 3–antineutrophil cytoplasmic antibody (PR3-ANCA) testing was positive. Serum complement levels were normal. An antinuclear antibody test and rheumatoid factor were both negative. Skin biopsies were obtained from the thigh ulcer, foot ulcer, and purpuric lesions on the right knee. The results demonstrated leukocytoclastic vasculitis and neutrophilic small vessel vasculitis with necrotizing neutrophilic dermatitis and panniculitis. Granulomatosis with polyangiitis (GPA) was diagnosed based on these findings.

Initial inpatient treatment included intravenous methylprednisolone (100 mg every 8 hours for 3 doses), followed by oral prednisone 60 mg daily. Two weeks later the ulcers were reevaluated and only mild improvement had occurred with the steroids. Therefore, rituximab (RTX) was initiated at 375 mg/m² (700 mg) intravenously once weekly for 4 weeks. After 3 doses of RTX, the ulcerations were healing dramatically and the treatment was well tolerated. A rapid prednisone taper was started, and the patient received her fourth and final dose of RTX. Two months after the initial infusion, the thigh ulcer and most of the ulcerations on the feet and lower legs had almost completely resolved. Photographs were taken 5 months after initial RTX infusion (Figure, D–F). A chest radiograph 4 months after initial RTX infusion showed resolution of lung nodules. Two months after RTX induction therapy, azathioprine was added for maintenance but was stopped due to poor tolerance. Oral methotrexate 17.5 mg once weekly was added 5 months after RTX for maintenance and was well tolerated. At that time the prednisone dose was 10 mg daily and was successfully tapered to 5 mg by 9 months after RTX induction therapy.

Granulomatosis with polyangiitis (Wegener granulomatosis) is a granulomatous small- and medium-sized vessel vasculitis that traditionally affects the upper and lower respiratory tract and kidneys.¹ Skin lesions also are quite common and include palpable purpura, ulcers, vesicles, papules, and subcutaneous nodules. Patients with active GPA also tend to have ANCAs directed against proteinase 3 (PR3-ANCA). Although GPA was once considered a fatal disease, treatment with cyclophosphamide combined with corticosteroids has been shown to substantially improve outcomes.¹ Rituximab, a chimeric monoclonal anti-CD20 antibody, works by depleting B lymphocytes and has been used with success to treat diseases such as lymphoma and rheumatoid arthritis.^2,3 The US Food and Drug Administration approved RTX for GPA and microscopic polyangiitis in 2011, with a number of trials supporting its efficacy.⁴

The success of RTX in treating GPA has been documented in case reports as well as several trials with extended follow-up. A single-center observational study of 53 patients showed that RTX was safe and effective for induction and maintenance of remission in patients with refractory GPA. This study also uncovered the potential for predicting relapse based on following B cell and ANCA levels and preventing relapse by initializing further treatment.⁵ Other small studies and case reports have shown similar success using RTX for refractory GPA.^6-10 These studies included various combinations of concurrent therapies and various follow-up intervals. The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared RTX versus cyclophosphamide for ANCA-positive vasculitis.¹¹ This multicenter, randomized, double-blind study found that RTX was as efficacious as cyclophosphamide for induction of remission in severe GPA.The data also suggested that RTX may be superior for relapsing disease.¹¹ Another multicenter, open-label, randomized trial (RITUXVAS) compared RTX to cyclophosphamide in ANCA-associated renal vasculitis. This trial also found the 2 treatments to be similar in both efficacy in inducing remission and adverse events.¹²

Some conflicting reports have appeared on the effectiveness of using RTX for the granulomatous versus vasculitic manifestations of GPA. Aires et al¹³ showed failure of improvement in most patients with granulomatous manifestations of GPA in a study of 8 patients. A retrospective study including 59 patients who were treated with RTX also showed that complete remission was more common in patients with primarily vasculitic manifestations, not granulomatous manifestations.¹⁴ However, some case series that included patients with refractory ophthalmic GPA, a primarily granulomatous manifestation, have found success using RTX.^15,16 More studies are needed to determine if there truly is a difference and whether this difference has an effect on when to use RTX. The skin lesions our patient demonstrated were due to the vasculitic component of the disease, and consequently, the rapid and complete response we observed would be consistent with the premise that the therapy works best for vasculitis.

