Article

Hormones and Cancer

, Volume 3, Issue 1, pp 44-51

First online:

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

  • Lee F. StarkerAffiliated withDepartment of Surgery, Yale University School of MedicineYale Endocrine Neoplasia Laboratory, Yale University School of MedicineDepartment of Surgical Sciences, Uppsala University
  • , Tobias ÅkerströmAffiliated withDepartment of Surgery, Yale University School of MedicineYale Endocrine Neoplasia Laboratory, Yale University School of Medicine
  • , William D. LongAffiliated withDepartment of Surgery, Yale University School of MedicineYale Endocrine Neoplasia Laboratory, Yale University School of Medicine
  • , Alberto Delgado-VerdugoAffiliated withYale Endocrine Neoplasia Laboratory, Yale University School of MedicineDepartment of Surgical Sciences, Uppsala University
  • , Patricia DonovanAffiliated withDepartment of Surgery, Yale University School of Medicine
  • , Robert UdelsmanAffiliated withDepartment of Surgery, Yale University School of Medicine
  • , Richard P. LiftonAffiliated withDepartment of Genetics, Yale University School of Medicine
  • , Tobias CarlingAffiliated withDepartment of Surgery, Yale University School of MedicineYale Endocrine Neoplasia Laboratory, Yale University School of MedicineCancer Genetics and Genomics Program, Yale Cancer Center, Yale University School of Medicine Email author 

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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