Endocrine Abstracts

Multiple endocrine neoplasia type 1 (MEN1) is a rare dominantly inherited neoplastic syndrome. Tipically, it affects three major locations: parathyroid, endocrine pancreas or duodenum (GEP) and anterior pituitary. MEN1 is caused by mutations in MEN1 gene and its testing is now used as a complement to clinical diagnosis which may be hindered by the variable penetrance and expression of the defects. Mutation carriers are life-long monitored, while unaffected relatives can avoid expensive and distressing clinical screening. In this study, 51 patients with either classic MEN1 or MEN1-related diseases were screened for MEN1 germline mutations by sequences analysis. The patients were referred with the following clinical classification: 11 cases with classic MEN1 (hyperparathyroidism, pituitary adenoma and GEP tumor), 20 with variant-1 (2 out 3 classic lesions), 4 with variant-2 (multiple parathyroid tumors <30 years), 2 with variant-3 (pancreatic islet tumors), 14 with variant-4 (familial isolated hyperparathyroidism, FIHP). We found MEN1 germline mutations in 5/11 classic MEN1 cases (c.213delCAGA, p.L418R, p.R420X, p.F452S, c.1521delG), 4/20 variant-1 cases (p.R420X, p.R465X, c.317insGCCCC, p.F452S), 2/4 variant-2 cases (c.207delC, c.247_250delCTGT), 3/14 variant-4 cases (p.D158E in 2 cases, c.1937insC). The mutations p.D158E, c.1521delG and p.L418R are novel, while the other mutations were previously described in MEN1 cases. The novel deletion creates a frameshift in exon 8 and premature stop codon in a classic MEN1 case with multiple pancreatic lesions, including one gastrinoma, and a lung carcinoid. In silico analyses predict deleterious effects for L418R, but not for D158E. However, this latter variant was present in 2 unrelated cases with FIHP, while L418R was found in a classic MEN1 case. In conclusion, our results confirm the mutation frequencies in the different MEN1-related clinical settings, consistent with a fundamental role of DNA testing in the management of the patients affected with either classic or variant MEN1 presentation.