Peeling Skin Syndrome 1

A number sign (#) is used with this entry because of evidence that peeling skin syndrome-1 (PSS1) is caused by homozygous mutation in the corneodesmosin gene (CDSN; 602593) on chromosome 6p21.

Description

Peeling skin syndrome is a rare genodermatosis with variable age of onset from birth to adulthood. Clinically, it is characterized by a pruritic or nonpruritic spontaneous superficial peeling of the skin, which sometimes is accompanied by erythema or vesiculation. The skin involvement is usually general, but in some patients the scalp, face, palms, and soles may be unaffected. Seasonal changes have been reported. The histologic picture is characterized by separation of the epidermis between the statum corneum and the stratum granulosum (summary by Hacham-Zadeh and Holubar, 1985).

Generalized PSS has been subclassified into a noninflammatory type, designated type A, and an inflammatory type, designated type B (Traupe, 1989; Judge et al., 2004). Type B, in which generalized peeling skin is associated with pruritus and atopy, is characterized by lifelong patchy peeling of the entire skin with onset at birth or shortly thereafter. Several patients have been reported with high IgE levels (summary by Oji et al., 2010). Type A, a continuous nonerythematous exfoliation, is usually congenital or appears during childhood (summary by Mallet et al., 2013).

Genetic Heterogeneity of Peeling Skin Syndrome

Peeling skin syndrome-2 (PSS2; 609796), an acral form of the disorder that mainly involves palmar and plantar skin, is caused by mutation in the TGM5 gene (603805) on chromosome 15q15. Peeling skin syndrome-3 (PSS3; 616265) is caused by mutation in the CHST8 gene (610190) on chromosome 19q13. Peeling skin syndrome-4 (PSS4; 607936) is caused by mutation in the CSTA gene (184600) on chromosome 3q21. Peeling skin syndrome-5 (PSS5; 617115) is caused by mutation in the SERPINB8 gene (601697) on chromosome 18q22. PSS6 (618084) is caused by mutation in the FLG2 gene (616284) on chromosome 1q21.

Clinical Features

Kurban and Azar (1969) described 3 affected males and an affected female among the 9 offspring of a first-cousin marriage. No previous instance of familial occurrence of this condition had been described. Fox (1921) and Bechet (1938) described sporadic cases. Abdel-Hafez et al. (1983) reported 2 affected males and an affected female in each of 2 families from Kuwait. In 1 family, the parents were consanguineous. Light and ultramicroscopic findings were described. Hacham-Zadeh and Holubar (1985) described affected Kurdish Jewish brother and sister with first-cousin parents. Other familial cases in the offspring of consanguineous parents were reported by Levy and Goldsmith (1982) and Heid et al. (1983).

Mevorah et al. (1987) reported a 28-year-old Caucasian woman with variably pruritic ichthyosiform dermatosis. At birth her skin was diffusely red and became generally encrusted; there was no ectropion. The universal erythema was later replaced by migratory erythematous scaling patches that spared the palms and soles and evolved on a background of diffusely thickened dirty-grayish skin. There was persistent diffuse erythema of the face, but no blisters or mucous membrane lesions. The typical pattern of lesion development, which occurred over 6 to 8 days and could be induced by moderate rubbing of the skin, began with a reddish spot that expanded with a thin horny collarette at its border; the surface was initially smooth, but later became covered with large grayish scales which flaked off, leaving regenerated background skin. The grayish thickening of her skin progressively diminished after puberty, but the erythematous peeling lesions showed no improvement, although they regressed markedly every summer. The pruritis showed reverse seasonal periodicity, becoming worse in summer. The patient also exhibited moderate uniform palmoplantar keratoderma with chapping, and she had slightly dystrophic fingernails, with some showing definite koilonychia. Her hair appeared grossly normal, and microscopic examination of hair shafts showed no significant changes. A brother who was reported to have exhibited a similar dermatosis died at 8 months of age; no medical records were available. Laboratory analysis of the proband revealed markedly elevated IgE levels. Light microscopy of lesional skin showed psoriasiform acanthosis, parakeratotic hyperkeratosis, absence of granular cell layer, and a moderate inflammatory infiltrate in the upper dermis; nonlesional skin showed slight acanthosis, orthokeratotic hyperkeratosis, and a normal granular cell layer. Ultrastructurally, the most striking finding was vacuolated electron-dense granules in the uppermost epidermal layers, which the authors considered to be abnormal keratohyalin. In addition, there was a 4-fold increase in cellular retinoic acid-binding protein (CRABP; see 180230).