Most of the trials assessing the efficacy of RTX utilize a tool such as the Wegener granulomatosis-specific Birmingham Vasculitis Activity Score.¹⁷ This measure of treatment response does include a skin item, but it is part of the composite response score. Consequently, a specific statement regarding skin improvement cannot be made. Additionally, little is reported pertaining to the treatment of skin-related findings in GPA. One report did specifically address the treatment of dermatologic manifestations of GPA utilizing systemic tacrolimus with oral prednisone successfully in 1 patient with GPA and a history of recurrent lower extremity nodules and ulcers.¹⁸ The efficacy of RTX in limited GPA was good in a small study of 8 patients. However, the study had only 1 patient with purpura and 1 patient with a subcutaneous nodule.¹⁹ Several other case series and studies have included patients with various cutaneous findings associated with GPA.^5-7,9,11 However, they did not comment specifically on skin response to treatment, and the focus appeared to be on other organ system involvement. One case series did report improvement of lower extremity gangrene with RTX therapy for ANCA-associated vasculitis.⁸ Our report demonstrates a case of severe skin disease that responded well to RTX. It is common to have various skin findings in GPA, and our patient presented with notable skin disease. Although skin findings may not be the more life-threatening manifestations of the disease, they can be quite debilitating, as shown in our case report.

Our patient with notable leg ulcerations required hospitalization due to GPA and received RTX in addition to corticosteroids for treatment. We observed a rapid and dramatic improvement in the skin findings, which seemed to exceed expectations from steroids alone. The other manifestations of the disease including lung nodules also improved. Although cyclophosphamide and corticosteroids have been quite successful in induction of remission, cyclophosphamide is not without serious adverse effects. There also are some patients who have contraindications to cyclophosphamide or do not see successful results. In our brief review of the literature, RTX, a B cell–depleting antibody, has shown to have success in treating refractory and severe GPA. There is little reported specifically about treating the skin manifestations of GPA. A few studies and case reports mention skin findings but do not comment on the success of RTX in treating them. Although the severity of other organ involvement in GPA may take precedence, the skin findings can be quite debilitating, as in our patient. Patients with GPA and notable skin findings may benefit from RTX, and it would be beneficial to include these results in future studies using RTX to treat GPA.

To the Editor:

RASopathies, a class of developmental disorders, are caused by mutations in genes that encode protein components of the RAS/mitogen-activated protein kinase (MAPK) pathway. Each syndrome exhibits its phenotypic features; however, because all of them cause dysregulation of the RAS/MAPK pathway, there are numerous overlapping phenotypic features between the syndromes including cardiac defects, cutaneous abnormalities, characteristic facial features, neurocognitive impairment, and increased risk for developing some neoplastic disorders.

Cardiofaciocutaneous (CFC) syndrome is a RASopathy and is a genetic sporadic disease characterized by multiple congenital anomalies associated with mental retardation. It has a complex dermatological phenotype with many cutaneous features that can be helpful to differentiate CFC syndrome from Noonan and Costello syndromes, which also are classified as RASopathies.

A 3-year-old girl presented with skin xerosis and follicular hyperkeratosis of the face, neck, trunk, and limbs (Figure 1). Facial follicular hyperkeratotic papules on an erythematous base were associated with alopecia of the eyebrows (ulerythema ophryogenes). Hair was sparse and curly (Figure 2A). Facial dysmorphic features included a prominent forehead with bitemporal constriction, bilateral ptosis, a broad nasal base, lip contour in a Cupid’s bow, low-set earlobes with creases (Figure 2B), and a short and webbed neck.

Congenital heart disease, hypothyroidism, bilateral hydronephrosis, delayed motor development, and seizures were noted for the first 2 years. Brain computed tomography detected a dilated ventricular system with hydrocephalus. There was no family history of consanguinity.

Pregnancy was complicated by polyhydramnios and preeclampsia. The neonate was delivered at full-term and was readmitted at 6 days of age due to respiratory failure secondary to congenital chylothorax. Cardiac malformation was diagnosed as the ostium secundum atrial septal defect and interventricular and atrioventricular septal defects. Up to this point she was being treated for Turner syndrome.

