Endocrine Abstracts (2004) 7 OC28

Biochemical and genetic screening in isolated and familial MEN1

S Lee1, E Roper2, R Kirk3, H Howie2, A Doane1, O Quarrell2, BJ Harrison4 & RJM Ross1

1Department of Endocrinology, Sheffield Teaching Hospitals, Sheffield, UK; 2Department of Clinical Genetics, Sheffield Children's Hospital, Sheffield, UK; 3North Trent Molecular Genetics Service, Sheffield Children's Hospital, Sheffield, UK; 4Department of Surgery, Sheffield Teaching Hospitals, Sheffield, UK.

Background: Multiple endocrine neoplasia type 1 (MEN1) is an inherited cancer syndrome characterized by the development of tumours in at least two of the following three main sites: parathyroid, pituitary and endocrine pancreas. Hyperparathyroidism is the most common presenting feature, with a typical age at onset of 20-25 years, and > 90% penetrance by 40 years. After extended family studies, an index case may have no affected relatives and be apparently 'isolated'. We report our experience of 13 MEN1 families, in particular highlighting the differences between the 5 isolated and 8 familial cases. Methods: All index cases had molecular analysis of their MEN1 gene performed by direct DNA sequencing of the entire protein-coding region of the gene (exons 2-9 and 10 part A). Biochemical screening was undertaken in all consenting first degree relatives, aged over 8 years. Results: 4 of the 5 isolated MEN1 patients were aged over 40 years at diagnosis (range 24-70y), whereas most familial patients presented during young adulthood, and all by age 40. Clinical screening confirmed the presence of MEN1 related tumour(s) in at least one relative in all familial cases. A mutation was detected in the MEN1 gene in all the familial cases. The mutations comprised frameshift mutations in exons 2, 3, 9 and 10, and, in 2 families, a splice-site mutation at the exon 9/intron 9 boundary. No mutation was found in the 5 isolated cases. Conclusion: Patients presenting with features of MEN1 after the age of 40, with no family history of MEN1, are unlikely to have an easily identifiable mutation in the MEN1 gene. Such isolated cases may have a de novo mutation in the MEN1 gene undetectable by our screening method, be mosaic for the mutation or represent an MEN1 phenocopy.

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