Clinical, genetic, and histopathologic investigation of CDC73-related familial hyperparathyroidism

Endocr Relat Cancer. 2008 Dec;15(4):1115-26. doi: 10.1677/ERC-08-0066. Epub 2008 Aug 28.

Abstract

CDC73 (HRPT2) germline mutations are responsible for more than half of cases of hyperparathyroidism-jaw tumor syndrome (HPT-JT) and for a subset of familial isolated HPT (FIHP). We performed a clinical, genetic, and histopathologic study in three unrelated Italian kindreds with HPT-JT and FIHP. We identified three germline inactivating mutations of the CDC73 gene in the probands and affected patients of the three kindreds, but also in some asymptomatic subjects. HPT-JT and FIHP patients had similar laboratory, clinical, and demographic features and shared primary HPT and other neoplasms, the most common of which was uterine polyposis. Genetic analysis of tumor samples demonstrated a second somatic CDC73 mutation only in a parathyroid adenoma and no cases with the loss of the wild-type allele or methylation of the CDC73 promoter, even though immunohistochemical analysis demonstrated the loss of nuclear parafibromin expression in all tumors, including a uterine polyp. In conclusion, our results indicate that FIHP and HPT-JT associated with CDC73 mutations do not have distinct clinical, genetic, and histopathologic features, but may represent variants of the same genetic disease. This study also confirms that uterine involvement represents a clinical manifestation of the syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • DNA Methylation
  • DNA Mutational Analysis
  • Female
  • Genotype
  • Humans
  • Hyperparathyroidism, Primary / genetics*
  • Hyperparathyroidism, Primary / pathology
  • Immunoenzyme Techniques
  • Jaw Neoplasms / genetics*
  • Jaw Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Neoplastic Syndromes, Hereditary / genetics*
  • Neoplastic Syndromes, Hereditary / pathology
  • Parathyroid Neoplasms / genetics*
  • Parathyroid Neoplasms / pathology
  • Pedigree
  • Promoter Regions, Genetic
  • Syndrome
  • Tumor Suppressor Proteins / genetics*
  • Uterine Neoplasms / genetics
  • Uterine Neoplasms / pathology
  • Young Adult

Substances

  • CDC73 protein, human
  • Tumor Suppressor Proteins