MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients

Abstract

BackgroundMultiple Endocrine Neoplasia type 1 (MEN1) is diagnosed when two out of the three primary MEN1-associated endocrine tumors occur in a patient. Up to 10–30 % of those patients have no mutation in the MEN1 gene. It is unclear if the phenotype and course of the disease of mutation-negative patients is comparable with mutation-positive patients and if these patients have true MEN1. The present study aims to describe and compare the clinical course of MEN1 mutation-negative patients with two out of the three main MEN1 manifestations and mutation-positive patients during long-term follow-up.MethodsThis is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population.ResultsA total of 293 (90.7 %) mutation-positive and 30 (9.3 %) mutation-negative MEN1 patients were included. Median age of developing the first main MEN1 manifestation was higher in mutation-negative patients (46 vs. 33 years) (P = 0.007). Mutation-negative patients did not develop a third main MEN1 manifestation in the course of follow-up compared to 48.3 % of mutation-positive patients (P < 0.001). Median survival in mutation-positive patients was estimated at 73.0 years (95 % CI, 69.5–76.5) compared to 87.0 years (95 % CI not available) in mutation-negative patients (P = 0.001).ConclusionsMutation-positive and mutation-negative MEN1 patients have a different phenotype and clinical course. Mutation-negative patients develop MEN1 manifestations at higher age and have a life expectancy comparable with the general population. The apparent differences in clinical course suggest that MEN1 mutation-negative patients do not have true MEN1, but another MEN1-like syndrome or sporadic co-incidence of two neuro-endocrine tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0708-1) contains supplementary material, which is available to authorized users.

The future: surgical advances in MEN1 therapeutic approaches and management strategies

“…This association was described for the first time in 1972 by Rosai and coworkers based on three case reports (Rosai et al 1972). TNETs-MEN1 are characterized by genotype-phenotype correlations with MEN1 mutations, strong heritability and a poor outcome with frequent recurrences and a higher risk of death (Goudet et al 2009, Thevenon et al 2015, de Laat et al 2016.…”

Parathyroid adenoma, pituitary macroadenoma and raised gastrin levels in a patient with negative genetic testing for Multiple Endocrine Neoplasia Type 1: a mere coincidence?

“…This monitoring has a cost burden and can cause considerable anxiety. Consensus guidelines support annual screening for relatives of MEN1 phenocopies, however its clinical value remains up for debate 1,2 .…”

“…• MEN1 involves tumour development in two or more endocrine glands associated with the syndrome, in a single patient (see Table 1) [1][2][3] .…”

The future: medical advances in MEN1 therapeutic approaches and management strategies

“…Nowadays, in approximately 90% of patients, a germline mutation of the MEN1 gene located on chromosome 11q13 is found (Machens et al 2007, Goudet et al 2011, Ito et al 2013, de Laat et al 2016. Early identification of MEN1 in patients enables presymptomatic screening of manifestations, which makes timely interventions possible with the intention to prevent morbidity and mortality (van Leeuwaarde et al 2016).…”