Clinical and genetic characteristics of Multiple Endocrine Neoplasia type 1 (MEN 1) syndrome in a small cohort of Swiss patients

Multiple endocrine neoplasia type 1 (MEN1) syndrome is a polyglandular autosomal dominant transmitted disease characterized by the combined occurrence of several endocrine gland tumors. The main features of the syndrome include parathyroid (95%), enteropancreatic (40-70%), and anterior pituitary (30-40%) tumors. Tumors in MEN1 syndrome display a more aggressive behavior than sporadic tumors and are more resistant to treatment. The disease's prevalence has been estimated between 1:10'000 - 1:100'000, affecting all age groups and demonstrating a very high penetrance with clinical and biochemical manifestations having developed in respectively 80 % and more than 98 % of MEN1 patients by the fifth decade. Primary hyperparathyroidism has been shown to be the first manifestation of the syndrome amongst more than 85% of patients. MEN1, the gene responsible for the disease, is located on chromosome 11q13. It consists of 10 exons and is translated into a 610-amino acid protein named menin that behaves as a tumor suppressor in endocrine organs. Menin has an important role in cell division and proliferation, transcription, DNA replication and repair, apoptosis and genome stability. More that 450 different mutations, scattered through the whole sequence and mostly inactivating or leading to a missing or truncated protein have been described. We studied the MEN1 patients that were treated or followed-up at CHUV between 1995- 2015. The objective was to review and analyze clinical and genetic characteristics of MEN1 syndrome among these patients as well as the inter- and intra-familial variability of expression and to search for possible genotype-phenotype correlations. A large amount of data was collected for each patient and entered into a database. Epidemiological data such as age ratio, mean age at first symptoms and at diagnosis, prevalence of each tumor and proportion of patients who underwent MEN1 mutational analysis was calculated. The data was then analyzed and compared to the literature. 21 patients being part of 11 different pedigrees and 80% of whom having developed clinical, radiological or biological signs of MEN1 at the time of the study were identified. Among 17 out of 21 patients displaying signs or symptoms of MEN1, 82% were affected by primary hyperparathyroidism, 76% had enteropancreatic NET, 18% pituitary tumors and 47% extended spectrum tumors, such as lipomas, carcinoids or adrenal tumors. Mutations of the MEN1 gene were found in only four out of eleven pedigrees and consisted of two large deletions, one missense and one nonsense. Mutational analysis was either not performed or not documented in the other pedigrees. Pedigree 1 being well documented, particularly interesting and displaying some unusual features, we focused our research and analysis on it. We report here the case of the proband, a 40 years old patient with a metastatic pituitary carcinoma, and his family. Several patients whose records were reviewed had benefited from a suboptimal care with no genetic testing being made and what seemed to be an insufficient screening and follow- up. We recommend that MEN1 patients should be identified and gathered in qualified centers. Follow-up should be coordinated by an endocrinologist with expertise in the subject