title: Nontruncated amino-terminal parathyroid hormone overproduction in two patients with parathyroid carcinoma: a possible link to HRPT2 gene inactivation.
abstract: OBJECTIVE
  Some patients with parathyroid carcinoma present with an over-production of nontruncated amino-terminal (NT-N) parathyroid hormone (PTH), a post-transcriptionally modified form of PTH(1-84). This is usually picked up on an elevated whole (W) PTH (third-generation)/total (T) (second-generation) PTH assay ratio (N > 0·8).
  
  
  METHODS
  Two parathyroid cancer patients with several episodes of hypercalcaemia and multiple surgeries are described. In both patients, W-PTH, T-PTH and circulating PTH molecular forms separated by high-pressure liquid chromatography (HPLC) were measured with the same assays. qPCR was used to study HRPT2 gene mutation.
  
  
  RESULTS
  The first patient had total calcium of 3·8 and 3·22 mmol/l before the fourth and fifth surgeries, and third/second-generation PTH ratios of 2·95 and 3·6, respectively. After the fourth surgery, the ratio remained normal for 1 year and increased progressively to 3·6 over 15 months. This preceded hypercalcaemia by 6 months. The ratio became normal after the fifth surgery. HPLC analysis disclosed an over-expression of NT-N PTH to 82·2% (N < 10%) relative to hPTH(1-84) before the fifth surgery. A deletion of all the tested exons of the HRPT2 gene was identified. In the second patient, W-PTH/T-PTH ratio was 0·89 when serum calcium was 3·3 mmol/l. NT-N PTH was also over-expressed at 51·9%. An inactivating mutation of the HRPT2 gene was also identified.
  
  
  CONCLUSIONS
  This may suggest that a progressive rise in third/second-generation ratio may have possible clinical utility to monitor parathyroid cancer recurrence. A possible association between NT-N PTH overproduction and HRPT2 gene inactivation is also suggested.
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Centre Hospitalier Universitaire Larrey, Toulouse Cedex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Caron
authors.forename: William F
authors.initials: WF
authors.lastname: Simonds
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Maiza
authors.forename: Mishaela
authors.initials: M
authors.lastname: Rubin
authors.forename: Tom
authors.initials: T
authors.lastname: Cantor
authors.forename: Louise
authors.initials: L
authors.lastname: Rousseau
authors.forename: John P
authors.initials: JP
authors.lastname: Bilezikian
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Souberbielle
authors.forename: Pierre
authors.initials: P
authors.lastname: D'Amour
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D006801:Humans; D006934:Hypercalcemia / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010281:Parathyroid Hormone / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D010282:Parathyroid Neoplasms / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C454900:CDC73 protein, human; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D025521:Tumor Suppressor Proteins; C040288:amino-terminal parathyroid hormone