Erythroderma, Congenital, With Palmoplantar Keratoderma, Hypotrichosis, And Hyper-Ige

A number sign (#) is used with this entry because of evidence that congenital erythroderma associated with palmoplantar keratoderma, hypotrichosis, and hyper-IgE (EPKHE) is caused by homozygous mutation in the DSG1 gene (125670) on chromosome 18q12.

Clinical Features

Samuelov et al. (2013) studied 2 sisters, born of first-cousin Arab Muslim parents, who exhibited hypotrichosis and congenital erythroderma reminiscent of congenital ichthyosiform erythroderma (see 242100), with skin erosions and scaling as well as yellowish papules and plaques at the periphery of the palms, along the volar surfaces of the fingers, and over the weight-bearing areas of the soles of the feet. In addition, both sisters had severe food allergies, markedly elevated IgE levels, and recurrent infections with malabsorption and wasting. One sister had eosinophilic esophagitis, whereas the other had severe esophageal reflux and a ventricular septal defect. Samuelov et al. (2013) also studied a 9-month-old girl, born of first-cousin parents of Druze descent, who had congenital erythroderma and severe dermatitis, hypotrichosis, recurrent skin and respiratory infections, multiple food allergies, and growth retardation. A similarly affected sister, who also had microcephaly and mild pulmonic stenosis, had died at 2 years of age from sepsis. Two additional family members were reported to have died at 2.5 years of age due to a similar disorder. 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 separation. Electron microscopy of affected skin showed an uneven distribution of desmosomes in the upper epidermis, whereas desmosome morphology and distribution appeared normal in the basal and lower spinous layers. Hair microscopy did not show any specific abnormality.

Molecular Genetics

In 2 unrelated consanguineous families with congenital erythroderma with palmoplantar keratoderma, hypotrichosis, and hyper-IgE features suggestive of Netherton syndrome (NTS; 256500), Samuelov et al. (2013) excluded pathogenic mutations in the SPINK5 gene (605010). Whole-exome sequencing revealed 2 different homozygous mutations in the DSG1 gene (125670.0008 and 125670.0009) that segregated with disease in each family. All heterozygous carriers in both families displayed well-demarcated palmoplantar hyperkeratotic papules and plaques, most often in a nonstriated pattern, consistent with other reports showing that heterozygous mutations in DSG1 can cause striate, focal, or diffuse forms of palmoplantar keratoderma (see PPKS1, 148700). Noting that NTS, peeling skin syndrome (270300), and the disorder in their patients share numerous clinical features and all involve superficial intraepidermal detachment, Samuelov et al. (2013) suggested that they represent a group of disorders characterized by aberrant cell-cell adhesion in upper epidermal layers that results in compromised barrier function, which may expose the immune system to abnormal stimulation and lead to multiple allergies.

Associations Pending Confirmation

For discussion of a possible association between EPKHE and variation in the DSP gene, see 125647.0020.