Oji et al. (2010) studied a large consanguineous Roma family from Germany in which 2 brothers and a distantly related boy and girl exhibited generalized superficial skin peeling from birth, associated with severe pruritus and atopic manifestations with seasonal variation. The initial clinical presentation was in the first week of life in all 4 patients, consisting of an unusual ichthyosiform erythroderma with white, superficial exfoliation, accompanied by normal birth weight and growth, with no signs of a syndromic form of ichthyosis. The affected individuals also exhibited severe pruritus, particularly in warm weather, food allergies to nuts and fish, and repeated episodes of angioedema, urticaria, and/or asthma. Total IgE levels were greatly elevated. Two of the children had unusually fine hair in infancy that was easily plucked, but the patients did not show any hair loss, and hair shaft analysis was negative for trichorrhexis invaginata. Punch biopsies of the skin were taken from all 4 patients, and histologic and ultrastructural analysis showed enhanced detachment of corneocytes.

Israeli et al. (2011) reported a 32-year-old Jewish man, born of first-cousin parents, who had a congenital pruritic rash that was initially diagnosed as Netherton syndrome (256500). Starting 3 days after birth, he developed widespread reddish peeling skin over his legs, arms, and trunk, with redness and edema of the face. The rash persisted into adulthood, with rare periods of mild improvement, mainly in the spring. In addition, from age 10 years, his nails were thick and yellowish. He had markedly elevated IgE levels, and skin biopsy showed mild hyperkeratosis, parakeratosis, intracorneal and subcorneal separation, hypergranulosis, and acanthosis, as well as a perivascular mononuclear infiltrate and scattered eosinophils in the dermis. Hair microscopy revealed normal hair shaft structures. A younger sister was reported to have similar skin findings.

Telem et al. (2012) studied a 10-month-old boy from an Ashkenazi Jewish family who had widespread patchy peeling of the skin, with an erythematous and slightly exudative surface underneath areas of superficial detachment. Nails, hair, and teeth were normal, and he had no other abnormalities. Microscopic examination of eyebrow and scalp hair revealed no structural abnormalities. Skin biopsy showed superficial perivascular mild spongiotic psoriasiform dermatitis with numerous areas of subcorneal separation. Telem et al. (2012) noted that the presentation was reminiscent of Netherton syndrome or peeling skin syndrome.

Mapping

In a large consanguineous kindred of Middle Eastern origin and 3 small outbred families with widespread peeling skin, 1 of which was previously reported by Levy and Goldsmith (1982), Cassidy et al. (2005) excluded the TGM5 (603805) locus on chromosome 15q15.2.

In a large consanguineous Roma family from Germany in which 2 brothers and a distantly related boy and girl had generalized skin peeling associated with pruritus and atopy, Oji et al. (2010) performed whole-genome linkage analysis and identified a candidate region on chromosome 6p. Fine mapping narrowed the critical interval to a 3.3-cM (5.7-Mb) interval with a lod score of 5.4, assuming 2 separate pedigrees with 2 affected individuals each. Homozygosity mapping identified a 3.0-Mb interval at chromosome 6p21 containing 195 genes.

Molecular Genetics

In 4 affected individuals from a large consanguineous Roma family from Germany with generalized skin peeling, pruritus, and atopy mapping to chromosome 6p21, Oji et al. (2010) analyzed the functional candidate gene CDSN, encoding corneodesmosin, and identified homozygosity for a nonsense mutation (K59X; 602593.0003). The mutation segregated with disease in the family and was not found in 220 ethnically matched chromosomes. Oji et al. (2010) generated 3-dimensional skin models and demonstrated that lack of corneodesmosin causes an epidermal barrier defect, which they suggested accounted for the predisposition to atopic disease.

In a Jewish man with generalized pruritic skin peeling, Israeli et al. (2011) sequenced the CDSN gene and identified homozygosity for a 1-bp deletion (c.746delG; 602593.0004) that was not found in 50 population-matched controls. The mutation status of his unaffected first-cousin parents and an affected sister was not reported.

In a 10-month-old boy from an Ashkenazi Jewish family with widespread patchy peeling of the skin, in whom mutation in the SPINK5 gene (605010) was excluded, Telem et al. (2012) identified homozygosity for a 4-bp duplication in the CDSN gene (c.164dupGCCT; 602593.0005). His unaffected parents were heterozygous for the duplication, which was not found in 50 Ashkenazi Jewish controls.

In a 50-year-old Caucasian woman with widespread skin peeling and erythema, who was originally described by Mevorah et al. (1987), Mallet et al. (2013) identified homozygosity for a nonsense mutation in the CDSN gene (G142X; 602593.0006). Her 2 healthy children were heterozygous for the mutation.