Peeling Skin Syndrome 4

A number sign (#) is used with this entry because of evidence that peeling skin syndrome-4 (PSS4) is caused by homozygous mutation in the CSTA gene (184600) on chromosome 3q21.

For a general phenotypic description and a discussion of genetic heterogeneity of peeling skin syndrome, see PSS1 (270300).

Clinical Features

Hatsell et al. (2003) reported 2 related Bedouin families in which 5 individuals had peeling skin of the hands and feet as well as generalized dry scaling skin over the remainder of the body. The authors considered the disorder to be a new variant of congenital exfoliative ichthyosis. The phenotype shared some features with ichthyosis bullosa of Siemens (IBS; 146800) and annular epidermolytic ichthyosis (607602), and clinical distinction seemed difficult. However, the histologic, ultrastructural, and genetic features in the affected members of the Bedouin families distinguished the ichthyosis from previously reported ichthyoses. Ichthyosis appeared shortly after birth as a fine peeling of nonerythematous skin on the palms and soles. The prominent well-demarcated areas of denuded skin in moist and traumatized regions resembled the 'mauserung' phenomenon of IBS. Unlike IBS, the disorder lacked epidermolysis on histologic examination. Electron microscopy revealed a prominent intercellular edema and numerous aggregates of keratin filaments in basal keratinocytes. The level of cleavage could not be determined by histologic examination or electron microscopy. Abnormal keratin-1 (KRT1; 139350) expression was seen in the affected epidermis; however, all other keratins, including K2e (KRT2; 600194), had a distribution comparable to that seen in normal controls. The mode of inheritance was consistent with autosomal recessive transmission.

Blaydon et al. (2011) studied the Bedouin kindred with exfoliative ichthyosis originally reported by Hatsell et al. (2003) and a Turkish family with a similar phenotype. Affected individuals in both families presented shortly after birth with dry, scaly skin over most of the body and coarse peeling of nonerythematous hyperkeratotic skin on the palms and soles, which was exacerbated by excessive moisture and minor trauma. Electron microscopy of skin biopsies from both families revealed mostly normal-appearing upper layers of the epidermis, but prominent intercellular edema of the basal and suprabasal cell layers with aggregates of tonofilaments in the basal keratinocytes, indicating that skin peeling was initiated by weakness in keratinocyte attachment at the basal and lower suprabasal level. A detailed view of cell-cell contacts showed a loss in number and tightness of the desmosomes in the basal layer compared to the upper epidermal layers and a partial loosening of their intercellular interaction.

Pavlovic et al. (2012) described a large Jordanian American family in which 10 members had an acral form of peeling skin syndrome. The proband was a 24-year-old man with a lifelong history of peeling skin on his hands and feet that worsened with exposure to heat, friction, perspiration, or water, and was also associated with pruritus. Acral skin could be easily peeled with light rubbing, leaving tender, superficial erosions that usually healed within 2 to 3 days; however, peeling recurred in the same or adjacent areas. Examination revealed erythematous, sharply demarcated, fine, scaling patches on the palms, soles, fingers, and toes that also affected the dorsal surfaces. Adjacent to the areas of scaling, asymmetric superficial erosions were seen. There was no vesiculation, and nails appeared normal. An 18-year-old sister exhibited similar acral skin peeling, and a family history of at least 8 other affected individuals was established. Histology of patient epidermis showed orthohyperkeratosis, with fine basophilic granules in some areas of the granular layer. Several layers of normal corneocytes were seen above the granular layer, but above these layers, there were approximately 20 layers of loosely packed, less densely stained, swollen cells resembling shadow cells. Above the edematous zone, several layers of normal-appearing corneocytes were present. The cleavage predominantly occurred in the edematous zone and also in the immediate subcorneal area. The spinous and basal layers, dermoepidermal junction, and dermis were unremarkable. Ultrastructurally, some cells of the granular layer showed small electron-lucent holes adjacent to normal-appearing tonofibrils and dense areas. The clear zone on light microscopy (shadow cells) demonstrated swollen cells with loosely assembled filament bundles. Occasional globular deposits were found between the corneocytes. There were numerous areas in which separation occurred between the corneocytes, as well as cytolysis and fragmentation of keratin filaments. Adjacent to areas of intercellular cleavage, cell-to-cell adhesion was firmly maintained by completely preserved, normal-appearing desmosomes.

