Molecular and clinico-pathological features of two families with the HNPCC syndrome and unusual phenotypes

We present the clinical and pathological features of 2 families with inherited predispositions to colorectal cancer. Both pedigrees fulfil the 'Amsterdam criteria' for the clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC), but both also have family members with unusual phenotypes. In one family (OX1), some individuals have developed colonic juvenile polyps; in the other family (SMTO), one individual has developed the sebaceous adenomas of Muir-Torre syndrome and another has developed multiple gastrointestinal (GI) polyps more typical of a variant of familial adenomatous polyposis. A germ-line HNPCC gene (hMLHl) mutation has been identified in family SMTO and the individual with multiple polyps may also have an uncharacterised germ-line hMSH2 mutation. In family OX1, no HNPCC mutation has been identified, but 2/2 colorectal cancers showed microsatellite instability, a finding which makes the diagnosis of HNPCC very likely. No germ-line APC mutations were found in either family. In pedigree OX1, the co-occurrence of juvenile polyposis and HNPCC is probably coincidental, The reason for the multiple polyps in the individual from pedigree SMTO is, however, unclear: this phenotype may have been influenced by the germ-line HNPCC mutation(s), or may result from independent genetic or environmental factors. These two pedigrees show that the families that present to the specialist GI surgeon and attend cancer genetics clinics may be highly selected, with more than one type of inherited predisposition to GI cancer. Such families require special screening protocols, such as regular upper-GI endoscopy in addition to colonoscopy. Unless the possibility of more than one disease is recognised, diagnostic and predictive genetic testing in these families may identify some mutation carriers, but may falsely reassure other family members.