Guldbakke KK

Piebaldism is a rare autosomal dominant disorder characterized by congenital poliosis and leukoderma. We present a case of a 10-year-old girl with a typical clinical presentation, followed by a concise review of the literature discussing the etiology, clinical features, diagnosis, and management of the condition.

Case Report
A 10-year-old girl presented for evaluation of a white forelock and multiple white patches of skin on the trunk and extremities (Figure). The white forelock was present at birth and a few white patches appeared on the chest at 3 months of age. During the subsequent 4 years, the white patches gradually progressed to involve the central forehead, abdomen, and extremities. Multiple frecklelike macules also appeared within the patches and the surrounding healthy skin.

Physical examination revealed a healthy girl with a prominent, large, diamond-shaped, depigmented patch on the central forehead that was associated with a white forelock. The hairs of the medial eyebrows and the eyelashes also were depigmented. Large, irregularly shaped, depigmented patches were present on the trunk and anterior extremities. There were multiple hyperpigmented macules overlying both the depigmented patches and the adjacent normally pigmented skin. The rest of the physical examination and the results of routine blood tests and urinalysis were unremarkable. The patient's mother and 4 siblings also were born with a white forelock. Similar depigmented patches on the trunk and extremities with a similar pattern and distribution were noted in all of them. Neither the patient nor her mother and siblings had midfacial anomalies, deafness, or heterochromia irides.

Comment
Piebaldism is a rare autosomal dominant disorder of melanocyte development resulting from mutations of the c-kit protooncogene.1,2 The disorder is characterized clinically by congenital poliosis and leukoderma. A white forelock is present at birth and may be the only manifestation in most affected individuals.3 The white forelock may have a triangular or diamond shape, and the underlying skin of the scalp also is amelanotic. Typical piebald lesions are typified by well-circumscribed, irregular, chalk white patches, often with hyperpigmented frecklelike macules noted on both depigmented and unaffected adjacent skin.4 The lesions often exhibit a classic distribution, involving the central forehead and anterior trunk, with extension to the flanks and anterior midarms, midknees, and midlegs. The medial third of the eyebrows and eyelashes also may be affected in severe cases.4 Characteristically, there is sparing of the dorsal midline, hands, feet, and periorificial areas. Piebaldism generally is a static disorder of pigmentation, though contraction of the affected areas with time or the appearance of new hyperpigmented macular lesions has been described.5 Progression of the depigmented patches has been reported in isolated cases with a novel Val620Ala mutation in Kit.6 Piebaldism rarely is associated with other disorders such as Hirschsprung disease, neurofibromatosis type 1, congenital dyserythropoietic anemia type II, Diamond-Blackfan anemia, and Grover disease.7-11 Individual case reports with associated deafness also have been described.12 Histopathologic evaluation of the depigmented lesions reveals absent or considerably reduced melanocytes. The hyperpigmented macules have a normal number of melanocytes and an increased number of melanosomes in the melanocytes and keratinocytes.4 The molecular basis of piebaldism was traced by Giebel and Spritz1 and Fleischman et al13 to mutations of the c-kit protooncogene. To date, 14 point mutations, 9 deletion mutations, 2 nucleotide splicing mutations, and 3 insertions of Kit have been described.6,14 c-kit Mutations are found in about 75% of patients with piebaldism.14 Mutations in the slug gene, which is a zinc-finger neural crest transcription factor, have been reported in piebaldism that lacked mutations in Kit.15 The human kit gene encodes the tyrosine kinase transmembrane cellular receptor for mast/stem cell growth factor, which is a critical factor for melanoblast migration, proliferation, differentiation, and survival.6 It would be pertinent to note here that the severity of the phenotype in piebaldism correlates with the site of the mutation within the kit gene. The most severe phenotypes are caused by mutations involving the intracellular tyrosine kinase domain, whereas the mildest phenotypes result from mutations involving the amino-terminal extracellular ligand-binding domain.6 The differential diagnosis of piebaldism includes any condition that may present with a depigmented lesion. Vitiligo is characterized by acquired depigmentation, typically in an acral and periorificial distribution. Piebaldism generally is distinguished from vitiligo by the presence of lesions from birth, hyperpigmented macules within and at the border of depigmented areas, and its static course. Moreover, piebaldism spares the dorsal midline, hands, feet, and periorificial areas. Waardenburg syndrome is an autosomal dominant disorder characterized by a congenital white forelock, lateral displacement of the medial canthi, a hypertrophic nasal root, heterochromia irides, and sensorineural hearing loss.16 At least 4 types of Waardenburg syndrome have been described based on the clinical and genetic criteria. The presence of hyperpigmented patches within the islands of depigmentation and on healthy skin; the absence of midfacial lesions, heterochromia irides, and deafness; and the location of depigmented patches on the trunk and extremities help to distinguish piebaldism from the various forms of Waardenburg syndrome.16 Ziprkowski-Margolis syndrome is a rare X-linked recessive syndrome characterized by deaf-mutism, heterochromic irides, piebaldlike hypomelanosis, and hyperpigmented macules, with a geographic appearance developing mainly on the trunk and extremities.17 Woolf syndrome is an autosomal recessive disorder consisting of piebaldism and deafness. Audiometry is crucial to exclude this diagnosis.18 Depending on its presentation, other conditions to consider include Addison disease, albinism, and systemic sclerosis, as well as use of depigmenting agents. Piebaldism is considered a relatively benign disorder, but it may have psychological impact because it is socially disabling, which presents a therapeutic challenge. Depigmented skin in piebaldism generally is considered unresponsive to medical or light therapy. Of note, the diagnosis of piebaldism should alert the clinician to the possibility of Waardenburg syndrome as determined by the results of ocular and auditory examinations. Sunscreens are recommended to avoid sunburns and to reduce the carcinogenic potential. To camouflage the exposed areas, makeup or temporary pigmenting agents such as the tanning product dihydroxyacetone may be used.19 The lesions of piebaldism do not respond to the topical agents used to treat vitiligo. Different surgical techniques have been tried, with variable success, including thin split-thickness grafts, minigrafting, transplant of autologous cultured melanocytes, and a combination of dermabrasion and grafting of the pigmented skin into the depigmented areas.20,21 Guerra et al22 reported achromic epidermis removed with the erbium:YAG laser and autologous cultured epidermal grafts were applied to the recipient bed in 6 patients. Autologous cultured epidermis, bearing a controlled number of melanocytes, induced repigmentation of all piebald lesions. The mean percentage repigmentation was 95.45%.22

Piebaldism is a rare autosomal dominant disorder characterized by congenital poliosis and leukoderma. We present a case of a 10-year-old girl with a typical clinical presentation, followed by a concise review of the literature discussing the etiology, clinical features, diagnosis, and management of the condition.

Case Report
A 10-year-old girl presented for evaluation of a white forelock and multiple white patches of skin on the trunk and extremities (Figure). The white forelock was present at birth and a few white patches appeared on the chest at 3 months of age. During the subsequent 4 years, the white patches gradually progressed to involve the central forehead, abdomen, and extremities. Multiple frecklelike macules also appeared within the patches and the surrounding healthy skin.

Physical examination revealed a healthy girl with a prominent, large, diamond-shaped, depigmented patch on the central forehead that was associated with a white forelock. The hairs of the medial eyebrows and the eyelashes also were depigmented. Large, irregularly shaped, depigmented patches were present on the trunk and anterior extremities. There were multiple hyperpigmented macules overlying both the depigmented patches and the adjacent normally pigmented skin. The rest of the physical examination and the results of routine blood tests and urinalysis were unremarkable. The patient's mother and 4 siblings also were born with a white forelock. Similar depigmented patches on the trunk and extremities with a similar pattern and distribution were noted in all of them. Neither the patient nor her mother and siblings had midfacial anomalies, deafness, or heterochromia irides.

