MOLECULAR AND CLINICOPATHOLOGICAL FEATURES OF 2 FAMILIES WITH THE HNPCC SYNDROME AND UNUSUAL PHENOTYPES

We present the clinical and pathological features of 2 families with i nherited predispositions to colorectal cancer, Both pedigrees fulfil t he 'Amsterdam criteria' for the clinical diagnosis of hereditary non-p olyposis colorectal cancer (HNPCC), but both also have family members with unusual phenotypes. In one family (OX1), some individuals have de veloped colonic juvenile polyps; in the other family (SMTO), one indiv idual has developed the sebaceous adenomas of Muir-Torre syndrome and another has developed multiple gastrointestinal (GI) polyps more typic al of a variant of familial adenomatous polyposis. A germ-line HNPCC g ene (hMLH1) mutation has been identified in family SMTO and the indivi dual with multiple polyps may also have an uncharacterised germ-line h MSH2 mutation. In family OX1, no HNPCC mutation has been identified, b ut 2/2 colorectal cancers showed microsatellite instability, a finding which makes the diagnosis of HNPCC very likely. No germ-line APC muta tions were found in either family. In pedigree OX1, the co-occurrence of juvenile polyposis and HNPCC is probably coincidental, The reason f or the multiple polyps in the individual from pedigree SMTO is, howeve r, unclear: this phenotype may have been influenced by the germ-line H NPCC mutation(s), or may result from independent genetic or environmen tal factors. These two pedigrees show that the families that present t o the specialist GI surgeon and attend cancer genetics clinics may be highly selected, with more than one type of inherited predisposition t o GI cancer, Such families require special screening protocols, such a s regular upper-GI endoscopy in addition to colonoscopy. Unless the po ssibility of more than one disease is recognised, diagnostic and predi ctive genetic testing in these families may identify some mutation car riers, but map falsely reassure other family members.