Skin fragility-woolly hair syndrome Q82.8

Whittock et al (2002).

Very rare (<20 people have been described worldwide), autosomal recessive (dominant?), monogenic genodermatosis characterized by focal and diffuse keratosis palmoplantaris, generalized skin fragility, traumatic blistering, hyperkeratotic plaques on the trunk and limbs and woolly hair (frizzy hair) with varying degrees of alopecia. The cause is a mutation in the desmoplakin gene(DSP gene; 125647) located on chromosome 6p24 (Whittock NV et al. 2002). However, phenotypically similar cases with mutations in the JUP gene(JUP codes for plakoglobin) have also been detected.

Etiopathogenetically, the combination of desmoplakin haploinsufficiency and a missense mutation leads to painful palmoplantar keratoses with recurrent secondary infections. Occasionally, more extensive trauma-related "detachments" of the skin may occur.

Already at the time of birth or shortly thereafter.

There is evidence of acantholysis in all skin layers, focal detachment of desmosomes and perinuclear condensation of the suprabasal keratin intermediate filament network.

The phenotype of skin fragility syndrome with woolly hair (SFWHS) is similar to that of dilated cardiomyopathy with woolly hair and keratoderma (DCWHK; 605676), another recessive disorder due to mutations in the gene encoding desmocollin 2(DSC2 gene) (Pigors M et al. 2015), apparently differs significantly in that DCWHK does not cause persistent skin fragility with neonatal onset and SFWHS does not cause cardiomyopathy (Favre B et al. 2018).

The immunohistochemistry of skin biopsies from the two affected individuals with SFWHS reported by Whittock et al. (2002) revealed that desmoplakin was not only found at the cell periphery (physiological finding) but also in the cytoplasm (pathological finding).

Mutations in the DSC3 gene also lead to a skin fragility syndrome, such as "hypotrichosis with recurrent skin blisters (HYPTSV/OMIM: 613102)". Onoufriadis et al. (2020) reported on a five-year-old Egyptian boy who had normal skin at birth but began to develop blisters on his hands, feet, knees and trauma sites at the age of four. He had no hair on his head at birth; although the hair grew in infancy, it was always sparse and easy to pull out. Trauma-related blisters and crusted erosions were present on his hands, knees, legs and feet. The scalp hair and eyebrows were sparse and thin. Follicular hyperkeratosis was also present on the scalp, trunk and extremities. The patient's skin was dry, the lips cracked with cheilitis angularis. The oral mucosa was O.B. The fingernails were conspicuous for leukonychia and thinning and tearing. Other features were slight thinning and irregular grooves in the enamel. Ultrastructurally, the desmosomes exhibited variable morphology, with some appearing nearly normal while others were small. Cell-cell detachment occurred mostly in the inner desmosomal plaques.

Unlike other forms of epidermolysis bullosa simplex, the condition of patients with SFWHS does not appear to improve with age.

According to Al-Owain M et al, the complexity of desmoplakin and its variable manifestations justifies the introduction of the term "desmoplakinopathies" to bring together all phenotypes related to defects in desmoplakin.

1. Al-Owain M et al. (2011) Novel homozygous mutation in DSP causing skin fragility-woolly hair syndrome: report of a large family and review of the desmoplakin-related phenotypes. Clin Genet 80:50-58.
2. Favre B et al. (2018) A recessive mutation in the DSP gene linked to cardiomyopathy, skin fragility and hair defects impairs the binding of desmoplakin to epidermal keratins and the muscle-specific intermediate filament desmin. Br J Dermatol179: 797-799.

3. Onoufriadis A et al. (2020) Homozygous nonsense mutation in DSC3 resulting in skin fragility and hypotrichosis. J Invest Derm 140: 1285-1288.

4. Peter DCV et al. (2018) Skin fragility, woolly hair syndrome with a desmoplakin mutation - a case from India. Int J Dermatol 57: e73-e75.
5. Pigors M et al. (2015) Desmoplakin mutations with palmoplantar keratoderma, woolly hair and cardiomyopathy. Acta Derm Venereol 95:337-340.

6. Simpson MA et al. (2009) Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair. Cardiology 113: 28-34.

7. Whittock NV et al. (2002) Compound heterozygosity for non-sense and missense mutations in desmoplakin underlies skin fragility/woolly hair syndrome. J Invest Derm 118: 232-238.