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June 1996

Linkage of an American Pedigree With Palmoplantar Keratoderma and Malignancy (Palmoplantar Ectodermal Dysplasia Type III) to 17q24Literature Survey and Proposed Updated Classification of the Keratodermas

Author Affiliations

From the Imperial Cancer Research Fund (ICRF) Skin Tumour Laboratory, London Hospital Medical College, London, England (Drs Stevens and Leigh); Human Genetic Resources Laboratory, ICRF, South Mimms, England (Mr Kelsell and Drs Bryant and Spurr); Genetic Epidemiology, ICRF, St James' Hospital, Leeds, England (Dr Bishop); Centre National de la Recherche Scientifique Unité de Recherche Associée, Evry, France (Dr Weissenbach); Division of Radiation Oncology, St Elizabeth Medical Center and the Department of Radiological Sciences, Wright State University School of Medicine, Dayton, Ohio (Dr D. Marger); and the Ohio State University College of Medicine, Columbus (Dr R. S. Marger).

Arch Dermatol. 1996;132(6):640-651. doi:10.1001/archderm.1996.03890300056010

Objectives:  To determine linkage in a pedigree with palmoplantar keratoderma (PPK) associated with squamous cell carcinoma of the esophagus.

Design:  A large American pedigree was studied and the clinical phenotype was described. Linkage analysis was performed using genomic DNA from key individuals.

Setting:  A community-based family study.

Patients:  The family pedigree was expanded from a single index case.

Main Outcome Measures:  To demonstrate linkage and the relative risk of squamous cell carcinoma of the esophagus in this pedigree.

Results:  Focal PPK was inherited as an autosomal dominant with variable expression, but signs were not limited to the palmoplantar epidermis. The generalized nature of this pattern of PPK was highlighted by the perifollicular papules and oral hyperkeratosis. Affected individuals (125 individuals) in 7 generations were identified, with 17 affected individuals having associated cancer. Seven of the 8 squamous cell carcinomas of the esophagus occurred in smokers. Other tumors were seen in nonsmokers, but these were not significantly increased. The combined male-female expected incidence of squamous cell carcinoma of the mouth and esophagus was 0.21; observed, 8 (relative risk of 38; P<.001). Linkage to the tylosis and esophageal cancer gene locus on 17q24 was demonstrated with a maximum 2-point lod score of 8.20 at zero recombination fraction for the DNA marker D17S1603.

Conclusion:  The distinctive clinical phenotype in this family suggests a new classification for PPKs, in particular a reappraisal of the phenotype as a focal PPK. A very similar phenotype is found in patients with keratin K16 gene mutations.(Arch Dermatol. 1996;132:640-651)