ABSTRACT
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.
Subject(s)
Ectodermal Dysplasia/genetics , Keratoderma, Palmoplantar/genetics , Neoplasms/genetics , Chromosomes, Human, Pair 17 , Ectodermal Dysplasia/complications , Female , Genetic Linkage , Humans , Keratoderma, Palmoplantar/classification , Keratoderma, Palmoplantar/complications , Male , Neoplasms/complications , Pedigree , Phenotype , United StatesABSTRACT
Myotonic dystrophy (DM) is an autosomal dominant genetic disease caused by an unstable CTG repeat sequence in the 3' untranslated region of the myotonin protein kinase gene. The CTG repeat is present 5-30 times in the normal population, whereas DM patients have CTG expansions of 50 to several thousand repeats. The age of onset of the disorder and the severity of the phenotype is roughly correlated with the size of the CTG expansion. We developed a molecular protocol for the diagnosis of DM based on an initial polymerase chain reaction screen to detect normal-sized alleles and small expansions, followed by an improved Southern protocol to detect larger expansions.
Subject(s)
Myotonic Dystrophy/diagnosis , Myotonic Dystrophy/genetics , Adult , Aged , Alleles , Base Sequence , Blotting, Southern , DNA Probes , Female , Humans , Male , Middle Aged , Molecular Sequence Data , Pedigree , Phenotype , Polymerase Chain Reaction , Repetitive Sequences, Nucleic AcidABSTRACT
Hyperkeratosis of the palms and soles (tylosis) is an uncommon genetic disorder. A small number of English families, however, have been described in which it is associated with carcinoma of the esophagus. The current report is of the first American family described with this condition. Members of those families affected with tylosis have at least a 90% risk of esophageal carcinoma by age 65 years. The paired conditions have an autosomal dominant mode of transmission and probably are controlled at a single genetic locus. The actual pathologic state might be mediated through an increase in epidermal growth factor receptors in the abnormal tissues.