The RASopathies are a class of human genetic syndromes that are caused by germ line mutations in genes that encode components of the RAS/MAPK pathway.¹ There are many syndromes classified as RASopathies (Table).^2,3

Cardiofaciocutaneous syndrome (Online Mendelian Inheritance in Man [OMIM] 115150) is a genetic disorder first described by Reynolds et al⁴ and is characterized by several cutaneous abnormalities, cardiac defects, dysmorphic craniofacial features, gastrointestinal dysmotility, and mental retardation. It occurs sporadically and is caused by functional activation of mutations in 4 different genes—BRAF, KRAS, MAP2K1, MAP2K2—of the RAS extracellular signal–regulated kinase molecular cascade that regulates cell differentiation, proliferation, and apoptosis.¹

As a RASopathy, CFC syndrome is a member of a family of syndromes with similar phenotypes, which includes mainly Noonan and Costello syndromes. Psychomotor retardation and physical anomalies, the common denominator of all syndromes, may be explained by the effects of the mutations during early development.^5,6

In CFC, relative macrocephaly, prominent forehead, bitemporal constriction, absence of eyebrows, palpebral ptosis, broad nasal root, bulbous nasal tip, and small chin commonly are found. The eyes are widely spaced and the palpebral fissures are downward slanting with epicanthic folds.^1,4,7

Follicular keratosis of the arms, legs, and face occurs in 80% of cases of CFC and ulerythema ophryogenes with sparse eyebrows in 90% of cases. Sparse, curly, and slow-growing hair is found in 93% of patients. Xerotic scaly skin, hyperkeratosis of the palms and soles, infantile hemangiomas, and multiple melanocytic nevi also may occur.⁸

Cardiac abnormalities are seen in 75.7% of patients.¹ Other features include mental retardation, delayed motor development, and structural abnormalities in the central nervous system, as well as seizures and electroencephalogram abnormalities. Unlike Noonan and Costello syndromes, it is unclear if patients with CFC syndrome are at an increased risk for cancer.¹

Noonan syndrome (OMIM #163950) is a disorder characterized by congenital heart defects, short stature, skeletal abnormalities, distinctive facial dysmorphic features, and variable cognitive deficits. Other associated features include cryptorchidism, lymphatic dysplasia, bleeding tendency, and occasional hematologic malignancies during childhood. This syndrome is related to mutations in the PTPN11, SOS1, SOS2, RAF1, BRAF, KRAS, NRAS, RIT1, and LZTR1 genes.^2,9-11 The typical ear shape and placement in Noonan syndrome is oval with an overfolded helix that is low set and posteriorly angulated, which is uncommon in CFC syndrome. Noonan syndrome is characterized by an inverted triangular face; hypertelorism; blue or blue-green iris color; webbed neck; limited skin involvement, mainly represented by multiple nevi; and a much milder developmental delay compared to CFC and Costello syndromes.^1,11

Costello syndrome (OMIM #218040) is a rare condition comprised of severe postnatal feeding difficulties, mental retardation, coarse facial features, cardiovascular abnormalities (eg, pulmonic stenosis, hypertrophic cardiomyopathy, atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities.¹² Costello syndrome is clinically diagnosed. This syndrome shows coarse facies with macrocephaly, downward-slanting palpebral fissures, epicanthal folds, bulbous nose with anteversed nostrils and low nasal bridge, full cheeks, large mouth, thick lips, large tongue, nasal papillomas, cutis laxa, low-set ears, short neck, diffuse skin hyperpigmentation, ulnar deviation of the hands, and nail dystrophy that are not observed in CFC. It is now accepted that the term Costello syndrome should be reserved for patients with HRAS mutation because of the specific risk profile of these patients.¹² Remarkably, patients with Costello syndrome are at increased tumor risk (eg, rhabdomyosarcoma, neuroblastoma, bladder carcinoma).^2,12

The diagnosis of CFC syndrome is purely clinical. There have been many attempts to delineate the syndrome, but none of the described traits are pathognomonic. In 2002, Kavamura et al⁷ created the CFC index, a useful diagnostic approach based on 82 clinical characteristics and their frequencies in the CFC population.

Skin abnormalities are helpful manifestations to differentiate CFC syndrome from Noonan and Costello syndromes. Patients with CFC syndrome present with follicular hyperkeratosis and absent eyebrows. Absent eyebrows, narrowed temples, and Cupid’s bow lip are hallmark features of CFC syndrome and are absent in Noonan and Costello syndromes. The presentation of palmoplantar hyperkeratosis also is a differentiating feature; in patients with Costello syndrome, it is found outside the pressure zones, whereas in those with CFC syndrome, it is present mainly in the pressure zones.¹ Dermatologists can assist geneticists in the differential diagnosis of these syndromes.