Comment
Piebaldism is a rare autosomal dominant disorder of melanocyte development resulting from mutations of the c-kit protooncogene.1,2 The disorder is characterized clinically by congenital poliosis and leukoderma. A white forelock is present at birth and may be the only manifestation in most affected individuals.3 The white forelock may have a triangular or diamond shape, and the underlying skin of the scalp also is amelanotic. Typical piebald lesions are typified by well-circumscribed, irregular, chalk white patches, often with hyperpigmented frecklelike macules noted on both depigmented and unaffected adjacent skin.4 The lesions often exhibit a classic distribution, involving the central forehead and anterior trunk, with extension to the flanks and anterior midarms, midknees, and midlegs. The medial third of the eyebrows and eyelashes also may be affected in severe cases.4 Characteristically, there is sparing of the dorsal midline, hands, feet, and periorificial areas. Piebaldism generally is a static disorder of pigmentation, though contraction of the affected areas with time or the appearance of new hyperpigmented macular lesions has been described.5 Progression of the depigmented patches has been reported in isolated cases with a novel Val620Ala mutation in Kit.6 Piebaldism rarely is associated with other disorders such as Hirschsprung disease, neurofibromatosis type 1, congenital dyserythropoietic anemia type II, Diamond-Blackfan anemia, and Grover disease.7-11 Individual case reports with associated deafness also have been described.12 Histopathologic evaluation of the depigmented lesions reveals absent or considerably reduced melanocytes. The hyperpigmented macules have a normal number of melanocytes and an increased number of melanosomes in the melanocytes and keratinocytes.4 The molecular basis of piebaldism was traced by Giebel and Spritz1 and Fleischman et al13 to mutations of the c-kit protooncogene. To date, 14 point mutations, 9 deletion mutations, 2 nucleotide splicing mutations, and 3 insertions of Kit have been described.6,14 c-kit Mutations are found in about 75% of patients with piebaldism.14 Mutations in the slug gene, which is a zinc-finger neural crest transcription factor, have been reported in piebaldism that lacked mutations in Kit.15 The human kit gene encodes the tyrosine kinase transmembrane cellular receptor for mast/stem cell growth factor, which is a critical factor for melanoblast migration, proliferation, differentiation, and survival.6 It would be pertinent to note here that the severity of the phenotype in piebaldism correlates with the site of the mutation within the kit gene. The most severe phenotypes are caused by mutations involving the intracellular tyrosine kinase domain, whereas the mildest phenotypes result from mutations involving the amino-terminal extracellular ligand-binding domain.6 The differential diagnosis of piebaldism includes any condition that may present with a depigmented lesion. Vitiligo is characterized by acquired depigmentation, typically in an acral and periorificial distribution. Piebaldism generally is distinguished from vitiligo by the presence of lesions from birth, hyperpigmented macules within and at the border of depigmented areas, and its static course. Moreover, piebaldism spares the dorsal midline, hands, feet, and periorificial areas. Waardenburg syndrome is an autosomal dominant disorder characterized by a congenital white forelock, lateral displacement of the medial canthi, a hypertrophic nasal root, heterochromia irides, and sensorineural hearing loss.16 At least 4 types of Waardenburg syndrome have been described based on the clinical and genetic criteria. The presence of hyperpigmented patches within the islands of depigmentation and on healthy skin; the absence of midfacial lesions, heterochromia irides, and deafness; and the location of depigmented patches on the trunk and extremities help to distinguish piebaldism from the various forms of Waardenburg syndrome.16 Ziprkowski-Margolis syndrome is a rare X-linked recessive syndrome characterized by deaf-mutism, heterochromic irides, piebaldlike hypomelanosis, and hyperpigmented macules, with a geographic appearance developing mainly on the trunk and extremities.17 Woolf syndrome is an autosomal recessive disorder consisting of piebaldism and deafness. Audiometry is crucial to exclude this diagnosis.18 Depending on its presentation, other conditions to consider include Addison disease, albinism, and systemic sclerosis, as well as use of depigmenting agents. Piebaldism is considered a relatively benign disorder, but it may have psychological impact because it is socially disabling, which presents a therapeutic challenge. Depigmented skin in piebaldism generally is considered unresponsive to medical or light therapy. Of note, the diagnosis of piebaldism should alert the clinician to the possibility of Waardenburg syndrome as determined by the results of ocular and auditory examinations. Sunscreens are recommended to avoid sunburns and to reduce the carcinogenic potential. To camouflage the exposed areas, makeup or temporary pigmenting agents such as the tanning product dihydroxyacetone may be used.19 The lesions of piebaldism do not respond to the topical agents used to treat vitiligo. Different surgical techniques have been tried, with variable success, including thin split-thickness grafts, minigrafting, transplant of autologous cultured melanocytes, and a combination of dermabrasion and grafting of the pigmented skin into the depigmented areas.20,21 Guerra et al22 reported achromic epidermis removed with the erbium:YAG laser and autologous cultured epidermal grafts were applied to the recipient bed in 6 patients. Autologous cultured epidermis, bearing a controlled number of melanocytes, induced repigmentation of all piebald lesions. The mean percentage repigmentation was 95.45%.22

Piebaldism is a rare autosomal dominant disorder characterized by congenital poliosis and leukoderma. We present a case of a 10-year-old girl with a typical clinical presentation, followed by a concise review of the literature discussing the etiology, clinical features, diagnosis, and management of the condition.

Case Report
A 10-year-old girl presented for evaluation of a white forelock and multiple white patches of skin on the trunk and extremities (Figure). The white forelock was present at birth and a few white patches appeared on the chest at 3 months of age. During the subsequent 4 years, the white patches gradually progressed to involve the central forehead, abdomen, and extremities. Multiple frecklelike macules also appeared within the patches and the surrounding healthy skin.

Physical examination revealed a healthy girl with a prominent, large, diamond-shaped, depigmented patch on the central forehead that was associated with a white forelock. The hairs of the medial eyebrows and the eyelashes also were depigmented. Large, irregularly shaped, depigmented patches were present on the trunk and anterior extremities. There were multiple hyperpigmented macules overlying both the depigmented patches and the adjacent normally pigmented skin. The rest of the physical examination and the results of routine blood tests and urinalysis were unremarkable. The patient's mother and 4 siblings also were born with a white forelock. Similar depigmented patches on the trunk and extremities with a similar pattern and distribution were noted in all of them. Neither the patient nor her mother and siblings had midfacial anomalies, deafness, or heterochromia irides.

Comment
Piebaldism is a rare autosomal dominant disorder of melanocyte development resulting from mutations of the c-kit protooncogene.1,2 The disorder is characterized clinically by congenital poliosis and leukoderma. A white forelock is present at birth and may be the only manifestation in most affected individuals.3 The white forelock may have a triangular or diamond shape, and the underlying skin of the scalp also is amelanotic. Typical piebald lesions are typified by well-circumscribed, irregular, chalk white patches, often with hyperpigmented frecklelike macules noted on both depigmented and unaffected adjacent skin.4 The lesions often exhibit a classic distribution, involving the central forehead and anterior trunk, with extension to the flanks and anterior midarms, midknees, and midlegs. The medial third of the eyebrows and eyelashes also may be affected in severe cases.4 Characteristically, there is sparing of the dorsal midline, hands, feet, and periorificial areas. Piebaldism generally is a static disorder of pigmentation, though contraction of the affected areas with time or the appearance of new hyperpigmented macular lesions has been described.5 Progression of the depigmented patches has been reported in isolated cases with a novel Val620Ala mutation in Kit.6 Piebaldism rarely is associated with other disorders such as Hirschsprung disease, neurofibromatosis type 1, congenital dyserythropoietic anemia type II, Diamond-Blackfan anemia, and Grover disease.7-11 Individual case reports with associated deafness also have been described.12 Histopathologic evaluation of the depigmented lesions reveals absent or considerably reduced melanocytes. The hyperpigmented macules have a normal number of melanocytes and an increased number of melanosomes in the melanocytes and keratinocytes.4 The molecular basis of piebaldism was traced by Giebel and Spritz1 and Fleischman et al13 to mutations of the c-kit protooncogene. To date, 14 point mutations, 9 deletion mutations, 2 nucleotide splicing mutations, and 3 insertions of Kit have been described.6,14 c-kit Mutations are found in about 75% of patients with piebaldism.14 Mutations in the slug gene, which is a zinc-finger neural crest transcription factor, have been reported in piebaldism that lacked mutations in Kit.15 The human kit gene encodes the tyrosine kinase transmembrane cellular receptor for mast/stem cell growth factor, which is a critical factor for melanoblast migration, proliferation, differentiation, and survival.6 It would be pertinent to note here that the severity of the phenotype in piebaldism correlates with the site of the mutation within the kit gene. The most severe phenotypes are caused by mutations involving the intracellular tyrosine kinase domain, whereas the mildest phenotypes result from mutations involving the amino-terminal extracellular ligand-binding domain.6 The differential diagnosis of piebaldism includes any condition that may present with a depigmented lesion. Vitiligo is characterized by acquired depigmentation, typically in an acral and periorificial distribution. Piebaldism generally is distinguished from vitiligo by the presence of lesions from birth, hyperpigmented macules within and at the border of depigmented areas, and its static course. Moreover, piebaldism spares the dorsal midline, hands, feet, and periorificial areas. Waardenburg syndrome is an autosomal dominant disorder characterized by a congenital white forelock, lateral displacement of the medial canthi, a hypertrophic nasal root, heterochromia irides, and sensorineural hearing loss.16 At least 4 types of Waardenburg syndrome have been described based on the clinical and genetic criteria. The presence of hyperpigmented patches within the islands of depigmentation and on healthy skin; the absence of midfacial lesions, heterochromia irides, and deafness; and the location of depigmented patches on the trunk and extremities help to distinguish piebaldism from the various forms of Waardenburg syndrome.16 Ziprkowski-Margolis syndrome is a rare X-linked recessive syndrome characterized by deaf-mutism, heterochromic irides, piebaldlike hypomelanosis, and hyperpigmented macules, with a geographic appearance developing mainly on the trunk and extremities.17 Woolf syndrome is an autosomal recessive disorder consisting of piebaldism and deafness. Audiometry is crucial to exclude this diagnosis.18 Depending on its presentation, other conditions to consider include Addison disease, albinism, and systemic sclerosis, as well as use of depigmenting agents. Piebaldism is considered a relatively benign disorder, but it may have psychological impact because it is socially disabling, which presents a therapeutic challenge. Depigmented skin in piebaldism generally is considered unresponsive to medical or light therapy. Of note, the diagnosis of piebaldism should alert the clinician to the possibility of Waardenburg syndrome as determined by the results of ocular and auditory examinations. Sunscreens are recommended to avoid sunburns and to reduce the carcinogenic potential. To camouflage the exposed areas, makeup or temporary pigmenting agents such as the tanning product dihydroxyacetone may be used.19 The lesions of piebaldism do not respond to the topical agents used to treat vitiligo. Different surgical techniques have been tried, with variable success, including thin split-thickness grafts, minigrafting, transplant of autologous cultured melanocytes, and a combination of dermabrasion and grafting of the pigmented skin into the depigmented areas.20,21 Guerra et al22 reported achromic epidermis removed with the erbium:YAG laser and autologous cultured epidermal grafts were applied to the recipient bed in 6 patients. Autologous cultured epidermis, bearing a controlled number of melanocytes, induced repigmentation of all piebald lesions. The mean percentage repigmentation was 95.45%.22

Inflammatory linear verrucous epidermal nevus (ILVEN) is a unilateral, persistent, linear, pruritic eruption that usually appears on an extremity in infancy or childhood. We present a case of ILVEN in a 4-year-old boy and provide a short review of the literature, with emphasis on our current understanding of the etiology, clinical presentation, diagnosis, and management of ILVEN.

