Clinical features of multiple endocrine neoplasia type 1 (MEN1) phenocopy without germline MEN1 gene mutations: analysis of 20 Japanese sporadic cases with MEN1

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is a familial tumour syndrome of endocrine tumours involving parathyroids, anterior pituitary and enteropancreatic neuroendocrine tissues, and is inherited in an autosomal dominant manner with high penetrance. Recently, the gene responsible for this syndrome, MEN1, was positionally cloned from chromosome 11q13. PATIENTS: To characterize sporadic MEN1 patients, we analysed the MEN1 gene by direct sequencing of the entire open reading frame from 20 individuals. RESULTS: We identified heterozygous germline mutations of the MEN1 gene in 8 of 20 (40%) cases. Seven were novel MEN1 germline mutations. Three mutations were splicing abnormalities, and all were confirmed to be splicing defects by RT-PCR. The clinical significance of detecting germline MEN1 mutations, not only in familial MEN1 but also in sporadic MEN1, was confirmed by the finding of asymptomatic mutant carriers among family members of the sporadic MEN1 patients. Seven of 8 cases with MEN1 mutations had enteropancreatic lesions in contrast to 4 of 12 (P < 0.018) in those cases with no mutation. Ten of the 12 cases without MEN1 mutation were more than 50-year-old. Six of these 10 cases had the same clinical features; primary hyperparathyroidism and a GH-secreting pituitary tumour. CONCLUSIONS: It is likely that the six cases without mutations were MEN1 phenocopies due to (i) two kinds of tumours with high natural incidence in older subjects developed by chance (ii) another familial tumour syndrome with low penetrance, e. g. familial acromegaly with primary hyperparathyroidism by mutation of another gene, or (iii) somatic mutation during early embryonic stages.