The treatment of disorders with follicular plugging and xerosis is challenging. Emollients with urea, glycolic acid, and lactic acid could improve the appearance of the skin. Treatment with mutated MEK gene inhibitors is under investigation to restore normal development of affected embryos with CFC.^2,13 This case and theoretical data show that skin manifestations can be helpful to differentiate CFC syndrome from other RASopathies such as Noonan and Costello syndromes.

To the Editor:

RASopathies, a class of developmental disorders, are caused by mutations in genes that encode protein components of the RAS/mitogen-activated protein kinase (MAPK) pathway. Each syndrome exhibits its phenotypic features; however, because all of them cause dysregulation of the RAS/MAPK pathway, there are numerous overlapping phenotypic features between the syndromes including cardiac defects, cutaneous abnormalities, characteristic facial features, neurocognitive impairment, and increased risk for developing some neoplastic disorders.

Cardiofaciocutaneous (CFC) syndrome is a RASopathy and is a genetic sporadic disease characterized by multiple congenital anomalies associated with mental retardation. It has a complex dermatological phenotype with many cutaneous features that can be helpful to differentiate CFC syndrome from Noonan and Costello syndromes, which also are classified as RASopathies.

A 3-year-old girl presented with skin xerosis and follicular hyperkeratosis of the face, neck, trunk, and limbs (Figure 1). Facial follicular hyperkeratotic papules on an erythematous base were associated with alopecia of the eyebrows (ulerythema ophryogenes). Hair was sparse and curly (Figure 2A). Facial dysmorphic features included a prominent forehead with bitemporal constriction, bilateral ptosis, a broad nasal base, lip contour in a Cupid’s bow, low-set earlobes with creases (Figure 2B), and a short and webbed neck.

Congenital heart disease, hypothyroidism, bilateral hydronephrosis, delayed motor development, and seizures were noted for the first 2 years. Brain computed tomography detected a dilated ventricular system with hydrocephalus. There was no family history of consanguinity.

Pregnancy was complicated by polyhydramnios and preeclampsia. The neonate was delivered at full-term and was readmitted at 6 days of age due to respiratory failure secondary to congenital chylothorax. Cardiac malformation was diagnosed as the ostium secundum atrial septal defect and interventricular and atrioventricular septal defects. Up to this point she was being treated for Turner syndrome.

The RASopathies are a class of human genetic syndromes that are caused by germ line mutations in genes that encode components of the RAS/MAPK pathway.¹ There are many syndromes classified as RASopathies (Table).^2,3

Cardiofaciocutaneous syndrome (Online Mendelian Inheritance in Man [OMIM] 115150) is a genetic disorder first described by Reynolds et al⁴ and is characterized by several cutaneous abnormalities, cardiac defects, dysmorphic craniofacial features, gastrointestinal dysmotility, and mental retardation. It occurs sporadically and is caused by functional activation of mutations in 4 different genes—BRAF, KRAS, MAP2K1, MAP2K2—of the RAS extracellular signal–regulated kinase molecular cascade that regulates cell differentiation, proliferation, and apoptosis.¹

As a RASopathy, CFC syndrome is a member of a family of syndromes with similar phenotypes, which includes mainly Noonan and Costello syndromes. Psychomotor retardation and physical anomalies, the common denominator of all syndromes, may be explained by the effects of the mutations during early development.^5,6

In CFC, relative macrocephaly, prominent forehead, bitemporal constriction, absence of eyebrows, palpebral ptosis, broad nasal root, bulbous nasal tip, and small chin commonly are found. The eyes are widely spaced and the palpebral fissures are downward slanting with epicanthic folds.^1,4,7

Follicular keratosis of the arms, legs, and face occurs in 80% of cases of CFC and ulerythema ophryogenes with sparse eyebrows in 90% of cases. Sparse, curly, and slow-growing hair is found in 93% of patients. Xerotic scaly skin, hyperkeratosis of the palms and soles, infantile hemangiomas, and multiple melanocytic nevi also may occur.⁸

Cardiac abnormalities are seen in 75.7% of patients.¹ Other features include mental retardation, delayed motor development, and structural abnormalities in the central nervous system, as well as seizures and electroencephalogram abnormalities. Unlike Noonan and Costello syndromes, it is unclear if patients with CFC syndrome are at an increased risk for cancer.¹

