Endocrine Abstracts

JOINT3889

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumor syndrome primarily associated with an increased risk of primary hyperparathyroidism (PHP), pituitary adenomas, and pancreatic-duodenal neuroendocrine tumors (DP-NET). Until now, no genotype-phenotype has been identified.

Materials and Methods: Consecutive patients with class 4 or 5 mutations followed at Rigshospitalet, Copenhagen (covering half of the Danish MEN1 population), were included. The aim of the study was to describe the clinical presentation and possible association to genotype using survival statistics with log-rank test. We focused on 5 outcomes; age at diagnosis of the 3 main MEN1 manifestation and age of surgery for PHP and DP-NET.

Results: The study included 96 patients (61 females). Mean age at data extraction was 45 ±22 years, mean age at genetic diagnosis was 33 ±19 years. Seventy-seven (80%) had PHP, 10% by age 20, 70% by age 40, 90% by age 60, and 100% by age 80. Sixty-one (79%) underwent parathyroidectomy. Pituitary adenomas were identified in 25 (26%) of patients, 5% at age 20, 20% at age 40, 30% at age 60, and 50% at age 80. Three patients had pituitary surgery. DP-NET were present in 67 (70%) patients, 5% at age 20, 35% at age 40, 75% at age 60, and 95% at age 80. Seventeen (25%) underwent pancreatic surgery. Nine patients died (3 MEN1 related), mean age 74 (range 49 to 93) years. Genetic variants: Frameshift 36/95, missense 24/95, nonsense 19/94, intron variant 11/95, splice variant 4/95, structural variant 1/95 (deletion exon 3-10). The variants were initially grouped in 3: 1) nonsense, frameshift and deletion (truncated protein) 2) missense (affecting protein function), 3) intron and splice variants (abnormal splicing). We found no significant genotype-phenotype, but the result of the initial analyses prompted us to compare missense variants with the rest. For all outcomes missense variants had a better prognosis with the lowest P-value for development of PHP and for surgery for DP-NET. By the age of 40 around 50% of patients with missense mutations had PHP vs. 80% among the rest (P = 0.03) and non with missense variants had surgery for DP-NET at the age of 40 vs. 20% among the rest (P = 0.07)

Conclusion: We confirmed almost 100% penetrans of both PHP and DP-NET. The prognosis was good with a life expectancy close to the background population. Our data suggest that missense variants might be associated with a slightly better prognosis.