Case Report
A 4-year-old boy presented for evaluation of an extremely pruritic linear plaque involving his right groin and right thigh since the age of one year (Figure 1). The plaque first appeared on the right buttock (Figure 2) and slowly enlarged, extending down spirally to involve the right inguinal region and upper inner thigh. There was no family history of similar dermatoses.

Results of a physical examination revealed multiple erythematous warty scaling papules coalesced to form a linear, verrucous, hyperpigmented plaque. The plaque extended from the right buttock and inguinal region to the right upper medial thigh following the lines of Blaschko. The rest of the physical examination results were unremarkable, and no associated physical anomaly was found. The eruption and the associated pruritus did not respond to either oral antihistamines or topical high potency steroids. Results of a biopsy specimen taken from the lesion revealed hyperkeratosis, parakeratosis, acanthosis, and a decreased granular layer. A perivascular infiltrate of lymphocytes also was evident in the upper dermis. A diagnosis of inflammatory linear verrucous epidermal nevus (ILVEN) was made based on clinical and histopathologic grounds.

Comment
The condition later known as ILVEN was first described by Unna in 1896.1 However, it was not until 1971 that the disorder was described and clearly defined as a distinct entity by Altman and Mehregan2 in a case series of 25 patients. The authors clearly delineated ILVEN as a clinical and histopathologic variety of linear verrucous nevus that clinically appears inflammatory and histopathologically appears psoriasiform. The etiology of ILVEN remains unknown. It is considered a variant of keratinocytic epidermal nevus. Most cases are sporadic, but a familial case, with the condition occurring in a mother and her daughter, has been described.3 Because ILVEN bears some histologic resemblance to psoriasis, some authors believe that the 2 conditions share a common pathogenesis, possibly mediated by cytokines.4 There is some evidence that interleukins 1 and 6, tumor necrosis factor α, and intercellular adhesion molecule-1 are upregulated in ILVEN, similar to psoriasis.4 It also has been proposed that activation of an autosomal-dominant lethal mutation that survives by mosaicism may be the cause. The mutated cells might survive in the vicinity of the normal cells.5 ILVEN usually appears in infancy or early childhood but may be present at birth; the condition is very rarely present in adulthood.6 ILVEN occurs predominantly in females (female-male ratio, 4:1), and no racial predominance has been noted. About 6% of patients with epidermal nevi had ILVEN.6 ILVEN typically presents with multiple, discrete, erythematous, slightly warty and scaly papules that tend to coalesce into linear plaques. In a retrospective study of 23 patients with ILVEN, Lee and Rogers7 documented a predilection for the buttock and legs, and most cases were unilateral. Onset usually was within the first 6 months of life, most patients (16 patients) were male, and extension beyond the original margins occurred in 6 patients (26%).7 Altman and Mehregan² described 6 characteristic features of ILVEN: (1) early age of onset, (2) predominance in females (4:1 female-male ratio), (3) frequent involvement of the left leg, (4) pruritus, (5) marked refractoriness to therapy, and (6) a distinctive psoriasiform and inflammatory histologic appearance. In a few children, ILVEN has been found to occur in association with musculoskeletal or other abnormalities, including supernumerary digits and strabismus,8 congenital bony anomalies of the ipsilateral extremities,9 congenital dislocation of the ipsilateral hip and Fallot tetralogy of the heart,10 autoimmune thyroiditis,11 lichen amyloidosis,12 nevus depigmentosus,13 arthritis14 and melanodontia.15 More recently, ILVEN was associated with ipsilateral undescended testicle.16 However, this finding was disputed by Happle,17 who interpreted the case as an epidermal nevus of the epidermolytic type and stated that the ipsilateral cryptorchidism should be considered as a coincidental finding. The histopathologic presentation of ILVEN is very similar to psoriasis. Results of a histologic examination reveal psoriasiform hyperplasia of the epidermis, alternating parakeratosis without a granular layer, and orthokeratosis with a thickened granular layer.18 The authors of a recent study19 looked at advanced immunohistochemical methods to differentiate ILVEN from psoriasis. The investigators found that the number of Ki-67—positive nuclei tends to be lower, and the number of keratin-10—positive cells and HLA-DR expression tend to be higher in patients with ILVEN. The density of CD8+, CD45RO+, CD2+, CD94, and CD161 also showed a marked difference between ILVEN and psoriasis. In addition, the number of T cells relevant in the pathogenesis of psoriasis was markedly reduced in ILVEN.19 Other dermatoses that need to be differentiated from ILVEN are summarized in the Table. Nevoid psoriasis in a Blaschko distribution closely mimics ILVEN, but the former usually is asymptomatic and responds well to antipsoriatic treatment. Psoriasis also may become superimposed on an epidermal nevus because of Köbnerization.20

Epidermal nevi may occur almost anywhere on the head, neck, legs, or trunk.6 Nevus verrucosus is a term for the localized lesions of epidermal nevi.21 Linear verrucous epidermal nevi are linear hamartomas of epidermal structures that usually appear at birth or during infancy. Linear verrucous epidermal nevi usually are found on the lower extremities and have resistance to treatment and risk of recurrence. The nevi rarely are seen on the face and very rarely involve the oral mucosa.21 Clinically, there is no erythema or pruritus. Immunohistochemical studies further help differentiate ILVEN from other noninflammatory linear epidermal nevi. The CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) is characterized by segmentally distributed asymptomatic erythematous verrucous areas, associated with ipsilateral extremity defects, ranging from digital hypoplasia to agenesis of the extremity.22 Hence, ILVEN reported in association with severe extremity defects is most likely CHILD syndrome.23 An alternative acronym that has been used to describe this association is PENCIL (psoriasiform epidermal nevus with congenital ipsilateral limb defects).24 Lichen striatus usually is asymptomatic and resolves spontaneously. There also are histologic differences between ILVEN and lichen striatus.25 Linear lichen planus mainly affects children and is characterized by discrete pruritic, polygonal, violaceous papules arranged in a linear fashion, usually along an entire extremity; however, the papules also may be zosteriform.26 Linear porokeratosis also usually presents during childhood as ringlike, hypertrophic, verrucous plaques with a linear morphology, usually on a single extremity, but other parts of the body also may be involved.27 More recently, Jang et al28 reported a case of mycosis fungoides, presenting with a clinical picture of ILVEN. Nevoid basal cell carcinoma (BCC) syndrome is characterized by BCCs in both sun-exposed and nonexposed skin. The diameter of the lesions varies from 1 to 10 mm and commonly involves the face, back, and chest. Features such as odontogenic cysts, palmar and plantar pitting, and facial milia may be associated. Basaloid follicular hamartoma, also known as linear unilateral basal cell nevus with comedones, may present as a unilateral linear lesion.29 In its early stages, the lesion shows hypopigmented smooth or striaelike areas, which later may develop darker-pigmented papules and tumors with or without ulceration. Of note, it may be histologically indistinguishable from the infundibulocystic type of BCC.29 The most widely applied medical treatments for ILVEN have been intralesional corticosteroids or potent topical corticosteroids, the latter often with occlusion.30 However, the clinical appearance and associated intense pruritus usually are refractory to treatment. Topical calcipotriol has been reported to provide some relief in some patients,31 but it is not recommended in children because of limited clinical safety data. A recent case report noted improvement of pruritus in ILVEN with topical pimecrolimus cream.32 Dithranol has been used with success in one case report,33 but this has been interpreted as an antipsoriatic effect in ILVEN with superimposed psoriasis.34 Other therapeutic choices reported in the literature include topical tretinoin combined with 5-fluorouracil,35 and acitretin.36 Destructive therapies, such as the application of liquid nitrogen, electrodesiccation, ablative laser and dermabrasion, have all been equally disappointing.37 Of note, case reports have shown efficacy of CO238 and pulsed dye laser treatment.39 

Conclusion
ILVEN may be an isolated finding or may be associated with other abnormalities. Most patients pre-sent in infancy or early childhood. The diagnosis may sometimes be difficult and necessitate biopsy and advanced immunohistochemical analysis. Most lesions do not persist and spontaneously resolve by adulthood.40 The management usually is only symptomatic and often unsatisfactory. 

Inflammatory linear verrucous epidermal nevus (ILVEN) is a unilateral, persistent, linear, pruritic eruption that usually appears on an extremity in infancy or childhood. We present a case of ILVEN in a 4-year-old boy and provide a short review of the literature, with emphasis on our current understanding of the etiology, clinical presentation, diagnosis, and management of ILVEN.

Case Report
A 4-year-old boy presented for evaluation of an extremely pruritic linear plaque involving his right groin and right thigh since the age of one year (Figure 1). The plaque first appeared on the right buttock (Figure 2) and slowly enlarged, extending down spirally to involve the right inguinal region and upper inner thigh. There was no family history of similar dermatoses.

Results of a physical examination revealed multiple erythematous warty scaling papules coalesced to form a linear, verrucous, hyperpigmented plaque. The plaque extended from the right buttock and inguinal region to the right upper medial thigh following the lines of Blaschko. The rest of the physical examination results were unremarkable, and no associated physical anomaly was found. The eruption and the associated pruritus did not respond to either oral antihistamines or topical high potency steroids. Results of a biopsy specimen taken from the lesion revealed hyperkeratosis, parakeratosis, acanthosis, and a decreased granular layer. A perivascular infiltrate of lymphocytes also was evident in the upper dermis. A diagnosis of inflammatory linear verrucous epidermal nevus (ILVEN) was made based on clinical and histopathologic grounds.