Noonan syndrome (OMIM #163950) is a disorder characterized by congenital heart defects, short stature, skeletal abnormalities, distinctive facial dysmorphic features, and variable cognitive deficits. Other associated features include cryptorchidism, lymphatic dysplasia, bleeding tendency, and occasional hematologic malignancies during childhood. This syndrome is related to mutations in the PTPN11, SOS1, SOS2, RAF1, BRAF, KRAS, NRAS, RIT1, and LZTR1 genes.^2,9-11 The typical ear shape and placement in Noonan syndrome is oval with an overfolded helix that is low set and posteriorly angulated, which is uncommon in CFC syndrome. Noonan syndrome is characterized by an inverted triangular face; hypertelorism; blue or blue-green iris color; webbed neck; limited skin involvement, mainly represented by multiple nevi; and a much milder developmental delay compared to CFC and Costello syndromes.^1,11

Costello syndrome (OMIM #218040) is a rare condition comprised of severe postnatal feeding difficulties, mental retardation, coarse facial features, cardiovascular abnormalities (eg, pulmonic stenosis, hypertrophic cardiomyopathy, atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities.¹² Costello syndrome is clinically diagnosed. This syndrome shows coarse facies with macrocephaly, downward-slanting palpebral fissures, epicanthal folds, bulbous nose with anteversed nostrils and low nasal bridge, full cheeks, large mouth, thick lips, large tongue, nasal papillomas, cutis laxa, low-set ears, short neck, diffuse skin hyperpigmentation, ulnar deviation of the hands, and nail dystrophy that are not observed in CFC. It is now accepted that the term Costello syndrome should be reserved for patients with HRAS mutation because of the specific risk profile of these patients.¹² Remarkably, patients with Costello syndrome are at increased tumor risk (eg, rhabdomyosarcoma, neuroblastoma, bladder carcinoma).^2,12

The diagnosis of CFC syndrome is purely clinical. There have been many attempts to delineate the syndrome, but none of the described traits are pathognomonic. In 2002, Kavamura et al⁷ created the CFC index, a useful diagnostic approach based on 82 clinical characteristics and their frequencies in the CFC population.

Skin abnormalities are helpful manifestations to differentiate CFC syndrome from Noonan and Costello syndromes. Patients with CFC syndrome present with follicular hyperkeratosis and absent eyebrows. Absent eyebrows, narrowed temples, and Cupid’s bow lip are hallmark features of CFC syndrome and are absent in Noonan and Costello syndromes. The presentation of palmoplantar hyperkeratosis also is a differentiating feature; in patients with Costello syndrome, it is found outside the pressure zones, whereas in those with CFC syndrome, it is present mainly in the pressure zones.¹ Dermatologists can assist geneticists in the differential diagnosis of these syndromes.

The treatment of disorders with follicular plugging and xerosis is challenging. Emollients with urea, glycolic acid, and lactic acid could improve the appearance of the skin. Treatment with mutated MEK gene inhibitors is under investigation to restore normal development of affected embryos with CFC.^2,13 This case and theoretical data show that skin manifestations can be helpful to differentiate CFC syndrome from other RASopathies such as Noonan and Costello syndromes.

To the Editor:

RASopathies, a class of developmental disorders, are caused by mutations in genes that encode protein components of the RAS/mitogen-activated protein kinase (MAPK) pathway. Each syndrome exhibits its phenotypic features; however, because all of them cause dysregulation of the RAS/MAPK pathway, there are numerous overlapping phenotypic features between the syndromes including cardiac defects, cutaneous abnormalities, characteristic facial features, neurocognitive impairment, and increased risk for developing some neoplastic disorders.

Cardiofaciocutaneous (CFC) syndrome is a RASopathy and is a genetic sporadic disease characterized by multiple congenital anomalies associated with mental retardation. It has a complex dermatological phenotype with many cutaneous features that can be helpful to differentiate CFC syndrome from Noonan and Costello syndromes, which also are classified as RASopathies.

A 3-year-old girl presented with skin xerosis and follicular hyperkeratosis of the face, neck, trunk, and limbs (Figure 1). Facial follicular hyperkeratotic papules on an erythematous base were associated with alopecia of the eyebrows (ulerythema ophryogenes). Hair was sparse and curly (Figure 2A). Facial dysmorphic features included a prominent forehead with bitemporal constriction, bilateral ptosis, a broad nasal base, lip contour in a Cupid’s bow, low-set earlobes with creases (Figure 2B), and a short and webbed neck.

Congenital heart disease, hypothyroidism, bilateral hydronephrosis, delayed motor development, and seizures were noted for the first 2 years. Brain computed tomography detected a dilated ventricular system with hydrocephalus. There was no family history of consanguinity.

