Erythrodermatoderma congenital with palmoplantar keratoderma, hypotrichosis and hyper-IgE l53.9

Congenital erythroderma with palmoplantar keratosis, hypotrichosis and hyper-IgE caused by a homozygous autosomal recessive mutation in the DSG1 gene (125670) on chromosome 18q12. DSG1 encodes desmoglein 1, which is an essential structural protein of desmosomes . These are cell-cell compounds that resist shear forces and are present at high levels in cells exposed to mechanical stress. The DSG1 gene is located in a cluster with other members of the desmoglein family on chromosome 18.

Samuelov et al (2013) studied two sisters born to first-degree Arab Muslim parents who had hypotrichosis and congenital erythroderma reminiscent of congenital ichthyosiform erythroderma, with skin erosions and scaling and yellowish papules and plaques on the periphery of the palms, along the volar surfaces of the fingers, and over the pressure-adapted areas of the soles of the feet. Both sisters suffered from severe food allergies, markedly elevated IgE levels and recurrent infections with malabsorption and emaciation. One sister was diagnosed with eosinophilic esophagitis. The second sister suffered from severe esophageal reflux and ventricular septal defect.

In a second Druze family, a 9-month-old girl suffered from congenital erythroderma as well as severe dermatitis, hypotrichosis, recurrent skin and respiratory infections, multiple food allergies, and growth retardation . A similarly affected sister with microcephaly and mild pulmonary stenosis had died of sepsis at the age of 2 years. Two other family members also died of septic processes at the age of 2.5 years.

Skin biopsies from both families showed psoriasiform dermatitis with alternating para- and orthokeratosis, hypo- and hypergranulosis, and widespread acantholysis within the spinous and granular layers, resulting in subcorneal and intragranular detachments. Electron microscopy of the affected skin showed uneven distribution of desmosomes in the upper epidermis, whereas the morphology and distribution of desmosomes in the basal and lower spinous layers appeared normal. The hair shafts were normal.

Whole-exome sequencing revealed two different homozygous mutations in the DSG1 gene (125670,0008 and 125670,0009). All heterozygous carriers in both families had well-demarcated palmoplantar hyperkeratotic papules and plaques, mostly in a nonstriated pattern, consistent with other reports showing that heterozygous mutations in DSG1 can cause striated, focal, or diffuse forms of palmoplantar keratoses (see PPKS1, 148700). Impaired cell-cell adhesion in the upper epidermal layers is thought to lead to impaired barrier function. This leads to permanent and abnormal stimulation and multiple allergies.

1. Samuelov L et al. (2013) Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nature Genet. 45: 1244-1248