Skin Fragility-Woolly Hair Syndrome

A number sign (#) is used with this entry because the skin fragility-woolly hair syndrome is caused by homozygous or compound heterozygous mutation in the desmoplakin gene (DSP; 125647) on chromosome 6p24.

Clinical Features

Whittock et al. (2002) reported 2 unrelated individuals with an autosomal recessive genodermatosis characterized by focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs, and woolly hair with varying degrees of alopecia. They referred to this disorder as skin fragility-woolly hair syndrome (SFWHS). The phenotype of SFWHS is similar to dilated cardiomyopathy with woolly hair and keratoderma (DCWHK; 605676), another recessive disorder due to desmoplakin mutations, but is significantly different in that DCWHK lacks persistent skin fragility with neonatal onset and SFWHS lacks cardiomyopathy. The combination of desmoplakin haploinsufficiency and a missense mutation resulted in a painful keratoderma on the hands and feet with recurrent secondary infection. Occasionally, there was more widespread trauma-induced 'sloughing' of the skin. In contrast to other genodermatoses such as epidermolysis bullosa simplex (see 131800), patients with SFWHS did not appear to improve with age. Unlike other forms of keratoderma, this disorder was disabling, and patients required a wheelchair for mobility.

Biochemical Features

Immunohistochemistry of skin biopsies from both affected individuals with SFWHS reported by Whittock et al. (2002) revealed that desmoplakin was located not only at the cell periphery but also in the cytoplasm. In addition, electron microscopy demonstrated acantholysis throughout all layers of the skin, focal detachment of desmosomes into the intercellular spaces, and perinuclear condensation of the suprabasal keratin intermediate filament network.

Molecular Genetics

In 2 probands with SFWHS, Whittock et al. (2002) performed mutation screening of desmoplakin and demonstrated compound heterozygosity for a nonsense/missense combination of mutations in both patients, cys809 to ter/asn287 to lys (C809X/N287K; see 125647.0004) and gln664 to ter/arg2366 to cys (Q664X/R2366C; see 125647.0006), respectively. Mutations in desmoplakin also cause some cases of the autosomal dominant skin disorder striate palmoplantar keratoderma (see 148700), which is characterized clinically by linear and focal hyperkeratosis of the palms and soles. Whittock et al. (2002) reported that heterozygous carriers of DSP C809X, N287K, Q664X, or R2366C mutations displayed no phenotypic abnormalities. The nonsense mutations C809X and Q664X would be expected to cause nonsense-mediated mRNA decay resulting in haploinsufficiency of desmoplakin. Whittock et al. (2002) concluded that desmoplakin haploinsufficiency can be tolerated in some cases, but that in combination with a missense mutation on the other allele, the consequences are a severe genodermatosis with specific clinical manifestations.