Cyclic Ichthyosis with Epidermolytic Hyperkeratosis: A Phenotype Conferred by Mutations in the 2B Domain of Keratin K1

• Published in: American journal of human genetics Vol. 64; no. 3; pp. 732 - 738
• Main Authors: Sybert, Virginia P., Francis, Julie S., Corden, Laura D., Smith, Lynne T., Weaver, Molly, Stephens, Karen, McLean, W. H. Irwin
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-03-1999; University of Chicago Press
• Subjects: Biological and medical sciences; Bullous diseases of the skin; Cyclic ichthyosis; Dermatology; DNA Mutational Analysis; Epidermolytic hyperkeratosis; Fluorescent Antibody Technique; Humans; Hyperkeratosis, Epidermolytic - complications; Hyperkeratosis, Epidermolytic - genetics; Hyperkeratosis, Epidermolytic - pathology; Keratins - genetics; Keratins - physiology; Male; Medical sciences; Mutation, Missense; Pedigree; Phenotype; Point Mutation; Skin - pathology; Skin - ultrastructure; Epidermolytic hyperkeratosis; Cyclic ichthyosis; Bullous dermatosis; Human; Dyskeratosis; Skin disease; Bullous ichtyosiform erythroderma; Family study; Pathogenesis; Hyperkeratosis; Mutation; Genetic determinism; Genetic disease
• DOI: 10.1086/302278
• EISSN: 1537-6605
• ISSN: 0002-9297

Bullous congenital ichthyosiform erythroderma (BCIE) is characterized by blistering and erythroderma in infancy and by erythroderma and ichthyosis thereafter. Epidermolytic hyperkeratosis is a hallmark feature of light and electron microscopy. Here we report on four individuals from two families with a unique clinical disorder with histological findings of epidermolytic hyperkeratosis. Manifesting erythema and superficial erosions at birth, which improved during the first few months of life, affected individuals later developed palmoplantar hyperkeratosis with patchy erythema and scale elsewhere on the body. Three affected individuals exhibit dramatic episodic flares of annular, polycyclic erythematous plaques with scale, which coalesce to involve most of the body surface. The flares last weeks to months. In the interim periods the skin may be normal, except for palmoplantar hyperkeratosis. Abnormal keratin-filament aggregates were observed in suprabasal keratinocytes from both probands, suggesting that the causative mutation might reside in keratin K1 or keratin K10. In one proband, sequencing of K1 revealed a heterozygous mutation, 1436T→C, predicting a change of isoleucine to threonine in the highly conserved helix-termination motif. In the second family, a heterozygous mutation, 1435A→T, was found in K1, predicting an isoleucine-to-phenylalanine substitution in the same codon. Both mutations were excluded in both a control population and all unaffected family members tested. These findings reveal that a clinical phenotype distinct from classic BCIE but with similar histology can result from K1 mutations and that mutations at this codon give rise to a clinically unique condition.