Hereditary hyperparathyroidism jaw-tumor syndrome (HPT-JT)

(OMIM phenotype number #145001)

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare, autosomal-dominant disease, secondary to germline-inactivating mutations of the tumor suppressor gene CDC73 (prevalence unknown). This diseases is characterized by benign and malignant parathyroid tumours, ossifying jaw tumours, various cystic and neoplastic renal abnormalities and benign and malignant uterine tumours. Primary hyperparathyroidism is the main finding of HPT-JT syndrome (up to 95% of individuals with HPT-JT). HPT-JT-associated primary hyperparathyroidism is often caused by a single benign parathyroid adenoma, and a second parathyroid tumor may occur after appearance of the first tumor. In 10%-15% of cases, primary hyperparathyroidism is caused by parathyroid carcinoma, and non-functioning parathyroid carcinomas have also been described. The onset of primary hyperparathyroidism in HPT-JT syndrome is in late adolescence or early adulthood. Individuals affected by primary hyperparathyroidism may be asymptomatic or present nephrolithiasis, reduced bone mass, fatigue, muscle weakness, bone or joint pain, and constipation.

The surgery is the typical approach to primary hyperparathyroidism in HPT-JT syndrome. In the case of a single parathyroid tumor, it has been suggested a minimally invasive surgical approach to remove the parathyroid tumor followed by close, monitoring for recurrent primary hyperparathyroidism.

Gene

HRPT2 (CDC73) gene, 1q31.2 (OMIM gene/locus number *607393).

Phenotype

Fibro-osseous tumors of the jaw, benign and/or malignant lesions over the course of the lifetime (most common: Wilms’ tumor, papillary renal carcinoma), polycystic kidney disease.

Main biochemical alterations

High Ca, low Pi, high Ur Pi, high Ur Ca, high PTH.

Images

Fig. Immunohistochemical expression. a; Weak parafibromin immunohistochemical cytoplasmic expression, with absence of nuclear positivity (40×); b surrounding control tissue showing normal expression of the protein. 

Reproduced from Cell Oncol (Dordr), A novel CDC73 gene mutation in an Italian family with hyperparathyroidism-jaw tumour (HPT-JT) syndrome, 2014;37:281-8, Chiofalo MG, Sparaneo A, Chetta M, et al., with permission of Springer.

References

  1. Carpten JD, Robbins CM, Villablanca A, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet. 2002 Dec;32(4):676-80.
  2. Szabó J, Heath B, Hill VM, et al. Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31. Am J Hum Genet. 1995 Apr;56(4):944-50.
  3. Jackson MA, Rich TA, Hu MI, et al. CDC73-Related Disorders. Editors In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
  4. Frank-Raue K, Haag C, Schulze E, et al. CDC73-related hereditary hyperparathyroidism: five new mutations and the clinical spectrum. Eur J Endocrinol. 2011 Sep;165(3):477-83. doi: 10.1530/EJE-11-0003. Epub 2011 Jun 7.
  5. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Nov;26(11):2717-8.-
  6. http://www.omim.org