Genetic Abnormalities in Primary Hyperparathyroidism (PHPT)

  • Numerous genetic abnormalities have been identified in the development of PHPT, including:
    • Anomalies in tumor suppressor genes
    • Proto-oncogenes
  • Specific DNA mutations in a parathyroid cell:
    • May confer a proliferative advantage over normal neighboring cells:
      • Thus allowing for clonal growth:
        • Large populations of these altered cells containing the same mutation within hyperfunctioning parathyroid tissue:
          • Suggest that such glands are a result of clonal expansion
  • The majority of PHPT cases are:
    • Sporadic
  • Nonetheless, PHPT also occurs within the spectrum of a number of inherited disorders such as:
    • Multiple endocrine neoplasia syndromes (MEN):
      • MEN type 1 (Wermer Syndrome)
      • MEN type 2A (Sipple Syndrome)
      • Isolated familial HPT
      • Familial HPT with jaw-tumor syndrome
        • All of these syndromes are inherited in an:
          • Autosomal dominant fashion
  • MEN type 1 (Wermer Syndrome):
    • The earliest and most common presentation of MEN type 1 is:
      • PHPT:
        • Develops in approximately 80% to 100% of patients:
          • By age 40 years
    • These patients also are predisposed to the development of:
      • Pancreatic neuroendocrine tumors
      • Pituitary adenomas
      • Less frequently:
        • Skin angiomas
        • Lipomas
        • Adrenocortical tumors
        • Neuroendocrine tumors of the:
          • Thymus
          • Bronchus
          • Stomach
    • MEN type 1 has been shown to result from:
      • A germline mutation in a tumor suppressor gene:
        • Called MEN1 gene:
          • Located on chromosome 11q12-13:
            • That encodes Menin:
              • A protein that is postulated to interact with the transcription factors JunD and nuclear factor-κB in the nucleus, in addition to replication protein A and other proteins
    • Pre-symptomatic screening for mutation carriers for MEN type 1 is difficult:
      • Because generally MEN1 mutations result in a nonfunctional protein and are scattered throughout the translated nine exons of the gene
    • MEN1 mutations also have been found in kindred’s initially suspected to represent isolated familial HPT
    • Screening for mutation carriers for MEN type 1:
      • Has a very high detection rate:
        • Greater than 94%
      • In Sweden it is used for patients with PHPT with a first-degree relative with a:
        • Major endocrine tumor
        • Age of onset is less than 30 years and/or
        • If multiple pancreatic tumors / parathyroid hyperplasia is detected
  • MEN type 2A (Sipple Syndrome):
    • Approximately 20% of patients with MEN type 2A develop PHPT:
      • Which is usually less severe
    • MEN type 2A is caused by a:
      • Germline mutation of the RET proto-oncogene:
        • Located on chromosome 10
      • Genotype and phenotype correlations have been noted in this syndrome:
        • In that individuals with mutations at:
          • Codon 634 are more likely to develop PHPT
  • Patients with the familial HPT with jaw-tumor syndrome:
    • Have an increased predisposition to:
      • Parathyroid carcinoma
    • This syndrome maps to a tumor suppressor locus:
      • HRPT2 (parafibromin):
        • On chromosome 1
  • Sporadic parathyroid adenomas and some hyperplastic parathyroid glands:
    • Have loss of heterozygosity (LOH) at 11q13:
      • The site of the MEN1 gene:
        • In approximately 25% to 40% of the cases
  • Over expression of PRAD1:
    • Which encodes cyclin D1:
      • A cell cycle control protein:
        • Is found approximately 18% of parathyroid adenomas
    • This was proven to result from a rearrangement on chromosome 11:
      • That places the PRAD1 gene under the control of the PTH promoter
  • Other chromosomal regions deleted in parathyroid adenomas and possibly reflecting loss of tumor suppressor genes include:
    • 1p, 6q, and 15q
  • Amplified regions suggesting oncogenes have been identified at:
    • 16p and 19p
  • RET mutations:
    • Are unusual in sporadic parathyroid tumors
  • Sporadic parathyroid cancers:
    • Are characterized by uniform loss of the:
      • Tumor suppressor gene RB
        • Which is involved in cell cycle regulation
    • 60% have HRPT2 (CDC73) mutations
    • These alterations are rare in benign parathyroid tumors:
      • May have implications for diagnosis
    • The p53 tumor suppressor gene is also inactivated in a subset (30%) of parathyroid carcinomas

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #PHPT #HeadandNeckSurgeon #CASO #CenterforAdvancedSurgicalOncology #EndocrineSurgery

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