Comment
The condition later known as ILVEN was first described by Unna in 1896.1 However, it was not until 1971 that the disorder was described and clearly defined as a distinct entity by Altman and Mehregan2 in a case series of 25 patients. The authors clearly delineated ILVEN as a clinical and histopathologic variety of linear verrucous nevus that clinically appears inflammatory and histopathologically appears psoriasiform. The etiology of ILVEN remains unknown. It is considered a variant of keratinocytic epidermal nevus. Most cases are sporadic, but a familial case, with the condition occurring in a mother and her daughter, has been described.3 Because ILVEN bears some histologic resemblance to psoriasis, some authors believe that the 2 conditions share a common pathogenesis, possibly mediated by cytokines.4 There is some evidence that interleukins 1 and 6, tumor necrosis factor α, and intercellular adhesion molecule-1 are upregulated in ILVEN, similar to psoriasis.4 It also has been proposed that activation of an autosomal-dominant lethal mutation that survives by mosaicism may be the cause. The mutated cells might survive in the vicinity of the normal cells.5 ILVEN usually appears in infancy or early childhood but may be present at birth; the condition is very rarely present in adulthood.6 ILVEN occurs predominantly in females (female-male ratio, 4:1), and no racial predominance has been noted. About 6% of patients with epidermal nevi had ILVEN.6 ILVEN typically presents with multiple, discrete, erythematous, slightly warty and scaly papules that tend to coalesce into linear plaques. In a retrospective study of 23 patients with ILVEN, Lee and Rogers7 documented a predilection for the buttock and legs, and most cases were unilateral. Onset usually was within the first 6 months of life, most patients (16 patients) were male, and extension beyond the original margins occurred in 6 patients (26%).7 Altman and Mehregan² described 6 characteristic features of ILVEN: (1) early age of onset, (2) predominance in females (4:1 female-male ratio), (3) frequent involvement of the left leg, (4) pruritus, (5) marked refractoriness to therapy, and (6) a distinctive psoriasiform and inflammatory histologic appearance. In a few children, ILVEN has been found to occur in association with musculoskeletal or other abnormalities, including supernumerary digits and strabismus,8 congenital bony anomalies of the ipsilateral extremities,9 congenital dislocation of the ipsilateral hip and Fallot tetralogy of the heart,10 autoimmune thyroiditis,11 lichen amyloidosis,12 nevus depigmentosus,13 arthritis14 and melanodontia.15 More recently, ILVEN was associated with ipsilateral undescended testicle.16 However, this finding was disputed by Happle,17 who interpreted the case as an epidermal nevus of the epidermolytic type and stated that the ipsilateral cryptorchidism should be considered as a coincidental finding. The histopathologic presentation of ILVEN is very similar to psoriasis. Results of a histologic examination reveal psoriasiform hyperplasia of the epidermis, alternating parakeratosis without a granular layer, and orthokeratosis with a thickened granular layer.18 The authors of a recent study19 looked at advanced immunohistochemical methods to differentiate ILVEN from psoriasis. The investigators found that the number of Ki-67—positive nuclei tends to be lower, and the number of keratin-10—positive cells and HLA-DR expression tend to be higher in patients with ILVEN. The density of CD8+, CD45RO+, CD2+, CD94, and CD161 also showed a marked difference between ILVEN and psoriasis. In addition, the number of T cells relevant in the pathogenesis of psoriasis was markedly reduced in ILVEN.19 Other dermatoses that need to be differentiated from ILVEN are summarized in the Table. Nevoid psoriasis in a Blaschko distribution closely mimics ILVEN, but the former usually is asymptomatic and responds well to antipsoriatic treatment. Psoriasis also may become superimposed on an epidermal nevus because of Köbnerization.20

Epidermal nevi may occur almost anywhere on the head, neck, legs, or trunk.6 Nevus verrucosus is a term for the localized lesions of epidermal nevi.21 Linear verrucous epidermal nevi are linear hamartomas of epidermal structures that usually appear at birth or during infancy. Linear verrucous epidermal nevi usually are found on the lower extremities and have resistance to treatment and risk of recurrence. The nevi rarely are seen on the face and very rarely involve the oral mucosa.21 Clinically, there is no erythema or pruritus. Immunohistochemical studies further help differentiate ILVEN from other noninflammatory linear epidermal nevi. The CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) is characterized by segmentally distributed asymptomatic erythematous verrucous areas, associated with ipsilateral extremity defects, ranging from digital hypoplasia to agenesis of the extremity.22 Hence, ILVEN reported in association with severe extremity defects is most likely CHILD syndrome.23 An alternative acronym that has been used to describe this association is PENCIL (psoriasiform epidermal nevus with congenital ipsilateral limb defects).24 Lichen striatus usually is asymptomatic and resolves spontaneously. There also are histologic differences between ILVEN and lichen striatus.25 Linear lichen planus mainly affects children and is characterized by discrete pruritic, polygonal, violaceous papules arranged in a linear fashion, usually along an entire extremity; however, the papules also may be zosteriform.26 Linear porokeratosis also usually presents during childhood as ringlike, hypertrophic, verrucous plaques with a linear morphology, usually on a single extremity, but other parts of the body also may be involved.27 More recently, Jang et al28 reported a case of mycosis fungoides, presenting with a clinical picture of ILVEN. Nevoid basal cell carcinoma (BCC) syndrome is characterized by BCCs in both sun-exposed and nonexposed skin. The diameter of the lesions varies from 1 to 10 mm and commonly involves the face, back, and chest. Features such as odontogenic cysts, palmar and plantar pitting, and facial milia may be associated. Basaloid follicular hamartoma, also known as linear unilateral basal cell nevus with comedones, may present as a unilateral linear lesion.29 In its early stages, the lesion shows hypopigmented smooth or striaelike areas, which later may develop darker-pigmented papules and tumors with or without ulceration. Of note, it may be histologically indistinguishable from the infundibulocystic type of BCC.29 The most widely applied medical treatments for ILVEN have been intralesional corticosteroids or potent topical corticosteroids, the latter often with occlusion.30 However, the clinical appearance and associated intense pruritus usually are refractory to treatment. Topical calcipotriol has been reported to provide some relief in some patients,31 but it is not recommended in children because of limited clinical safety data. A recent case report noted improvement of pruritus in ILVEN with topical pimecrolimus cream.32 Dithranol has been used with success in one case report,33 but this has been interpreted as an antipsoriatic effect in ILVEN with superimposed psoriasis.34 Other therapeutic choices reported in the literature include topical tretinoin combined with 5-fluorouracil,35 and acitretin.36 Destructive therapies, such as the application of liquid nitrogen, electrodesiccation, ablative laser and dermabrasion, have all been equally disappointing.37 Of note, case reports have shown efficacy of CO238 and pulsed dye laser treatment.39 

Conclusion
ILVEN may be an isolated finding or may be associated with other abnormalities. Most patients pre-sent in infancy or early childhood. The diagnosis may sometimes be difficult and necessitate biopsy and advanced immunohistochemical analysis. Most lesions do not persist and spontaneously resolve by adulthood.40 The management usually is only symptomatic and often unsatisfactory. 

Inflammatory linear verrucous epidermal nevus (ILVEN) is a unilateral, persistent, linear, pruritic eruption that usually appears on an extremity in infancy or childhood. We present a case of ILVEN in a 4-year-old boy and provide a short review of the literature, with emphasis on our current understanding of the etiology, clinical presentation, diagnosis, and management of ILVEN.

Case Report
A 4-year-old boy presented for evaluation of an extremely pruritic linear plaque involving his right groin and right thigh since the age of one year (Figure 1). The plaque first appeared on the right buttock (Figure 2) and slowly enlarged, extending down spirally to involve the right inguinal region and upper inner thigh. There was no family history of similar dermatoses.

Results of a physical examination revealed multiple erythematous warty scaling papules coalesced to form a linear, verrucous, hyperpigmented plaque. The plaque extended from the right buttock and inguinal region to the right upper medial thigh following the lines of Blaschko. The rest of the physical examination results were unremarkable, and no associated physical anomaly was found. The eruption and the associated pruritus did not respond to either oral antihistamines or topical high potency steroids. Results of a biopsy specimen taken from the lesion revealed hyperkeratosis, parakeratosis, acanthosis, and a decreased granular layer. A perivascular infiltrate of lymphocytes also was evident in the upper dermis. A diagnosis of inflammatory linear verrucous epidermal nevus (ILVEN) was made based on clinical and histopathologic grounds.

