Peeling Skin Syndrome 6

A number sign (#) is used with this entry because of evidence that peeling skin syndrome-6 (PSS6) is caused by homozygous mutation in the FLG2 gene (616284) on chromosome 1q21.

Description

Peeling skin syndrome-6 is characterized by generalized ichthyotic dry skin and bullous peeling lesions on the trunk and limbs at sites of minor trauma. There is residual hyperpigmentation in areas of healing, but no scarring. Skin symptoms are exacerbated by warmth and humidity; however, the disorder improves markedly with age (Bolling et al., 2018; Mohamad et al., 2018).

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

Clinical Features

Alfares et al. (2017) reported a 13-year-old Saudi girl who had skin dryness and peeling from birth, with bullous skin eruptions on the trunk and flexor surfaces of the arms, generally at the site of trauma or contact with hard objects, including shoes. After rupture, the underlying skin was erythematous and pruritic, and remained hyperpigmented for several months. The skin manifestations were exacerbated in winter and during dry weather. The blistering subsided significantly with age, and she had no history of asthma or rhinitis. Examination showed generalized ichthyosis xerosis with diffuse fine scales, as well as mild diffuse thickening of the palms. The proband could peel her skin painlessly for a few centimeters, leaving raw red linear bands that later became hyperpigmented. She had 2 affected sibs, a 15-year-old sister and 11 year-old brother, in whom the symptoms were milder and less frequent; the published family pedigree also showed 2 affected cousins. Skin biopsy of lesional skin from the proband showed thin epidermis with orthokeratosis and no significant inflammation. Electron microscopy revealed splitting within the stratum corneum that extended to the granular layer, with intact attached lamina densa and lucida at the dermal surface, suggestive of peeling skin syndrome.

Bolling et al. (2018) described an 11-year-old Moroccan girl who was erythrodermic at birth, and afterward exhibited dry skin with superficial peeling upon minor trauma, leaving red denuded areas that healed with hyperpigmentation, but without scarring. Warm and humid environments exacerbated the peeling tendency. She developed hyperkeratosis and ichthyosis over the knees and elbows. The condition improved markedly during childhood. She had a similarly affected older brother, who also showed remarkable improvement with age. Hair, nails, and mucosae were normal. Histopathology showed separation in the lower stratum corneum with parakeratosis, and electron microscopy revealed abnormal keratin bundles and keratohyalin granules in the stratum granulosum. Corneocytes were swollen, interdigitating, and loosely packed, with light gray globular inclusions and abnormal central vesicles. Immunofluorescence microscopy at age 4 years showed absent FLG2 in perilesional skin, and keratin-2 (KRT2; 600194), corneodesmosin (CDSN; 602593), desmocollin-1 (DSC1; 125643), desmoglein-1 (DSG1; 125670), loricrin (LOR; 152445), and filaggrin-1 (FLG; 135940) were reduced or absent in proband skin samples. However, all these staining results were normal or near-normal at age 10 years.

Mohamad et al. (2018) studied an affected sister and brother from a consanguineous Arab Moslem family with peeling skin syndrome that primarily involved the limbs as well as the trunk, with sparing of the face and palmoplantar skin. The lesions, which were most prominent during the heat of summer months and were also triggered by minor skin trauma, left residual discolored skin after healing. Disease manifestations improved with age. Skin biopsy showed subcorneal separation with little to no dermal inflammatory infiltrate. Electron microscopy revealed intraepidermal separation within the lower corneal layers and a reduction in the number of keratohyalin granules, most of which were deformed and irregularly shaped. First-degree cousins of the affected sibs were reported to exhibit an atopic diathesis, although they had no skin manifestations; however, the affected sibs had normal IgE levels.

Molecular Genetics

In 3 affected sibs from a consanguineous Saudi family with peeling skin syndrome, who were negative for mutations in known PSS-associated genes, Alfares et al. (2017) performed exome sequencing and identified homozygosity for a nonsense mutation in the FLG2 gene (S211X; 616284.0001). Their unaffected first-cousin parents were heterozygous for the mutation, which was not found in 1,302 ethnically matched controls and was present at a low frequency (less than 0.0008%) in the ExAC and gnomAD databases.

In the 11-year-old female proband from a consanguineous Moroccan family with generalized ichthyotic PSS, who was negative for mutation in a gene panel for skin fragility disorders, Bolling et al. (2018) performed whole-exome sequencing with comprehensive gene-network analysis and identified homozygosity for the S211X mutation in the FLG2 gene. Her affected brother was also homozygous for the mutation, whereas her unaffected parents and 2 unaffected sibs were heterozygous carriers.

By whole-exome sequencing in 2 affected sibs from a consanguineous Arab Moslem family with PSS, who were negative for mutation in 3 known PSS-associated genes, Mohamad et al. (2018) identified homozygosity for a nonsense mutation in the FLG2 gene (Y355X; 616284.0002). Their unaffected parents and 4 unaffected sibs were heterozygous for the mutation, which was not found in 151 population matched controls or in public variant databases.