title: Impact of Delay in Diagnosis in Outcomes in MEN1: Results From the Dutch MEN1 Study Group.
abstract: OBJECTIVE
  Identifying a germline mutation in the multiple endocrine neoplasia type 1 (MEN1) gene in an index case has consequences for a whole family. Eligible family members should be offered genetic counseling and MEN1 mutation testing. Subsequently, clinical screening of mutation carriers according to the guidelines should be initiated. We assessed whether there is a lag time from MEN1 diagnosis of the index case to MEN1 diagnosis of family members. In addition, we determined whether this lag time was associated with an increased morbidity and mortality risk.
  
  
  METHODS
  A cohort study was performed using the Dutch MEN1 database, including >90% of the Dutch MEN1 population >16 years of age (n = 393).
  
  
  RESULTS
  Fifty-eight MEN1 families were identified, of whom 57 were index cases and 247 were non-index cases (n = 304). The median lag time in MEN1 diagnosis of family members was 3.5 (range, 0-30) years. At the time of MEN1 diagnosis, 30 (12.1%) non-index cases had a duodenopancreatic neuroendocrine tumor, of whom 20% had metastases with a mean lag time of 10.9 years, in comparison with 7.1 years without metastases. Twenty-five (10.1%) non-index cases had a pituitary tumor, of whom 80% had a microadenoma and 20% had a macroadenoma, with mean lag times of 7.2 and 10.6 years, respectively. Ninety-five (38.4%) non-index cases had a primary hyperparathyroidism with a mean lag time of 9.5 years in comparison with seven patients without a primary hyperparathyroidism with a mean lag time of 3 years (P = .005). Ten non-index cases died because of a MEN1-related cause that developed during or before the lag time.
  
  
  CONCLUSIONS
  There is a clinically relevant delay in MEN1 diagnosis in families because of a lag time between the diagnosis of an index case and the rest of the family. More emphasis should be placed on the conduct of proper counseling and genetic testing in all eligible family members.
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: van Leeuwaarde
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Bernadette P M
authors.initials: BP
authors.lastname: van Nesselrooij
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Ad R
authors.initials: AR
authors.lastname: Hermus
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Olaf M
authors.initials: OM
authors.lastname: Dekkers
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Anouk N
authors.initials: AN
authors.lastname: van der Horst-Schrivers
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Madeleine L
authors.initials: ML
authors.lastname: Drent
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Bisschop
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Havekes
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Menno R
authors.initials: MR
authors.lastname: Vriens
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: de Laat
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Carolina R C
authors.initials: CR
authors.lastname: Pieterman
authors.affiliation: Departments of Endocrine Oncology (R.S.v.L., J.M.d.L., C.R.C.P., G.D.V.) and Clinical Genetics (B.P.M.v.N.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Endocrinology (A.R.H.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; Departments of Endocrinology and Metabolism and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Clinical Epidemiology (O.M.D.), Aarhus University, 8000 Aarhus, Denmark; Department of Internal Medicine (W.W.d.H.), Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Endocrinology (A.N.v.d.H.-S.), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine (M.L.D.), Section of Endocrinology, VU University Medical Center, 1081 HZ Amsterdam, The Netherlands; Department of Endocrinology and Metabolism (P.H.B.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6229 GT Maastricht, The Netherlands; and Department of Endocrine Surgery (M.R.V.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Gerlof D
authors.initials: GD
authors.lastname: Valk
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D057210:Delayed Diagnosis / Q000706:statistics & numerical data*; D005190:Family; D005260:Female; D005820:Genetic Testing / Q000706:statistics & numerical data*; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009017:Morbidity; D018761:Multiple Endocrine Neoplasia Type 1 / Q000175:diagnosis* / Q000453:epidemiology* / Q000235:genetics; D009426:Netherlands / Q000453:epidemiology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016019:Survival Analysis; D055815:Young Adult
chemical_list: C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins