title: Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism.
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.
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Lee F
authors.initials: LF
authors.lastname: Starker
authors.forename: Tobias
authors.initials: T
authors.lastname: Akerström
authors.forename: William D
authors.initials: WD
authors.lastname: Long
authors.forename: Alberto
authors.initials: A
authors.lastname: Delgado-Verdugo
authors.forename: Patricia
authors.initials: P
authors.lastname: Donovan
authors.forename: Robert
authors.initials: R
authors.lastname: Udelsman
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.forename: Tobias
authors.initials: T
authors.lastname: Carling
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000235:genetics* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C095550:CASR protein, human; C454900:CDC73 protein, human; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D044169:Receptors, Calcium-Sensing; D025521:Tumor Suppressor Proteins