Pregnancy was complicated by polyhydramnios and preeclampsia. The neonate was delivered at full-term and was readmitted at 6 days of age due to respiratory failure secondary to congenital chylothorax. Cardiac malformation was diagnosed as the ostium secundum atrial septal defect and interventricular and atrioventricular septal defects. Up to this point she was being treated for Turner syndrome.

The RASopathies are a class of human genetic syndromes that are caused by germ line mutations in genes that encode components of the RAS/MAPK pathway.¹ There are many syndromes classified as RASopathies (Table).^2,3

Cardiofaciocutaneous syndrome (Online Mendelian Inheritance in Man [OMIM] 115150) is a genetic disorder first described by Reynolds et al⁴ and is characterized by several cutaneous abnormalities, cardiac defects, dysmorphic craniofacial features, gastrointestinal dysmotility, and mental retardation. It occurs sporadically and is caused by functional activation of mutations in 4 different genes—BRAF, KRAS, MAP2K1, MAP2K2—of the RAS extracellular signal–regulated kinase molecular cascade that regulates cell differentiation, proliferation, and apoptosis.¹

As a RASopathy, CFC syndrome is a member of a family of syndromes with similar phenotypes, which includes mainly Noonan and Costello syndromes. Psychomotor retardation and physical anomalies, the common denominator of all syndromes, may be explained by the effects of the mutations during early development.^5,6

In CFC, relative macrocephaly, prominent forehead, bitemporal constriction, absence of eyebrows, palpebral ptosis, broad nasal root, bulbous nasal tip, and small chin commonly are found. The eyes are widely spaced and the palpebral fissures are downward slanting with epicanthic folds.^1,4,7

Follicular keratosis of the arms, legs, and face occurs in 80% of cases of CFC and ulerythema ophryogenes with sparse eyebrows in 90% of cases. Sparse, curly, and slow-growing hair is found in 93% of patients. Xerotic scaly skin, hyperkeratosis of the palms and soles, infantile hemangiomas, and multiple melanocytic nevi also may occur.⁸

Cardiac abnormalities are seen in 75.7% of patients.¹ Other features include mental retardation, delayed motor development, and structural abnormalities in the central nervous system, as well as seizures and electroencephalogram abnormalities. Unlike Noonan and Costello syndromes, it is unclear if patients with CFC syndrome are at an increased risk for cancer.¹

Noonan syndrome (OMIM #163950) is a disorder characterized by congenital heart defects, short stature, skeletal abnormalities, distinctive facial dysmorphic features, and variable cognitive deficits. Other associated features include cryptorchidism, lymphatic dysplasia, bleeding tendency, and occasional hematologic malignancies during childhood. This syndrome is related to mutations in the PTPN11, SOS1, SOS2, RAF1, BRAF, KRAS, NRAS, RIT1, and LZTR1 genes.^2,9-11 The typical ear shape and placement in Noonan syndrome is oval with an overfolded helix that is low set and posteriorly angulated, which is uncommon in CFC syndrome. Noonan syndrome is characterized by an inverted triangular face; hypertelorism; blue or blue-green iris color; webbed neck; limited skin involvement, mainly represented by multiple nevi; and a much milder developmental delay compared to CFC and Costello syndromes.^1,11

Costello syndrome (OMIM #218040) is a rare condition comprised of severe postnatal feeding difficulties, mental retardation, coarse facial features, cardiovascular abnormalities (eg, pulmonic stenosis, hypertrophic cardiomyopathy, atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities.¹² Costello syndrome is clinically diagnosed. This syndrome shows coarse facies with macrocephaly, downward-slanting palpebral fissures, epicanthal folds, bulbous nose with anteversed nostrils and low nasal bridge, full cheeks, large mouth, thick lips, large tongue, nasal papillomas, cutis laxa, low-set ears, short neck, diffuse skin hyperpigmentation, ulnar deviation of the hands, and nail dystrophy that are not observed in CFC. It is now accepted that the term Costello syndrome should be reserved for patients with HRAS mutation because of the specific risk profile of these patients.¹² Remarkably, patients with Costello syndrome are at increased tumor risk (eg, rhabdomyosarcoma, neuroblastoma, bladder carcinoma).^2,12

The diagnosis of CFC syndrome is purely clinical. There have been many attempts to delineate the syndrome, but none of the described traits are pathognomonic. In 2002, Kavamura et al⁷ created the CFC index, a useful diagnostic approach based on 82 clinical characteristics and their frequencies in the CFC population.

