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.
Highlights
Multiple Endocrine Neoplasia type 1 (MEN1) is diagnosed when two out of the three primary MEN1associated endocrine tumors occur in a patient
The other patients were all mutation-positive siblings of already known MEN1 families; 91 were pre-symptomatic at testing, and 131 patients were tested after development of the first MEN1 manifestation
We have demonstrated that these patients have a more favorable clinical course, justifying the concept that these patients might not have a true MEN1 syndrome, but a MEN1like syndrome or sporadic co-incidence of two tumors
Summary
Multiple Endocrine Neoplasia type 1 (MEN1) is diagnosed when two out of the three primary MEN1associated endocrine tumors occur in a patient. In 10–30 % of patients who were diagnosed with MEN1 based upon clinical criteria, no mutation was de Laat et al BMC Medicine (2016) 14:182 found in the MEN1 gene [4,5,6]. These so called ‘phenocopies’ are an upcoming diagnostic challenge. With an magnetic resonance imaging (MRI) scan, which is widely available, small pituitary adenomas were found in as many as 10 % of healthy volunteers [8] These numbers implicate that a large number of patients might strictly meet the clinical criteria for MEN1 because of the co-incidence of pHPT and pituitary adenoma. It is questionable whether those patients are at risk of developing other MEN1-associated tumors and will benefit from intensive lifelong screening for MEN1-related manifestations
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