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

Joanne M. de Laat, Rob B. van der Luijt, Carolina R C Pieterman, Maria P. Oostveen, Ad R. Hermus, Olaf M. Dekkers, Wouter W. de Herder, Anouk N. van der Horst-Schrivers, Madeleine L. Drent, Peter H. Bisschop, Bas Havekes, Menno R. Vriens, Gerlof D. Valk

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: 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. Methods: This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population. Results: 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). Conclusions: 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.

Original languageEnglish
Article number182
JournalBMC Medicine
Volume14
Issue number1
DOIs
Publication statusPublished - 15 Nov 2016

Cite this

de Laat, J. M., van der Luijt, R. B., Pieterman, C. R. C., Oostveen, M. P., Hermus, A. R., Dekkers, O. M., ... Valk, G. D. (2016). MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. BMC Medicine, 14(1), [182]. https://doi.org/10.1186/s12916-016-0708-1
de Laat, Joanne M. ; van der Luijt, Rob B. ; Pieterman, Carolina R C ; Oostveen, Maria P. ; Hermus, Ad R. ; Dekkers, Olaf M. ; de Herder, Wouter W. ; van der Horst-Schrivers, Anouk N. ; Drent, Madeleine L. ; Bisschop, Peter H. ; Havekes, Bas ; Vriens, Menno R. ; Valk, Gerlof D. / MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. In: BMC Medicine. 2016 ; Vol. 14, No. 1.
@article{7c2e33505d0048e992fee7a42a49e64f,
title = "MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients",
abstract = "Background: 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. Methods: This is a cohort study performed using the Dutch MEN1 database, including > 90 {\%} of the Dutch MEN1 population. Results: 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). Conclusions: 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.",
keywords = "Diagnosis, MEN1, Survival",
author = "{de Laat}, {Joanne M.} and {van der Luijt}, {Rob B.} and Pieterman, {Carolina R C} and Oostveen, {Maria P.} and Hermus, {Ad R.} and Dekkers, {Olaf M.} and {de Herder}, {Wouter W.} and {van der Horst-Schrivers}, {Anouk N.} and Drent, {Madeleine L.} and Bisschop, {Peter H.} and Bas Havekes and Vriens, {Menno R.} and Valk, {Gerlof D.}",
year = "2016",
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doi = "10.1186/s12916-016-0708-1",
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de Laat, JM, van der Luijt, RB, Pieterman, CRC, Oostveen, MP, Hermus, AR, Dekkers, OM, de Herder, WW, van der Horst-Schrivers, AN, Drent, ML, Bisschop, PH, Havekes, B, Vriens, MR & Valk, GD 2016, 'MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients' BMC Medicine, vol. 14, no. 1, 182. https://doi.org/10.1186/s12916-016-0708-1

MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. / de Laat, Joanne M.; van der Luijt, Rob B.; Pieterman, Carolina R C; Oostveen, Maria P.; Hermus, Ad R.; Dekkers, Olaf M.; de Herder, Wouter W.; van der Horst-Schrivers, Anouk N.; Drent, Madeleine L.; Bisschop, Peter H.; Havekes, Bas; Vriens, Menno R.; Valk, Gerlof D.

In: BMC Medicine, Vol. 14, No. 1, 182, 15.11.2016.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients

AU - de Laat, Joanne M.

AU - van der Luijt, Rob B.

AU - Pieterman, Carolina R C

AU - Oostveen, Maria P.

AU - Hermus, Ad R.

AU - Dekkers, Olaf M.

AU - de Herder, Wouter W.

AU - van der Horst-Schrivers, Anouk N.

AU - Drent, Madeleine L.

AU - Bisschop, Peter H.

AU - Havekes, Bas

AU - Vriens, Menno R.

AU - Valk, Gerlof D.

PY - 2016/11/15

Y1 - 2016/11/15

N2 - Background: 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. Methods: This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population. Results: 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). Conclusions: 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.

AB - Background: 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. Methods: This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population. Results: 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). Conclusions: 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.

KW - Diagnosis

KW - MEN1

KW - Survival

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U2 - 10.1186/s12916-016-0708-1

DO - 10.1186/s12916-016-0708-1

M3 - Article

VL - 14

JO - HIV Medicine

JF - HIV Medicine

SN - 1741-7015

IS - 1

M1 - 182

ER -

de Laat JM, van der Luijt RB, Pieterman CRC, Oostveen MP, Hermus AR, Dekkers OM et al. MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. BMC Medicine. 2016 Nov 15;14(1). 182. https://doi.org/10.1186/s12916-016-0708-1