Endocrine Abstracts

Aims: MEN1 is characterised by parathyroid, pituitary and pancreatic tumours in association with neoplasia of intra-thoracic endocrine tissue, adrenal glands and cutaneous manifestations. Mutations of the tumour suppressor Menin are causative and affected patients possess heterozygous germline mutations in MEN1, with acquisition of a second hit in the wild-type allele initiating tumourigenesis. Phenotype–genotype correlations can provide insights into the molecular function of Menin and help guide management and surveillance. We therefore sought to analyse patients with MEN1 presenting to a tertiary centre.

Methods: Case notes and electronic records were reviewed and those with a confirmed MEN1 phenotype were selected. Mutation loci and functional consequences were deduced using Ensembl and mutations were cross referenced with COSMIC and the Universal Mutation Database for MEN1.

Results: Of 48 patients, 41 patients had confirmed germline mutations in MEN1 identified by sequencing exons 2–10 (62%) or targeted screening (38%). One patient possessed wild-type MEN1 confirmed by multiplex ligation-dependent probe amplification. Results were pending or unavailable for six patients. Twenty-two different mutations were identified, with 10 in multiple family members. Mutations were present in exons 2, 3, 6, 7, 9 and 10 and introns 4, 6 and 9. Twenty-seven percent were missense, 27% nonsense and 36% frame-shift mutations. One mutation, Q554X in exon 10 was novel. The majority of patients developed PHPT and pituitary and pancreatic involvement were associated with mutations distributed throughout MEN1. Age of onset was variable.

Discussion: Our results reflect previous studies suggesting there are no obvious MEN1 phenotype-genotype correlations. A novel mutation, Q554X, was found in a patient with PHPT and a gastrinoma. The mutation is predicted to cause truncation at codon 554 resulting in loss of a nuclear localisation signal and C terminus which is thought to be critical for DNA binding and emphasises the importance of this region in Menin function.