The goal of these studies is to explore the efficacy, toxicity, and mechanisms of action of new treatments, and to better understand the pathogenesis of dermatologic diseases, particularly skin cancer and the disorders of cornification. Patients followed long-term at NIH have established the efficacy and characterized the toxicity of isotretinoin and etretinate for several skin disorders. These patients continue to be monitored to characterize skeletal toxicity, an important chronic side effect. Understanding the scope of chronic retinoid toxicity is important because of the expanding number of synthetic retinoids under clinical study. The peripheral skeletal involvement that frequently occurs after chronic etretinate therapy was first identified in this cohort. We have now discovered that osteoporosis is also a toxicity of etretinate. In patients with Darier's disease, we have identified a novel, common, cystic bone abnormality. Studies directed at skin cancer treatment and prevention are continuing. We demonstrated the effectiveness of oral iostretinoin as a chemopreventive agent in patients with high rates of skin cancer formation. These patients are now maintained on long-term isotretinoin chemoprevention to determine optimum dosing. A recently completed phase I/II study of gamma interferon for basal cell carcinoma demonstrated shrinking of all tumors, but few completely regressed. We have begun a phase I/II study of topical antiflammin, a novel peptide inhibitor of phospholipase A2, which has homology to uteroglobin and lipocortin. Our collaboration with the Lab. of Skin Biology has expanded (Z01-AR-41089-04 LSB). We were the first to find linkage of the epidermolytic hyperkeratosis gene to the type II keratin gene cluster on chromosome 12q, and have now identified mutations in keratin 1 or 10 in 12 families. Based on our clinical studies we have created a new classification of the disease including 6 distinct clinical phenotypes. Correlation of mutations with clinical phenotypes will lead to a better understanding of the relationship between keratin structure and function. In a pedigree with a non-epidermolytic form of palmar/plantar keratoderma (Unna-Thost disease) we found complete linkage with the type II keratin region and discovered a mutation in the V1 domain of the keratin 1 gene as the cause of this disease. Our fine mapping study of Darier's disease narrowed the location of the disease gene to a 5 cM interval on chromosome 12q23-q24.1. In lamellar ichthyosis we were first to find linkage to chromosome 14q11 and have now identified mutations in transglutamise 1 as the cause of the disease. Detailed clinical analysis will allow correlation of mutations with clinical phenotypes.

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National Institute of Arthritis and Musculoskeletal and Skin Diseases
United States
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