Skin abnormalities are helpful manifestations to differentiate CFC syndrome from Noonan and Costello syndromes. Patients with CFC syndrome present with follicular hyperkeratosis and absent eyebrows. Absent eyebrows, narrowed temples, and Cupid’s bow lip are hallmark features of CFC syndrome and are absent in Noonan and Costello syndromes. The presentation of palmoplantar hyperkeratosis also is a differentiating feature; in patients with Costello syndrome, it is found outside the pressure zones, whereas in those with CFC syndrome, it is present mainly in the pressure zones.¹ Dermatologists can assist geneticists in the differential diagnosis of these syndromes.

The treatment of disorders with follicular plugging and xerosis is challenging. Emollients with urea, glycolic acid, and lactic acid could improve the appearance of the skin. Treatment with mutated MEK gene inhibitors is under investigation to restore normal development of affected embryos with CFC.^2,13 This case and theoretical data show that skin manifestations can be helpful to differentiate CFC syndrome from other RASopathies such as Noonan and Costello syndromes.

To the Editor:
Down syndrome (DS) is associated with rare dermatological disorders, and the prevalence of some common dermatoses is greater in patients with DS. We report a case of milialike idiopathic calcinosis cutis (MICC) associated with syringomas in a patient with DS. We emphasize that MICC is one of the rare dermatoses associated with DS.

A 4-year-old girl with DS presented with a 4-mm, flesh-colored, regular-bordered, exophytic papular lesion on the left upper eyelid of 8 months' duration (Figure 1). It was clinically recognized as syringoma. On dermatologic examination of the patient, there also were 1- to 3-mm, round, whitish, painless, milialike papules on the dorsal surface of the hands and wrists (Figure 2). Some of these papules were surrounded by erythema. There was no sign of perforation. Her personal and family history were unremarkable.

Histopathologic examination of a biopsy from a  milialike lesion on the hand showed a hyperkeratotic epidermis. In the dermis there was a roundish calcific nodule surrounded by a fibrovascular rim. The patient's guardians refused a biopsy from the lesion on the eyelid.

Laboratory tests including serum vitamin D, thyroid and parathyroid hormone, calcium, phosphorus, and urinary calcium levels, as well as renal function tests, were within reference range. On the basis of these clinical and histopathological findings, the patient was diagnosed with MICC and palpebral syringoma.

Many dermatoses associated with DS have been reported including elastosis perforans serpiginosa, alopecia areata, and syringomas.^1-3 Sano et al4 first described MICC and syringomas in a patient with DS in 1978. Milialike idiopathic calcinosis cutis is characterized by asymptomatic, millimetric, firm, round, whitish papules that are sometimes surrounded by erythema. These papules may show perforation leading to transepidermal elimination of calcium, similar to the transdermal elimination of elastic fibrils in elastosis perforans serpiginosa. Although MICC usually is described in acral sites of children with DS, it also is reported in adults without DS and on other parts of the body.^5-7

The cause of MICC is unknown. One hypothesis of the development of MICC is an increase of the calcium content in the sweat leading to calcification of the acrosyringium.⁸ Milia are small keratin cysts that usually develop by occlusion of the hair follicle, sweat duct, or sebaceous duct. However, milia also can occur from occlusion of the eccrine ducts where syringomas originate.⁹ Therefore, syringomas can be seen in association with milia and calcium deposits.^5,9-11

We believe that MICC in DS may be more common than usually recognized, as the lesions often are asymptomatic. It is important to differentiate MICC from other dermatological diseases such as molluscum contagiosum, verruca plana, milia, and inclusion cysts. Histopathology and dermoscopy could aid in the accurate diagnosis of MICC.

To the Editor:
Down syndrome (DS) is associated with rare dermatological disorders, and the prevalence of some common dermatoses is greater in patients with DS. We report a case of milialike idiopathic calcinosis cutis (MICC) associated with syringomas in a patient with DS. We emphasize that MICC is one of the rare dermatoses associated with DS.

A 4-year-old girl with DS presented with a 4-mm, flesh-colored, regular-bordered, exophytic papular lesion on the left upper eyelid of 8 months' duration (Figure 1). It was clinically recognized as syringoma. On dermatologic examination of the patient, there also were 1- to 3-mm, round, whitish, painless, milialike papules on the dorsal surface of the hands and wrists (Figure 2). Some of these papules were surrounded by erythema. There was no sign of perforation. Her personal and family history were unremarkable.

