Endocrine Abstracts

Background: Multiple Endocrine Neoplasia (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreas and pituitary. Recent consensus guidelines have recommended screening of MEN1 gene mutations in patients who have at least two of the parathyroid hyperplasia, pancreatic endocrine tumour or pituitary adenoma, or are suspicious of having MEN1 (multiple parathyroid tumours before age 30, recurrent hyperparathyroidism, gastrinoma or multiple islet cell tumours at any age, and familial isolated hyperparathyroidism). We examined the appropriateness of these clinical criteria in the largest reported clinical series. Methods: We performed direct DNA sequencing of the coding regions of the MEN1 gene in 186 probands. We also screened for gross deletions in the gene in 59 probands, who met the clinical criteria for MEN1 but did not show mutation on sequencing, using Multiplex Ligation-dependent Probe Amplification (MLPA). Results: Mutations were identified in 68 (37%) probands by sequencing, including 29 novel mutations. The likelihood of finding a mutation was correlated with the number of MEN1-related tumours (mutation detection rate 79%, 37%, 15% in probands with 3, 2 and 1 main MEN1-related tumours; p= <0.00001) and increased in the presence of a family history (mutation detection rate 91%, 69%, 29% vs. 69%, 23%, 0% in sporadic cases with 3, 2 or 1 main MEN1-related tumours; p= <0.00001). MLPA analysis showed a deletion of exon 10 in one proband. Overall, 83% probands met the proposed clinical criteria for diagnostic mutation testing. The pick up rate was 42% in these probands, compared to 0% in those who did not meet the proposed criteria. Conclusion: This large series supports present referral criteria for diagnostic mutation screening, but suggests that patients with sporadic isolated tumours rarely have MEN1 mutations. Gross deletions of the MEN1 gene are a rare cause of MEN1 in the UK.