Moosbrugger-Martinz et al. (2015) reported a 25-year-old Iranian man, born of first-cousin parents, who had congenital erythroderma, hyperhidrosis, and diffuse palmoplantar hyperkeratosis with coarse peeling of the skin. Examination showed symmetric diffuse yellowish palmoplantar hyperkeratosis with transgression to the dorsal aspects of the hands and feet. Peeling of skin was observed on the hands, feet, and distal extremities, leaving behind well-demarcated denuded areas with subjacent erythema and erosions. Generalized fine scaling, lichenification over the elbows, and hyperkeratosis of the knees were also present. Hair, nails, and teeth were normal. A 33-year-old sister exhibited similar, but milder, skin features. Histology of sole and ankle skin showed mild orthohyperkeratosis, a prominent granular layer, and mild spongiosis in the spinous layer, but no signs of epidermolytic hyperkeratosis, and only mild dermal inflammation. Electron microscopy of ankle skin showed normal corneodesmosomes, mild intercellular edema in the spinous layer but not in the basal layer, normal-appearing desmosomes, prominent keratin filaments within the basal keratinocytes, and reduced cornified envelope thickness. Barrier abnormalities were indicated by disturbed lamellar lipid organization in the stratum corneum with nonlamellar electron-dense material and vesicular contents, premature and inhomogeneous lamellar body secretion, and delayed processing of secreted lamellar body contents. These findings correlated with slightly elevated transepidermal water loss levels.

Mapping

By linkage analysis in a large Bedouin pedigree with congenital exfoliative ichthyosis, Hatsell et al. (2003) found suggestive linkage to chromosome 12q13. Blaydon et al. (2011) performed high-resolution homozygosity mapping in 2 affected individuals from the same Bedouin pedigree and identified a large block of homozygosity on chromosome 3q21 between SNPs rs6783609 and rs6438966. Analysis of the SNP data revealed no significant blocks of shared homozygosity on chromosomal region 12q13; linkage to 3q21 was confirmed by genotyping microsatellite markers across the region.

Molecular Genetics

In a consanguineous Bedouin kindred with autosomal recessive exfoliative ichthyosis mapping to chromosome 3q21, originally reported by Hatsell et al. (2003), Blaydon et al. (2011) identified homozygosity for a splice site mutation in the candidate gene CSTA (184600.0001) that segregated with disease in the family and was not detected in 300 control chromosomes. In affected members of a Turkish family with a similar phenotype of exfoliative ichthyosis, Blaydon et al. (2011) identified homozygosity for a nonsense mutation in CSTA (184600.0002).

In a patient with an acral form of peeling skin syndrome from a large Jordanian American family that was originally reported by Pavlovic et al. (2012) and in which no mutation was found in the TGM5 (603805), CDSN (602593), KRT14 (148066), or KRT5 (148040) genes, Krunic et al. (2013) performed whole-exome sequencing and identified a homozygous nonsense mutation in the CSTA gene (K22X; 184600.0003). The mutation, which was located in a 20-Mb region of homozygosity, segregated with disease in the family. Krunic et al. (2013) noted considerable overlap between the features in their patients diagnosed with acral PSS and those in patients diagnosed with exfoliative ichthyosis who also carried homozygous mutations in CSTA (Blaydon et al., 2011), and suggested that the different diagnoses represented differences in clinical description rather than in disease pathophysiology.

By direct sequencing of candidate genes in a 25-year-old Iranian man with generalized peeling skin and diffuse palmoplantar hyperkeratosis, Moosbrugger-Martinz et al. (2015) excluded mutation in TGM5 and identified homozygosity for a nonsense mutation in the CSTA gene (R58X; 184600.0004). The authors noted that histology in this patient showed an attenuated cornified cell envelope and epidermal barrier impairment, without prominent intercellular edema in the basal layer as previously observed in patients with CSTA mutations (Blaydon et al., 2011); rather, skin biopsy showed mild intercellular edema primarily in the spinous layer.