Histopathologic examination of a biopsy from a  milialike lesion on the hand showed a hyperkeratotic epidermis. In the dermis there was a roundish calcific nodule surrounded by a fibrovascular rim. The patient's guardians refused a biopsy from the lesion on the eyelid.

Laboratory tests including serum vitamin D, thyroid and parathyroid hormone, calcium, phosphorus, and urinary calcium levels, as well as renal function tests, were within reference range. On the basis of these clinical and histopathological findings, the patient was diagnosed with MICC and palpebral syringoma.

Many dermatoses associated with DS have been reported including elastosis perforans serpiginosa, alopecia areata, and syringomas.^1-3 Sano et al4 first described MICC and syringomas in a patient with DS in 1978. Milialike idiopathic calcinosis cutis is characterized by asymptomatic, millimetric, firm, round, whitish papules that are sometimes surrounded by erythema. These papules may show perforation leading to transepidermal elimination of calcium, similar to the transdermal elimination of elastic fibrils in elastosis perforans serpiginosa. Although MICC usually is described in acral sites of children with DS, it also is reported in adults without DS and on other parts of the body.^5-7

The cause of MICC is unknown. One hypothesis of the development of MICC is an increase of the calcium content in the sweat leading to calcification of the acrosyringium.⁸ Milia are small keratin cysts that usually develop by occlusion of the hair follicle, sweat duct, or sebaceous duct. However, milia also can occur from occlusion of the eccrine ducts where syringomas originate.⁹ Therefore, syringomas can be seen in association with milia and calcium deposits.^5,9-11

We believe that MICC in DS may be more common than usually recognized, as the lesions often are asymptomatic. It is important to differentiate MICC from other dermatological diseases such as molluscum contagiosum, verruca plana, milia, and inclusion cysts. Histopathology and dermoscopy could aid in the accurate diagnosis of MICC.

To the Editor:
Down syndrome (DS) is associated with rare dermatological disorders, and the prevalence of some common dermatoses is greater in patients with DS. We report a case of milialike idiopathic calcinosis cutis (MICC) associated with syringomas in a patient with DS. We emphasize that MICC is one of the rare dermatoses associated with DS.

A 4-year-old girl with DS presented with a 4-mm, flesh-colored, regular-bordered, exophytic papular lesion on the left upper eyelid of 8 months' duration (Figure 1). It was clinically recognized as syringoma. On dermatologic examination of the patient, there also were 1- to 3-mm, round, whitish, painless, milialike papules on the dorsal surface of the hands and wrists (Figure 2). Some of these papules were surrounded by erythema. There was no sign of perforation. Her personal and family history were unremarkable.

Histopathologic examination of a biopsy from a  milialike lesion on the hand showed a hyperkeratotic epidermis. In the dermis there was a roundish calcific nodule surrounded by a fibrovascular rim. The patient's guardians refused a biopsy from the lesion on the eyelid.

Laboratory tests including serum vitamin D, thyroid and parathyroid hormone, calcium, phosphorus, and urinary calcium levels, as well as renal function tests, were within reference range. On the basis of these clinical and histopathological findings, the patient was diagnosed with MICC and palpebral syringoma.

Many dermatoses associated with DS have been reported including elastosis perforans serpiginosa, alopecia areata, and syringomas.^1-3 Sano et al4 first described MICC and syringomas in a patient with DS in 1978. Milialike idiopathic calcinosis cutis is characterized by asymptomatic, millimetric, firm, round, whitish papules that are sometimes surrounded by erythema. These papules may show perforation leading to transepidermal elimination of calcium, similar to the transdermal elimination of elastic fibrils in elastosis perforans serpiginosa. Although MICC usually is described in acral sites of children with DS, it also is reported in adults without DS and on other parts of the body.^5-7

The cause of MICC is unknown. One hypothesis of the development of MICC is an increase of the calcium content in the sweat leading to calcification of the acrosyringium.⁸ Milia are small keratin cysts that usually develop by occlusion of the hair follicle, sweat duct, or sebaceous duct. However, milia also can occur from occlusion of the eccrine ducts where syringomas originate.⁹ Therefore, syringomas can be seen in association with milia and calcium deposits.^5,9-11

We believe that MICC in DS may be more common than usually recognized, as the lesions often are asymptomatic. It is important to differentiate MICC from other dermatological diseases such as molluscum contagiosum, verruca plana, milia, and inclusion cysts. Histopathology and dermoscopy could aid in the accurate diagnosis of MICC.