Familial isolated primary hyperparathyroidism (FIHP)

(OMIM phenotype number #145000)

Familial isolated primary hyperparathyroidism (FIHP) is characterized by primary hyperparathyroidism not associated with other features. FIHP is essentially a diagnosis of exclusion. The clinical picture is characterized by familial primary hyperparathyroidism in the absence of clinical, radiological or biochemical features for diagnoses of MEN 1, MEN2A, HPT-JT, or FHH. The incidence is approximately 1% of all cases of primary hyperparathyroidism.
It has been described individuals affected by FIHP with a germline CDC73 pathogenic variant, presenting a more severe clinical presentation and younger age of onset than individuals with FIHP without CDC73 pathogenic variant. In most cases, these subjects with FIHP have at least one family member with a histopathologic diagnosis of parathyroid carcinoma and/or had a parathyroid adenoma with atypical or cystic features.
In approximately 20% of subjects with FIHP, MEN1 germline pathogenic variants have been described (see also MEN), and in 14%-18% of individuals with FIHP, heterozygous CASR pathogenic variants have also been reported.
Histologically, FIHP manifests itself as parathyroid chief cell hyperplasia, single and multiple gland adenoma as well as parathyroid carcinoma.

Genes

  • MEN1 gene, 11q13.1 (OMIM gene/locus number #613733).
  • CaSR gene, 3q21.1 (OMIM gene/locus number #601199).
  • HRPT2 (CDC73) gene, 1q31.2 (OMIM gene/locus number #607393).

Phenotype

Endocrine disorder resulting from a persistent hypercalcemia supported by an inadequate secretion of PTH. Systemic signs: renal (polyuria, hypercalciuria, nephrolithiasis) skeletal, neuromuscular (myopathy, chondrocalcinosis, arthritis), central nervous system (fatigue, cognitive changes), gastrointestinal (peptic ulcer, pancreatitis), cardiovascular (hypertension, reduction QT interval), bone-specific signs: osteoporosis with a reduction of bone mineral density mainly of the cortical bone, osteitis fibrosa cystica in severe cases (subperiostal resorption of the phalange, salt and pepper appearance of the skull, bone cysts, brown tumors of the long bones).

Main biochemical alterations

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

References

  1. Warner J, Epstein M, Sweet A, et al. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J Med Genet. 2004 Mar;41(3):155-60.
  2. 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.
  3. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  4. http://www.omim.org