title: MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients.
abstract: Multiple 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.
  
  
  
  This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population.
  
  
  
  A 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).
  
  
  
  Mutation-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.
authors.affiliation: Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: de Laat
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rob B
authors.initials: RB
authors.lastname: van der Luijt
authors.affiliation: Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Carolina R C
authors.initials: CR
authors.lastname: Pieterman
authors.affiliation: Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Oostveen
authors.affiliation: Department of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ad R
authors.initials: AR
authors.lastname: Hermus
authors.affiliation: Departments of Endocrinology and Metabolism & Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Olaf M
authors.initials: OM
authors.lastname: Dekkers
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.affiliation: Department of Endocrinology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Anouk N
authors.initials: AN
authors.lastname: van der Horst-Schrivers
authors.affiliation: Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Madeleine L
authors.initials: ML
authors.lastname: Drent
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Bisschop
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Havekes
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Menno R
authors.initials: MR
authors.lastname: Vriens
authors.affiliation: Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. G.D.Valk@umcutrecht.nl.
authors.forename: Gerlof D
authors.initials: GD
authors.lastname: Valk
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D018761:Multiple Endocrine Neoplasia Type 1 / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D009426:Netherlands / Q000453:epidemiology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins
keywords: Diagnosis; MEN1; Survival