Comment
The condition later known as ILVEN was first described by Unna in 1896.1 However, it was not until 1971 that the disorder was described and clearly defined as a distinct entity by Altman and Mehregan2 in a case series of 25 patients. The authors clearly delineated ILVEN as a clinical and histopathologic variety of linear verrucous nevus that clinically appears inflammatory and histopathologically appears psoriasiform. The etiology of ILVEN remains unknown. It is considered a variant of keratinocytic epidermal nevus. Most cases are sporadic, but a familial case, with the condition occurring in a mother and her daughter, has been described.3 Because ILVEN bears some histologic resemblance to psoriasis, some authors believe that the 2 conditions share a common pathogenesis, possibly mediated by cytokines.4 There is some evidence that interleukins 1 and 6, tumor necrosis factor α, and intercellular adhesion molecule-1 are upregulated in ILVEN, similar to psoriasis.4 It also has been proposed that activation of an autosomal-dominant lethal mutation that survives by mosaicism may be the cause. The mutated cells might survive in the vicinity of the normal cells.5 ILVEN usually appears in infancy or early childhood but may be present at birth; the condition is very rarely present in adulthood.6 ILVEN occurs predominantly in females (female-male ratio, 4:1), and no racial predominance has been noted. About 6% of patients with epidermal nevi had ILVEN.6 ILVEN typically presents with multiple, discrete, erythematous, slightly warty and scaly papules that tend to coalesce into linear plaques. In a retrospective study of 23 patients with ILVEN, Lee and Rogers7 documented a predilection for the buttock and legs, and most cases were unilateral. Onset usually was within the first 6 months of life, most patients (16 patients) were male, and extension beyond the original margins occurred in 6 patients (26%).7 Altman and Mehregan² described 6 characteristic features of ILVEN: (1) early age of onset, (2) predominance in females (4:1 female-male ratio), (3) frequent involvement of the left leg, (4) pruritus, (5) marked refractoriness to therapy, and (6) a distinctive psoriasiform and inflammatory histologic appearance. In a few children, ILVEN has been found to occur in association with musculoskeletal or other abnormalities, including supernumerary digits and strabismus,8 congenital bony anomalies of the ipsilateral extremities,9 congenital dislocation of the ipsilateral hip and Fallot tetralogy of the heart,10 autoimmune thyroiditis,11 lichen amyloidosis,12 nevus depigmentosus,13 arthritis14 and melanodontia.15 More recently, ILVEN was associated with ipsilateral undescended testicle.16 However, this finding was disputed by Happle,17 who interpreted the case as an epidermal nevus of the epidermolytic type and stated that the ipsilateral cryptorchidism should be considered as a coincidental finding. The histopathologic presentation of ILVEN is very similar to psoriasis. Results of a histologic examination reveal psoriasiform hyperplasia of the epidermis, alternating parakeratosis without a granular layer, and orthokeratosis with a thickened granular layer.18 The authors of a recent study19 looked at advanced immunohistochemical methods to differentiate ILVEN from psoriasis. The investigators found that the number of Ki-67—positive nuclei tends to be lower, and the number of keratin-10—positive cells and HLA-DR expression tend to be higher in patients with ILVEN. The density of CD8+, CD45RO+, CD2+, CD94, and CD161 also showed a marked difference between ILVEN and psoriasis. In addition, the number of T cells relevant in the pathogenesis of psoriasis was markedly reduced in ILVEN.19 Other dermatoses that need to be differentiated from ILVEN are summarized in the Table. Nevoid psoriasis in a Blaschko distribution closely mimics ILVEN, but the former usually is asymptomatic and responds well to antipsoriatic treatment. Psoriasis also may become superimposed on an epidermal nevus because of Köbnerization.20

Epidermal nevi may occur almost anywhere on the head, neck, legs, or trunk.6 Nevus verrucosus is a term for the localized lesions of epidermal nevi.21 Linear verrucous epidermal nevi are linear hamartomas of epidermal structures that usually appear at birth or during infancy. Linear verrucous epidermal nevi usually are found on the lower extremities and have resistance to treatment and risk of recurrence. The nevi rarely are seen on the face and very rarely involve the oral mucosa.21 Clinically, there is no erythema or pruritus. Immunohistochemical studies further help differentiate ILVEN from other noninflammatory linear epidermal nevi. The CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) is characterized by segmentally distributed asymptomatic erythematous verrucous areas, associated with ipsilateral extremity defects, ranging from digital hypoplasia to agenesis of the extremity.22 Hence, ILVEN reported in association with severe extremity defects is most likely CHILD syndrome.23 An alternative acronym that has been used to describe this association is PENCIL (psoriasiform epidermal nevus with congenital ipsilateral limb defects).24 Lichen striatus usually is asymptomatic and resolves spontaneously. There also are histologic differences between ILVEN and lichen striatus.25 Linear lichen planus mainly affects children and is characterized by discrete pruritic, polygonal, violaceous papules arranged in a linear fashion, usually along an entire extremity; however, the papules also may be zosteriform.26 Linear porokeratosis also usually presents during childhood as ringlike, hypertrophic, verrucous plaques with a linear morphology, usually on a single extremity, but other parts of the body also may be involved.27 More recently, Jang et al28 reported a case of mycosis fungoides, presenting with a clinical picture of ILVEN. Nevoid basal cell carcinoma (BCC) syndrome is characterized by BCCs in both sun-exposed and nonexposed skin. The diameter of the lesions varies from 1 to 10 mm and commonly involves the face, back, and chest. Features such as odontogenic cysts, palmar and plantar pitting, and facial milia may be associated. Basaloid follicular hamartoma, also known as linear unilateral basal cell nevus with comedones, may present as a unilateral linear lesion.29 In its early stages, the lesion shows hypopigmented smooth or striaelike areas, which later may develop darker-pigmented papules and tumors with or without ulceration. Of note, it may be histologically indistinguishable from the infundibulocystic type of BCC.29 The most widely applied medical treatments for ILVEN have been intralesional corticosteroids or potent topical corticosteroids, the latter often with occlusion.30 However, the clinical appearance and associated intense pruritus usually are refractory to treatment. Topical calcipotriol has been reported to provide some relief in some patients,31 but it is not recommended in children because of limited clinical safety data. A recent case report noted improvement of pruritus in ILVEN with topical pimecrolimus cream.32 Dithranol has been used with success in one case report,33 but this has been interpreted as an antipsoriatic effect in ILVEN with superimposed psoriasis.34 Other therapeutic choices reported in the literature include topical tretinoin combined with 5-fluorouracil,35 and acitretin.36 Destructive therapies, such as the application of liquid nitrogen, electrodesiccation, ablative laser and dermabrasion, have all been equally disappointing.37 Of note, case reports have shown efficacy of CO238 and pulsed dye laser treatment.39 

Conclusion
ILVEN may be an isolated finding or may be associated with other abnormalities. Most patients pre-sent in infancy or early childhood. The diagnosis may sometimes be difficult and necessitate biopsy and advanced immunohistochemical analysis. Most lesions do not persist and spontaneously resolve by adulthood.40 The management usually is only symptomatic and often unsatisfactory. 

Pemphigus describes a group of autoimmune chronic bullous diseases, originally named in 1791.1 The term pemphigus stems from the Greek pemphix meaning blister or bubble.2 Pemphigus is usually divided into 2 major forms depending on blister location: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Pemphigus vegetans is a variant of PV, and pemphigus erythematosus (PE) and fogo selvagem are variants of PF. During the past 3 decades, uncommon forms of pemphigus have been described, including pemphigus herpetiformis, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus.3 The incidence of pemphigus ranges from 0.76 to 5 new cases per million per year.2 In a recent analysis of 1209 patients with pemphigus in Iran, the PV to PF ratio was found to be 12:1. However, this ratio varies widely in different parts of the world.4 In one report, 73% of cases of pemphigus in France were PV.5 PV also is the most common clinical type of pemphigus in Kuwait, Israel, and Singapore.6-8 In a report on pemphigus in South Africa, the most common clinical variant was PF, and 80% of these patients were black.9 Of note, in the Indian population in this region, PV was more common. A high percentage of PF is endemic in rural Brazil, Tunisia, and Columbia.9 

Case Report
A 58-year-old white woman presented with a 6-month history of superficial erosions on the chest, upper back, hairline, and retroauricular areas. She denied any photosensitivity, and there was no mucosal involvement. The patient's medical history was otherwise unremarkable. Superficial erosions with a positive Nikolsky sign were present on the chest (Figure), upper back, and frontal hairline, as well as in the retroauricular areas bilaterally. Two punch biopsies (one lesional and one perilesional) were performed. Routine histology results showed intraepidermal vesicles in the upper granular layer containing acantholytic cells. Results of direct immunofluorescence demonstrated IgG and complement 3 (C3) in the intercellular spaces in the epidermal cell surface. Of note, antinuclear antibody and anti–double-stranded DNA were negative. These findings were consistent with our clinical diagnosis of PF.

The patient was initially started on a high potency topical corticosteroid (clobetasol propionate ointment) for 4 weeks with no improvement. She was then given prednisone 60 mg/d for approximately one month when new lesions ceased to appear; then the medication was slowly tapered off. Dapsone also was added to her regimen after an initial baseline level of glucose-6-phosphate dehydrogenase and a baseline complete blood count were obtained. Dapsone was initiated at 50 mg/d while prednisone was being slowly tapered. Cacit D3 in a single morning dose (1000 mg calcium and 880 IU vitamin D) also was added to the regimen. Of note, the patient was taking celecoxib for intermittent joint pain, but a literature search at that time did not reveal an association with similar eruptions; our patient was asked to discontinue the celecoxib at the initiation of oral prednisone. She was seen at regular follow-up visits every month. As the patient improved clinically, dapsone was reduced to 25 mg and finally discontinued after about 6 months. Oral prednisone taper continued slowly over a total of 18 months. No lesions were present for the last 3 monthly visits.

