title: Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism.
abstract: BACKGROUND
  Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant syndrome with incomplete penetrance that can associate in a single patient parathyroid adenoma or carcinoma, fibro-osseous jaw tumor, cystic kidney lesion, and uterine tumor. Germline mutations of the HRPT2 gene (CDC73) coding for parafibromin are identified in approximately 50%-75% of HPT-JT cases and in approximately 14% of familial isolated hyperparathyroidism. A whole deletion of this gene has recently been reported in 1 sporadic case and in a family presenting with HPT-JT.
  
  
  OBJECTIVE
  The objective of the study was to report molecular abnormalities of the HRPT2 gene in patients with primary hyperparathyroidism in a French National cohort from the Groupe d'Étude des Tumeurs Endocrines.
  
  
  METHODS
  Patients' genomic DNA was screened by PCR-based sequencing for point mutations affecting HRPT2 and real-time quantitative PCR analysis for gross deletions.
  
  
  RESULTS
  We report 20 index patients with a germinal HRPT2 abnormality. Median age at diagnosis of primary hyperparathyroidism was 23 years (range 14-65 years). Median serum total calcium level at diagnosis was 3.19 mmol/L (range 2.8-4.3 mmol/L). Thirteen different mutations were identified by routine sequencing, including 7 mutations never reported. Seven patients (35%) carried a gross deletion of this gene (3 complete and 4 partial deletions). No genotype-phenotype correlation could be identified. A gross deletion of the HRPT2 gene was identified in 7% of patients for whom a routine screening by direct sequencing came up as negative.
  
  
  CONCLUSIONS
  Gross deletion analysis of the HRPT2 gene is indicated for all patients negative for mutation, presenting with HPT-JT or familial isolated hyperparathyroidism, parathyroid carcinoma, or in patients with apparently sporadic parathyroid adenoma diagnosed at a young age, having a severe hypercalcemia.
authors.affiliation: Faculté de Médecine, Université Pierre et Marie Curie, Paris VI, 75005 Paris, France.
authors.forename: Léopoldine
authors.initials: L
authors.lastname: Bricaire
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Odou
authors.forename: Catherine
authors.initials: C
authors.lastname: Cardot-Bauters
authors.forename: Brigitte
authors.initials: B
authors.lastname: Delemer
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: North
authors.forename: Sylvie
authors.initials: S
authors.lastname: Salenave
authors.forename: Delphine
authors.initials: D
authors.lastname: Vezzosi
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Kuhn
authors.forename: Arnaud
authors.initials: A
authors.lastname: Murat
authors.forename: Philippe
authors.initials: P
authors.lastname: Caron
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Sadoul
authors.forename: Caroline
authors.initials: C
authors.lastname: Silve
authors.forename: Philippe
authors.initials: P
authors.lastname: Chanson
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.forename: Eric
authors.initials: E
authors.lastname: Clauser
authors.forename: Nicole
authors.initials: N
authors.lastname: Porchet
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D005602:France; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C454900:CDC73 protein, human; D025521:Tumor Suppressor Proteins