Peeling Skin Syndrome 2

A number sign (#) is used with this entry because of evidence that peeling skin syndrome-2 (PSS2), an acral form of the disorder, is caused by homozygous or compound heterozygous mutation in the TGM5 gene (603805) on chromosome 15q15.

Description

Peeling skin syndrome (PSS) is an autosomal recessive genodermatosis characterized by the shedding of the outer epidermis. In an acral form of the disorder (PSS2), the dorsa of the hands and feet are predominantly affected, and ultrastructural analysis shows separation at the junction between the granular cells and the stratum corneum in the outer epidermis (summary by Cassidy et al., 2005).

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

Clinical Features

Cassidy et al. (2005) described 2 families, 1 Dutch and 1 Scottish, with noninflammatory acral peeling skin syndrome in which peeling was accompanied by erythema. Affected patients experienced periodic, painless, and superficial skin peeling. Although the skin peeling occurred spontaneously, manual removal of strips of skin was easy. The abnormality was exacerbated by elevated ambient temperature and humidity. Peeled areas showed some residual erythema for a few days but healed spontaneously and without scarring. Histologic and ultrastructural analyses of cases of the peeling skin syndrome demonstrated that the level of blistering is high in the epidermis, at the junction of the stratum granulosum (the last living layer) and the stratum corneum (the terminally differentiated and continuously shed, cornified squamous layers). Thus the disorder is histologically distinguishable from the various forms of epidermolysis bullosa, in which blistering occurs in the basal keratinocytes of the epidermis, within or close to the dermal-epidermal basement membrane, or in the upper papillary dermis. The Dutch family included 5 affected individuals in 2 interbred sibships. Genealogic analysis established consanguinity dating to the 1780s. Consanguinity in the Scottish family could not be determined.

Shwayder et al. (1997) and Hashimoto et al. (2000) described families with acral PSS.

Kharfi et al. (2009) reported 2 Tunisian brothers, aged 5 years and 3 years, with focal cutaneous exfoliation of the hands and feet. The scaling occurred spontaneously, and sheets of skin could be peeled off painlessly; the underlying erythematous areas healed without scarring in a few days. The symptoms worsened with elevated ambient temperature, humidity, and friction. Only the palmoplantar areas and dorsa of hands and feet were affected. Family history included 3 more affected individuals, but they were not available for study. Histologic examination of the border of a palmar lesion showed a thickened stratum corneum with cleavage in the clear zone; ultrastructural studies showed enlarged intercellular spaces in the stratum corneum, with stellate and electron-dense keratohyalin granules of various sizes in the granular cells. No desmosomal abnormalities were observed, and cleavage occurred in the intercellular spaces between corneocytes.

Kiritsi et al. (2010) studied 6 unrelated children and 1 adult patient from Germany, 1 child from Sweden, and 1 child from Finland who were clinically diagnosed with epidermolysis bullosa simplex (see 131800). The patients had blisters and peeling of acral skin; healing occurred spontaneously, sometimes with residual erythema, burning sensation, or itching, but without scarring or atrophy. Sweating, heat, humidity, or mechanical trauma aggravated symptoms. In most cases, only the volar and dorsal surfaces of hands and feet were affected, but the 47-year-old patient also exhibited exfoliation of the elbows and knees. In the older children and the adult patient, peeling of the skin was the most prominent symptom, but blisters occurred occasionally. Two of the children reported having a mildly affected parent, and the adult patient reportedly had a child with mild features of the disease. Skin samples from some of the patients showed a discrete split in the stratum corneum, suggestive of acral PSS.

Mapping

By genomewide linkage analysis in a consanguineous Dutch kindred, Cassidy et al. (2005) mapped a gene for an acral form of peeling skin syndrome to chromosome 15q15.2, in the interval between markers D15S1040 and D15S1016.

Molecular Genetics

In all affected members of a Dutch and a Scottish kindred with acral PSS, Cassidy et al. (2005) identified homozygosity for a missense mutation in the TGM5 gene (G113C; 603805.0001) that completely abolished crosslinking activity. Another homozygous TGM5 missense variant present in affected individuals, T109M, did not significantly reduce TGM5 activity, and was considered to be a rare polymorphism. The mutation was present on the same haplotype in the 2 kindreds, indicating a probable ancestral mutation. Other families with a more widespread peeling skin phenotype similar to that described in PSS (270300) lacked TGM5 mutations.

In 2 Tunisian brothers with APSS, Kharfi et al. (2009) sequenced the TGM5 gene and identified homozygosity for a missense mutation (K445N; 603805.0002) that was present in heterozygosity in their unaffected first-cousin parents. The mutation was not found in 120 North African controls.

In 6 unrelated children and 1 adult patient from Germany, 1 child from Sweden, and 1 child from Finland with blistering and peeling acral skin that was initially diagnosed as epidermolysis bullosa simplex and who were negative for mutations in KRT5 (148040) and KRT14 (148066), Kiritsi et al. (2010) identified homozygous or compound heterozygous mutations in the TGM5 gene (603805.0001; 603805.0003). Kiritsi et al. (2010) concluded that APSS may resemble EBS in young individuals. The authors also noted that in 3 families, vertical transmission of disease was considered, because either parents or offspring were reported to have had skin blistering in childhood; however, clinical examination of the putative affected heterozygotes was not reported.

In 6 patients from 6 unrelated families with APSS, van der Velden et al. (2012) identified homozygosity for the G113C mutation in the TGM5 gene, as well as homozygosity for the T109M polymorphism. All patients reported exfoliation or blisters of hands and feet from infancy, with symptoms aggravated by heat, humidity, or friction. Genealogic research dating to the year 1650 revealed no consanguinity between the families. Haplotype analysis of these 6 families, including 5 from the Netherlands and 1 from Germany, as well as of the 2 Dutch and Scottish families previously studied by Cassidy et al. (2005), revealed that all mutation carriers were homozygous for an approximately 0.16-Mb region that begins centromeric of and includes the TGM5 gene. Van der Velden et al. (2012) noted that in contrast to the 2 Tunisian patients reported by Kharfi et al. (2009), all 21 reported European APSS patients carried the G113C mutation linked to the T109M variant, suggesting an ancestral founder mutation in the European population.

In 11 patients with APSS, Pigors et al. (2012) identified homozygosity or compound heterozygosity for mutations in the TGM5 gene (see, e.g., 603805.0001 and 603805.0004-603805.0006). In addition, the recurrent G113C mutation was detected in heterozygosity in 3 of 100 controls, suggesting that APSS may be more widespread than anticipated, with the mild phenotype remaining either undiagnosed or misdiagnosed.