Comment
PF comprises 2 major categories: endemic and sporadic. The endemic form, also known as fogo selvagem, primarily affects children and young adults in rural Brazil. In contrast, the sporadic form of PF is generally a disease of middle-aged individuals and the elderly. Of note, there are several cases of nonendemic PF occurring in children,10 and 2 cases reported in the neonatal period.11 Many patients with PE show serologic findings suggestive of systemic lupus erythematosus (SLE), especially the presence of anti-nuclear antibodies.2,12 PF is an autoimmune blistering disease of unknown etiology with antibodies produced against desmoglein 1 (Dsg1).13 Dsg1 is an adhesive cadherin protein found in the desmosomal cell junction in the suprabasal layers of the epidermis.14,15 Binding of the antibody results in the loss of cell adhesion or acantholysis and formation of the clinical picture of PF.16 The blisters are subcorneal, occurring in and around the granular cell layer of the epidermis.13 Blister formation is superficial because the most differentiated layer of the epidermis is the only area in which Dsg1 is critically important to cell adhesion, and there is no protection redundancy of adhesion molecules by coexpression of Dsg3.17 Of interest, one study has demonstrated that the autoantibodies in up to 7% of patients with PF and up to 50% of patients with PV recognize both Dsg1 and Dsg3 isoforms.18 It also is reported that some patients can progress from PF to PV or vice versa, though the latter is less common.19 It has been shown that this transition correlates well with the qualitative and quantitative changes in the profile of Dsg1 and Dsg3 antibodies.20 Patients with PF have been reported to have a predominance of circulating IgG4 antiepidermal autoantibodies, followed by a lesser degree of IgG1, IgG2, and IgG3 subclasses.21 PF has shown a strong association with several HLA-DRB1 haplotypes.22,23 Most recently, an association with HLA-DRB1*0101 was found in the Mexican population.24 Sunlight exposure25 and several drugs such as penicillamine26,27 have been identified as possible triggering factors for the disease. In children, bacteria, cytomegalovirus, and otitis also have been implicated.10 Similarly, an unusual case of childhood PF apparently triggered by conjunctivitis was reported.28 PF manifests clinically as recurrent shallow erosions accompanied by erythema, scaling, and crusting.29 Lesions usually are found in a seborrheic distribution (central face, neck, chest, or upper back).30 Patients develop superficial fragile vesicles, which often are not seen. In contrast to PV, PF patients rarely have mucosal involvement.11 The onset of disease may be slow, starting with only a few transient scattered crusted lesions.2 The condition may then stay localized for years or progress into generalized involvement, sometimes resulting in an exfoliative erythroderma.31 In general, patients are not severely ill but often complain of burning and pain associated with the skin lesions.2 Fogo selvagem, formerly known as Brazilian PF, occurs in an endemic fashion in certain regions of Brazil.32 The condition has been described in certain regions of Brazil since the turn of the century.33 The prevalence in some rural areas of Brazil is as high as 3.4%.34 There also have been reports of other possible foci of endemic PF in Tunisia and Columbia.35,36 Endemic PF differs from sporadic PF in its geographic distribution, high familial incidence, and young age of onset.36 The clinical manifestations, histology, and immunopathologic features are indistinguishable from sporadic PF.29,32 The distinct epidemiology of the condition is suggestive of an environmental or infectious agent. Studies have identified that most patients are young peasants or children who live in close proximity to rivers, which exposes the children to the hematophagous insect belonging to the Simulium nigrimanum species, also known by its popular name borrachudo (blackfly).37,38 PE was first described by Senear and Usher39 in 1926. Originally, the term PE was introduced to describe patients with immunologic features of both SLE and pemphigus.2 Many patients with PE show serologic findings suggestive of SLE, especially the presence of antinuclear antibodies.12,40 However, there are only a few reports of PE occurring in patients who have clearly defined SLE.41,42 In most of these cases, the diagnosis of SLE had been established months to years earlier.42 PE also may be associated with a variety of autoantibodies and may require extensive immunotherapy.43 PE has characteristic findings on direct immunofluorescence, usually IgG and C3 at the basement membrane zone of erythematous facial skin, in addition to the epidermal cell surface IgG.12,44 Clinically, the lesions of PE resemble those of PF but are most commonly restricted to the upper trunk, head, and neck.42 PE may remain localized for years, or it may evolve into more generalized PF.40 PE also has been associated with myasthenia gravis and thymomas.45 The histologic changes of PF, PE, and fogo selvagem are identical.2 Early blisters indicate acantholysis just below the stratum corneum and in the granular layer. The stratum corneum often is lost from the surface of these lesions. The deeper epidermis, below the granular layer, remains intact. Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity.12 Immunofluorescence using both direct and indirect techniques is the most reliable method of diagnosing pemphigus.46 Most patients with pemphigus have IgG and C3 deposits at the epidermal cell surfaces and circulating IgG against the same components.47 However, the cell staining pattern of both direct and indirect immunofluorescence is virtually identical in PV and PF, making it difficult to distinguish between them.48 One innovation has been the introduction of an antigen-specific ELISA (enzyme-linked immunosorbent assay) test for the diagnosis of pemphigus: if a serum is positive against Dsg3, the test results indicate a diagnosis of PV, regardless of reactivity against Dsg1; if a serum is negative for Dsg3 and positive for Dsg1, the test results indicate a diagnosis of PF.48 The differential diagnosis of PF includes other forms of pemphigus, bullous impetigo, subcorneal pustular dermatosis, linear IgA dermatosis, and seborrheic dermatitis.2,30 Before the advent of glucocorticoid therapy, PF was fatal in about 60% of patients.12 The aim of current therapy is to suppress the production of pathogenic antibodies, stop the development of new lesions, and heal old lesions.49 The therapy of PF differs from that of PV only in that treatment can be less aggressive because morbidity and mortality are lower.26 In all patients, a complete review of medications should be done to exclude the possibility of drug-induced PF. The most commonly implicated medications are penicillamine,27 captopril,50 lisinopril,51 nifedipine,52 and topical imiquimod.53 Because PF may be localized for many years and the prognosis without systemic therapy may be good, patients do not necessarily require systemic therapy. This patient group may be treated successfully with topical corticosteroids.29,54 Patients with active and widespread disease require systemic therapy.16 An initial dose of prednisone at 1.0 mg/kg can usually be tapered down toward an alternate-day dosage within 1 to 3 months.29 One patient has been kept on a low dose of corticosteroids successfully as maintenance over an extended period.55 Patients with the most severe disease (ie, disease unresponsive to corticosteroids) should be considered for adjuvant immunosuppressive drugs as steroid-sparing agents.29,49 The goal of immunosuppressive therapy is to suppress the production of antibodies. One of the medications used is mycophenolate mofetil, which is shown to be an effective steroid-sparing agent.56,57 Oral cyclophosphamide, which also is an effective adjuvant alkylating agent in the treatment of severe and refractory PV and PF, can be combined with pulse intravenous corticosteroids. However, the use of alkylating agents should be done with care because of the risk of side effects such as hemorrhagic cystitis, susceptibility to infection, potential infertility, mutagenic potential, and lifetime risk for transitional cell carcinoma of the bladder and hematologic malignancies.58 Other immunosuppressive medications that have been used include azathioprine,59,60 methotrexate,61,62 and cyclosporine.63,64 In patients for whom conventional therapies have failed, alternative therapies such as intravenous immunoglobulin,65 plasmapheresis,⁶⁶ and extracorporeal photochemotherapy67,68 have been employed successfully. A single case of PF occurring after unrelated cord blood transplantation was reported to be successfully treated with rituximab, an anti-CD20 antibody.69 Dapsone has been used both as monotherapy and in combination regimens. In a study of 9 patients, 5 had at least 50% improvement.70 Only patients with low titers or undetectable circulating antibodies responded to monotherapy. The value of dapsone in the treatment of PF remains to be clearly established.71 There have been a few case reports indicating that a combination of tetracycline and niacinamide is an effective alternative to steroids in superficial pemphigus.72 Other agents reported in the literature include gold,43,73 chlorambucil,74 and hydroxychloroquine sulfate.75 It is commonly perceived that PF is more benign than PV. Although uncommon, there are several reports of death occurring in PF.65,76 Infection is often the cause of death, and therapy is frequently a contributing factor because it causes the immunosuppression necessary to treat active disease.77 The effective management of PF requires a knowledge of the pathophysiology and pharmacologic effects of the agents used, an ability to make an accurate diagnosis, and an understanding of the patient's expectations.49 

Pemphigus describes a group of autoimmune chronic bullous diseases, originally named in 1791.1 The term pemphigus stems from the Greek pemphix meaning blister or bubble.2 Pemphigus is usually divided into 2 major forms depending on blister location: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Pemphigus vegetans is a variant of PV, and pemphigus erythematosus (PE) and fogo selvagem are variants of PF. During the past 3 decades, uncommon forms of pemphigus have been described, including pemphigus herpetiformis, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus.3 The incidence of pemphigus ranges from 0.76 to 5 new cases per million per year.2 In a recent analysis of 1209 patients with pemphigus in Iran, the PV to PF ratio was found to be 12:1. However, this ratio varies widely in different parts of the world.4 In one report, 73% of cases of pemphigus in France were PV.5 PV also is the most common clinical type of pemphigus in Kuwait, Israel, and Singapore.6-8 In a report on pemphigus in South Africa, the most common clinical variant was PF, and 80% of these patients were black.9 Of note, in the Indian population in this region, PV was more common. A high percentage of PF is endemic in rural Brazil, Tunisia, and Columbia.9 

Case Report
A 58-year-old white woman presented with a 6-month history of superficial erosions on the chest, upper back, hairline, and retroauricular areas. She denied any photosensitivity, and there was no mucosal involvement. The patient's medical history was otherwise unremarkable. Superficial erosions with a positive Nikolsky sign were present on the chest (Figure), upper back, and frontal hairline, as well as in the retroauricular areas bilaterally. Two punch biopsies (one lesional and one perilesional) were performed. Routine histology results showed intraepidermal vesicles in the upper granular layer containing acantholytic cells. Results of direct immunofluorescence demonstrated IgG and complement 3 (C3) in the intercellular spaces in the epidermal cell surface. Of note, antinuclear antibody and anti–double-stranded DNA were negative. These findings were consistent with our clinical diagnosis of PF.

The patient was initially started on a high potency topical corticosteroid (clobetasol propionate ointment) for 4 weeks with no improvement. She was then given prednisone 60 mg/d for approximately one month when new lesions ceased to appear; then the medication was slowly tapered off. Dapsone also was added to her regimen after an initial baseline level of glucose-6-phosphate dehydrogenase and a baseline complete blood count were obtained. Dapsone was initiated at 50 mg/d while prednisone was being slowly tapered. Cacit D3 in a single morning dose (1000 mg calcium and 880 IU vitamin D) also was added to the regimen. Of note, the patient was taking celecoxib for intermittent joint pain, but a literature search at that time did not reveal an association with similar eruptions; our patient was asked to discontinue the celecoxib at the initiation of oral prednisone. She was seen at regular follow-up visits every month. As the patient improved clinically, dapsone was reduced to 25 mg and finally discontinued after about 6 months. Oral prednisone taper continued slowly over a total of 18 months. No lesions were present for the last 3 monthly visits.

