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 keratinization. During the last decade over 300 patients studied have characterized the efficacy and toxicity of isotretinoin and etretinate in the treatment of a variety of disorders. Patients requiring long-term retinoid therapy are monitored to characterize chronic skeletal toxicities. The high rate of peripheral skeletal involvement after chronic etretinate therapy was first identified in these patients. A trial of Peptide T for psoriasis, a synthetic oligopeptide which has been associated with improvement in HIV related psoriasiform eruptions, showed minimal efficacy. We demonstrated the effectiveness of oral isotretinoin as a chemopreventive agent in patients with high rates of skin cancer formation. They are now maintained on long-term isotretinoin for cancer prevention. A study of recombinant human interferon gamma for basal cell carcinoma is nearing completion. All tumors treated have become smaller, but few underwent complete histological regression. In collaboration, we have identified linkage of the nevoid basal cell carcinoma syndrome gene to 9q31. In tumors, loss of heterozygosity in that region suggests that a mutation in a tumor suppressor gene is the probable cause of the disease. Linkage analysis is being pursued for fine mapping of the region. We were the first to identify linkage of the epidermolytic hyperkeratosis gene to the type II keratin gene cluster on chromosome 12q. We have now identified mutations in 11 families and have identified 7 distinct clinical phenotypes. The correlation between these mutations and clinical phenotypes should lead to a better understanding of the relationship between keratin structure and function.
