Hormones and Cancer

, Volume 3, Issue 1–2, pp 44–51

Frequent Germ-Line Mutations of the MEN1, CASR, and HRPT2/CDC73 Genes in Young Patients with Clinically Non-familial Primary Hyperparathyroidism

  • Lee F. Starker
  • Tobias Åkerström
  • William D. Long
  • Alberto Delgado-Verdugo
  • Patricia Donovan
  • Robert Udelsman
  • Richard P. Lifton
  • Tobias Carling
Article

Abstract

Familial primary hyperparathyroidism (FPHPT) may occur due to an underlying germ-line mutation in the MEN1, CASR, or HRPT2/CDC73 genes. The disease may be undiagnosed in the absence of a history suggestive of FHPT. Young PHPT patients (≤45 years of age) are more likely to harbor occult FPHPT. A total of 1,161 (136 were ≤45 years of age) PHPT patients underwent parathyroidectomy from 2001 to 2009. Thirty-four patients declined participation. Sixteen patients were diagnosed in the clinical routine with FPHPT (11 MEN1, four MEN2A, and one HPT-JT) and were not included in the genetic analysis. Eighty-six young (≤45 years of age) patients with clinically non-syndromic PHPT underwent genetic analysis. Sanger sequencing of all coding regions of the MEN1, CASR, and the HRPT2/CDC73 genes was performed. Eight of 86 (9.3%) young patients with clinically non-familial PHPT displayed deleterious germ-line mutations in the susceptibility genes (4 MEN1, 3 CASR, and 1 HRPT2/CDC73). There was one insertion, one deletion, two nonsense, and four missense mutations, all predicted to be highly damaging to protein function and absent in 3,244 control chromosomes. Germ-line mutations in known susceptibility genes within young patients with PHPT, including those diagnosed in the clinical routine, was 24/102 (23.5%; 15 MEN1, four RET, three CASR, and two HRPT2/CDC73). We demonstrate that germ-line inactivating mutations in susceptibility genes are common in young patients with clinically non-familial PHPT. Thus, enhanced use of genetic analysis may be warranted in clinically non-familial young PHPT patients.

Keywords

Hyperparathyroidism MEN1 Parathyroid Familial syndromes 

Supplementary material

12672_2011_100_MOESM1_ESM.docx (173 kb)
ESM 1(DOCX 172 kb)

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Lee F. Starker
    • 1
    • 2
    • 5
  • Tobias Åkerström
    • 1
    • 2
  • William D. Long
    • 1
    • 2
  • Alberto Delgado-Verdugo
    • 2
    • 5
  • Patricia Donovan
    • 1
  • Robert Udelsman
    • 1
  • Richard P. Lifton
    • 4
  • Tobias Carling
    • 1
    • 2
    • 3
  1. 1.Department of SurgeryYale University School of MedicineNew HavenUSA
  2. 2.Yale Endocrine Neoplasia LaboratoryYale University School of MedicineNew HavenUSA
  3. 3.Cancer Genetics and Genomics Program, Yale Cancer CenterYale University School of MedicineNew HavenUSA
  4. 4.Department of GeneticsYale University School of MedicineNew HavenUSA
  5. 5.Department of Surgical SciencesUppsala UniversityUppsalaSweden

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