Comment
PF comprises 2 major categories: endemic and sporadic. The endemic form, also known as fogo selvagem, primarily affects children and young adults in rural Brazil. In contrast, the sporadic form of PF is generally a disease of middle-aged individuals and the elderly. Of note, there are several cases of nonendemic PF occurring in children,10 and 2 cases reported in the neonatal period.11 Many patients with PE show serologic findings suggestive of systemic lupus erythematosus (SLE), especially the presence of anti-nuclear antibodies.2,12 PF is an autoimmune blistering disease of unknown etiology with antibodies produced against desmoglein 1 (Dsg1).13 Dsg1 is an adhesive cadherin protein found in the desmosomal cell junction in the suprabasal layers of the epidermis.14,15 Binding of the antibody results in the loss of cell adhesion or acantholysis and formation of the clinical picture of PF.16 The blisters are subcorneal, occurring in and around the granular cell layer of the epidermis.13 Blister formation is superficial because the most differentiated layer of the epidermis is the only area in which Dsg1 is critically important to cell adhesion, and there is no protection redundancy of adhesion molecules by coexpression of Dsg3.17 Of interest, one study has demonstrated that the autoantibodies in up to 7% of patients with PF and up to 50% of patients with PV recognize both Dsg1 and Dsg3 isoforms.18 It also is reported that some patients can progress from PF to PV or vice versa, though the latter is less common.19 It has been shown that this transition correlates well with the qualitative and quantitative changes in the profile of Dsg1 and Dsg3 antibodies.20 Patients with PF have been reported to have a predominance of circulating IgG4 antiepidermal autoantibodies, followed by a lesser degree of IgG1, IgG2, and IgG3 subclasses.21 PF has shown a strong association with several HLA-DRB1 haplotypes.22,23 Most recently, an association with HLA-DRB1*0101 was found in the Mexican population.24 Sunlight exposure25 and several drugs such as penicillamine26,27 have been identified as possible triggering factors for the disease. In children, bacteria, cytomegalovirus, and otitis also have been implicated.10 Similarly, an unusual case of childhood PF apparently triggered by conjunctivitis was reported.28 PF manifests clinically as recurrent shallow erosions accompanied by erythema, scaling, and crusting.29 Lesions usually are found in a seborrheic distribution (central face, neck, chest, or upper back).30 Patients develop superficial fragile vesicles, which often are not seen. In contrast to PV, PF patients rarely have mucosal involvement.11 The onset of disease may be slow, starting with only a few transient scattered crusted lesions.2 The condition may then stay localized for years or progress into generalized involvement, sometimes resulting in an exfoliative erythroderma.31 In general, patients are not severely ill but often complain of burning and pain associated with the skin lesions.2 Fogo selvagem, formerly known as Brazilian PF, occurs in an endemic fashion in certain regions of Brazil.32 The condition has been described in certain regions of Brazil since the turn of the century.33 The prevalence in some rural areas of Brazil is as high as 3.4%.34 There also have been reports of other possible foci of endemic PF in Tunisia and Columbia.35,36 Endemic PF differs from sporadic PF in its geographic distribution, high familial incidence, and young age of onset.36 The clinical manifestations, histology, and immunopathologic features are indistinguishable from sporadic PF.29,32 The distinct epidemiology of the condition is suggestive of an environmental or infectious agent. Studies have identified that most patients are young peasants or children who live in close proximity to rivers, which exposes the children to the hematophagous insect belonging to the Simulium nigrimanum species, also known by its popular name borrachudo (blackfly).37,38 PE was first described by Senear and Usher39 in 1926. Originally, the term PE was introduced to describe patients with immunologic features of both SLE and pemphigus.2 Many patients with PE show serologic findings suggestive of SLE, especially the presence of antinuclear antibodies.12,40 However, there are only a few reports of PE occurring in patients who have clearly defined SLE.41,42 In most of these cases, the diagnosis of SLE had been established months to years earlier.42 PE also may be associated with a variety of autoantibodies and may require extensive immunotherapy.43 PE has characteristic findings on direct immunofluorescence, usually IgG and C3 at the basement membrane zone of erythematous facial skin, in addition to the epidermal cell surface IgG.12,44 Clinically, the lesions of PE resemble those of PF but are most commonly restricted to the upper trunk, head, and neck.42 PE may remain localized for years, or it may evolve into more generalized PF.40 PE also has been associated with myasthenia gravis and thymomas.45 The histologic changes of PF, PE, and fogo selvagem are identical.2 Early blisters indicate acantholysis just below the stratum corneum and in the granular layer. The stratum corneum often is lost from the surface of these lesions. The deeper epidermis, below the granular layer, remains intact. Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity.12 Immunofluorescence using both direct and indirect techniques is the most reliable method of diagnosing pemphigus.46 Most patients with pemphigus have IgG and C3 deposits at the epidermal cell surfaces and circulating IgG against the same components.47 However, the cell staining pattern of both direct and indirect immunofluorescence is virtually identical in PV and PF, making it difficult to distinguish between them.48 One innovation has been the introduction of an antigen-specific ELISA (enzyme-linked immunosorbent assay) test for the diagnosis of pemphigus: if a serum is positive against Dsg3, the test results indicate a diagnosis of PV, regardless of reactivity against Dsg1; if a serum is negative for Dsg3 and positive for Dsg1, the test results indicate a diagnosis of PF.48 The differential diagnosis of PF includes other forms of pemphigus, bullous impetigo, subcorneal pustular dermatosis, linear IgA dermatosis, and seborrheic dermatitis.2,30 Before the advent of glucocorticoid therapy, PF was fatal in about 60% of patients.12 The aim of current therapy is to suppress the production of pathogenic antibodies, stop the development of new lesions, and heal old lesions.49 The therapy of PF differs from that of PV only in that treatment can be less aggressive because morbidity and mortality are lower.26 In all patients, a complete review of medications should be done to exclude the possibility of drug-induced PF. The most commonly implicated medications are penicillamine,27 captopril,50 lisinopril,51 nifedipine,52 and topical imiquimod.53 Because PF may be localized for many years and the prognosis without systemic therapy may be good, patients do not necessarily require systemic therapy. This patient group may be treated successfully with topical corticosteroids.29,54 Patients with active and widespread disease require systemic therapy.16 An initial dose of prednisone at 1.0 mg/kg can usually be tapered down toward an alternate-day dosage within 1 to 3 months.29 One patient has been kept on a low dose of corticosteroids successfully as maintenance over an extended period.55 Patients with the most severe disease (ie, disease unresponsive to corticosteroids) should be considered for adjuvant immunosuppressive drugs as steroid-sparing agents.29,49 The goal of immunosuppressive therapy is to suppress the production of antibodies. One of the medications used is mycophenolate mofetil, which is shown to be an effective steroid-sparing agent.56,57 Oral cyclophosphamide, which also is an effective adjuvant alkylating agent in the treatment of severe and refractory PV and PF, can be combined with pulse intravenous corticosteroids. However, the use of alkylating agents should be done with care because of the risk of side effects such as hemorrhagic cystitis, susceptibility to infection, potential infertility, mutagenic potential, and lifetime risk for transitional cell carcinoma of the bladder and hematologic malignancies.58 Other immunosuppressive medications that have been used include azathioprine,59,60 methotrexate,61,62 and cyclosporine.63,64 In patients for whom conventional therapies have failed, alternative therapies such as intravenous immunoglobulin,65 plasmapheresis,⁶⁶ and extracorporeal photochemotherapy67,68 have been employed successfully. A single case of PF occurring after unrelated cord blood transplantation was reported to be successfully treated with rituximab, an anti-CD20 antibody.69 Dapsone has been used both as monotherapy and in combination regimens. In a study of 9 patients, 5 had at least 50% improvement.70 Only patients with low titers or undetectable circulating antibodies responded to monotherapy. The value of dapsone in the treatment of PF remains to be clearly established.71 There have been a few case reports indicating that a combination of tetracycline and niacinamide is an effective alternative to steroids in superficial pemphigus.72 Other agents reported in the literature include gold,43,73 chlorambucil,74 and hydroxychloroquine sulfate.75 It is commonly perceived that PF is more benign than PV. Although uncommon, there are several reports of death occurring in PF.65,76 Infection is often the cause of death, and therapy is frequently a contributing factor because it causes the immunosuppression necessary to treat active disease.77 The effective management of PF requires a knowledge of the pathophysiology and pharmacologic effects of the agents used, an ability to make an accurate diagnosis, and an understanding of the patient's expectations.49 

Pemphigus describes a group of autoimmune chronic bullous diseases, originally named in 1791.1 The term pemphigus stems from the Greek pemphix meaning blister or bubble.2 Pemphigus is usually divided into 2 major forms depending on blister location: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Pemphigus vegetans is a variant of PV, and pemphigus erythematosus (PE) and fogo selvagem are variants of PF. During the past 3 decades, uncommon forms of pemphigus have been described, including pemphigus herpetiformis, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus.3 The incidence of pemphigus ranges from 0.76 to 5 new cases per million per year.2 In a recent analysis of 1209 patients with pemphigus in Iran, the PV to PF ratio was found to be 12:1. However, this ratio varies widely in different parts of the world.4 In one report, 73% of cases of pemphigus in France were PV.5 PV also is the most common clinical type of pemphigus in Kuwait, Israel, and Singapore.6-8 In a report on pemphigus in South Africa, the most common clinical variant was PF, and 80% of these patients were black.9 Of note, in the Indian population in this region, PV was more common. A high percentage of PF is endemic in rural Brazil, Tunisia, and Columbia.9 

Case Report
A 58-year-old white woman presented with a 6-month history of superficial erosions on the chest, upper back, hairline, and retroauricular areas. She denied any photosensitivity, and there was no mucosal involvement. The patient's medical history was otherwise unremarkable. Superficial erosions with a positive Nikolsky sign were present on the chest (Figure), upper back, and frontal hairline, as well as in the retroauricular areas bilaterally. Two punch biopsies (one lesional and one perilesional) were performed. Routine histology results showed intraepidermal vesicles in the upper granular layer containing acantholytic cells. Results of direct immunofluorescence demonstrated IgG and complement 3 (C3) in the intercellular spaces in the epidermal cell surface. Of note, antinuclear antibody and anti–double-stranded DNA were negative. These findings were consistent with our clinical diagnosis of PF.

The patient was initially started on a high potency topical corticosteroid (clobetasol propionate ointment) for 4 weeks with no improvement. She was then given prednisone 60 mg/d for approximately one month when new lesions ceased to appear; then the medication was slowly tapered off. Dapsone also was added to her regimen after an initial baseline level of glucose-6-phosphate dehydrogenase and a baseline complete blood count were obtained. Dapsone was initiated at 50 mg/d while prednisone was being slowly tapered. Cacit D3 in a single morning dose (1000 mg calcium and 880 IU vitamin D) also was added to the regimen. Of note, the patient was taking celecoxib for intermittent joint pain, but a literature search at that time did not reveal an association with similar eruptions; our patient was asked to discontinue the celecoxib at the initiation of oral prednisone. She was seen at regular follow-up visits every month. As the patient improved clinically, dapsone was reduced to 25 mg and finally discontinued after about 6 months. Oral prednisone taper continued slowly over a total of 18 months. No lesions were present for the last 3 monthly visits.

Comment
PF comprises 2 major categories: endemic and sporadic. The endemic form, also known as fogo selvagem, primarily affects children and young adults in rural Brazil. In contrast, the sporadic form of PF is generally a disease of middle-aged individuals and the elderly. Of note, there are several cases of nonendemic PF occurring in children,10 and 2 cases reported in the neonatal period.11 Many patients with PE show serologic findings suggestive of systemic lupus erythematosus (SLE), especially the presence of anti-nuclear antibodies.2,12 PF is an autoimmune blistering disease of unknown etiology with antibodies produced against desmoglein 1 (Dsg1).13 Dsg1 is an adhesive cadherin protein found in the desmosomal cell junction in the suprabasal layers of the epidermis.14,15 Binding of the antibody results in the loss of cell adhesion or acantholysis and formation of the clinical picture of PF.16 The blisters are subcorneal, occurring in and around the granular cell layer of the epidermis.13 Blister formation is superficial because the most differentiated layer of the epidermis is the only area in which Dsg1 is critically important to cell adhesion, and there is no protection redundancy of adhesion molecules by coexpression of Dsg3.17 Of interest, one study has demonstrated that the autoantibodies in up to 7% of patients with PF and up to 50% of patients with PV recognize both Dsg1 and Dsg3 isoforms.18 It also is reported that some patients can progress from PF to PV or vice versa, though the latter is less common.19 It has been shown that this transition correlates well with the qualitative and quantitative changes in the profile of Dsg1 and Dsg3 antibodies.20 Patients with PF have been reported to have a predominance of circulating IgG4 antiepidermal autoantibodies, followed by a lesser degree of IgG1, IgG2, and IgG3 subclasses.21 PF has shown a strong association with several HLA-DRB1 haplotypes.22,23 Most recently, an association with HLA-DRB1*0101 was found in the Mexican population.24 Sunlight exposure25 and several drugs such as penicillamine26,27 have been identified as possible triggering factors for the disease. In children, bacteria, cytomegalovirus, and otitis also have been implicated.10 Similarly, an unusual case of childhood PF apparently triggered by conjunctivitis was reported.28 PF manifests clinically as recurrent shallow erosions accompanied by erythema, scaling, and crusting.29 Lesions usually are found in a seborrheic distribution (central face, neck, chest, or upper back).30 Patients develop superficial fragile vesicles, which often are not seen. In contrast to PV, PF patients rarely have mucosal involvement.11 The onset of disease may be slow, starting with only a few transient scattered crusted lesions.2 The condition may then stay localized for years or progress into generalized involvement, sometimes resulting in an exfoliative erythroderma.31 In general, patients are not severely ill but often complain of burning and pain associated with the skin lesions.2 Fogo selvagem, formerly known as Brazilian PF, occurs in an endemic fashion in certain regions of Brazil.32 The condition has been described in certain regions of Brazil since the turn of the century.33 The prevalence in some rural areas of Brazil is as high as 3.4%.34 There also have been reports of other possible foci of endemic PF in Tunisia and Columbia.35,36 Endemic PF differs from sporadic PF in its geographic distribution, high familial incidence, and young age of onset.36 The clinical manifestations, histology, and immunopathologic features are indistinguishable from sporadic PF.29,32 The distinct epidemiology of the condition is suggestive of an environmental or infectious agent. Studies have identified that most patients are young peasants or children who live in close proximity to rivers, which exposes the children to the hematophagous insect belonging to the Simulium nigrimanum species, also known by its popular name borrachudo (blackfly).37,38 PE was first described by Senear and Usher39 in 1926. Originally, the term PE was introduced to describe patients with immunologic features of both SLE and pemphigus.2 Many patients with PE show serologic findings suggestive of SLE, especially the presence of antinuclear antibodies.12,40 However, there are only a few reports of PE occurring in patients who have clearly defined SLE.41,42 In most of these cases, the diagnosis of SLE had been established months to years earlier.42 PE also may be associated with a variety of autoantibodies and may require extensive immunotherapy.43 PE has characteristic findings on direct immunofluorescence, usually IgG and C3 at the basement membrane zone of erythematous facial skin, in addition to the epidermal cell surface IgG.12,44 Clinically, the lesions of PE resemble those of PF but are most commonly restricted to the upper trunk, head, and neck.42 PE may remain localized for years, or it may evolve into more generalized PF.40 PE also has been associated with myasthenia gravis and thymomas.45 The histologic changes of PF, PE, and fogo selvagem are identical.2 Early blisters indicate acantholysis just below the stratum corneum and in the granular layer. The stratum corneum often is lost from the surface of these lesions. The deeper epidermis, below the granular layer, remains intact. Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity.12 Immunofluorescence using both direct and indirect techniques is the most reliable method of diagnosing pemphigus.46 Most patients with pemphigus have IgG and C3 deposits at the epidermal cell surfaces and circulating IgG against the same components.47 However, the cell staining pattern of both direct and indirect immunofluorescence is virtually identical in PV and PF, making it difficult to distinguish between them.48 One innovation has been the introduction of an antigen-specific ELISA (enzyme-linked immunosorbent assay) test for the diagnosis of pemphigus: if a serum is positive against Dsg3, the test results indicate a diagnosis of PV, regardless of reactivity against Dsg1; if a serum is negative for Dsg3 and positive for Dsg1, the test results indicate a diagnosis of PF.48 The differential diagnosis of PF includes other forms of pemphigus, bullous impetigo, subcorneal pustular dermatosis, linear IgA dermatosis, and seborrheic dermatitis.2,30 Before the advent of glucocorticoid therapy, PF was fatal in about 60% of patients.12 The aim of current therapy is to suppress the production of pathogenic antibodies, stop the development of new lesions, and heal old lesions.49 The therapy of PF differs from that of PV only in that treatment can be less aggressive because morbidity and mortality are lower.26 In all patients, a complete review of medications should be done to exclude the possibility of drug-induced PF. The most commonly implicated medications are penicillamine,27 captopril,50 lisinopril,51 nifedipine,52 and topical imiquimod.53 Because PF may be localized for many years and the prognosis without systemic therapy may be good, patients do not necessarily require systemic therapy. This patient group may be treated successfully with topical corticosteroids.29,54 Patients with active and widespread disease require systemic therapy.16 An initial dose of prednisone at 1.0 mg/kg can usually be tapered down toward an alternate-day dosage within 1 to 3 months.29 One patient has been kept on a low dose of corticosteroids successfully as maintenance over an extended period.55 Patients with the most severe disease (ie, disease unresponsive to corticosteroids) should be considered for adjuvant immunosuppressive drugs as steroid-sparing agents.29,49 The goal of immunosuppressive therapy is to suppress the production of antibodies. One of the medications used is mycophenolate mofetil, which is shown to be an effective steroid-sparing agent.56,57 Oral cyclophosphamide, which also is an effective adjuvant alkylating agent in the treatment of severe and refractory PV and PF, can be combined with pulse intravenous corticosteroids. However, the use of alkylating agents should be done with care because of the risk of side effects such as hemorrhagic cystitis, susceptibility to infection, potential infertility, mutagenic potential, and lifetime risk for transitional cell carcinoma of the bladder and hematologic malignancies.58 Other immunosuppressive medications that have been used include azathioprine,59,60 methotrexate,61,62 and cyclosporine.63,64 In patients for whom conventional therapies have failed, alternative therapies such as intravenous immunoglobulin,65 plasmapheresis,⁶⁶ and extracorporeal photochemotherapy67,68 have been employed successfully. A single case of PF occurring after unrelated cord blood transplantation was reported to be successfully treated with rituximab, an anti-CD20 antibody.69 Dapsone has been used both as monotherapy and in combination regimens. In a study of 9 patients, 5 had at least 50% improvement.70 Only patients with low titers or undetectable circulating antibodies responded to monotherapy. The value of dapsone in the treatment of PF remains to be clearly established.71 There have been a few case reports indicating that a combination of tetracycline and niacinamide is an effective alternative to steroids in superficial pemphigus.72 Other agents reported in the literature include gold,43,73 chlorambucil,74 and hydroxychloroquine sulfate.75 It is commonly perceived that PF is more benign than PV. Although uncommon, there are several reports of death occurring in PF.65,76 Infection is often the cause of death, and therapy is frequently a contributing factor because it causes the immunosuppression necessary to treat active disease.77 The effective management of PF requires a knowledge of the pathophysiology and pharmacologic effects of the agents used, an ability to make an accurate diagnosis, and an understanding of the patient's expectations.49