Familial hypocalciuric hypercalcemia (HHC)

Type I

Familial hypocalciuric hypercalcemia type I (HHC1) (OMIM phenotype number #145980)

Type II

Familial hypocalciuric hypercalcemia type II (HHC2) (OMIM phenotype number #145981)

Type III

Familial hypocalciuric hypercalcemia type III (HHC3) (OMIM phenotype number #600740)

Familial hypocalciuric hypercalcemia (HHC) is a benign condition associated with hypercalcemia, low urinary calcium excretion (assessed via a calcium/creatinine clearance ratio), normal to minimally elevated PTH levels, and hypermagnesemia.
HHC is usually asymptomatic but in some cases: fatigue, weakness, excessive thirst and concentration problems have been reported. Some adults present also pancreatitis, chondrocalcinosis and premature vascular calcification.
Usually, this condition does not require specific therapy, and responds poorly to parathyroidectomy.
HCC is a genetically heterogeneous disorder with three variants: types 1, 2, and 3.
In adult subjects, inactivating mutations of CaSR gene have been described in HHC type I (65% of cases), autosomal dominant disease, resulting in a reduction in the sensitivity of parathyroid and renal cells to calcium levels so hypercalcemia is perceived as normal.
HHC type II is caused by heterozygous mutation, with loss of function in the GNA11 gene, encoding G-protein subunit α11 (Gα11), involved in calcium-sensing receptor signaling.
HHC type III is caused by heterozygous mutation in the AP2S1 gene, which results in altered calcium-sensing receptor endocytosis.

Genes

  • CaSR gene, 3q21.1 (OMIM gene/locus number #601199).
  • GNA11 gene, 19p13.3 (OMIM gene/locus number #139313).
  • AP2S1 gene, 19q13.32 (OMIM gene/locus number #602242).

Phenotype

Usually asymptomatic, rare bone involvement, pancreatitis and chondrocalcinosis.

Main biochemical alterations

High Ca, low Ur Ca, CaCl/CrCl<0.01, high Mg, normal/high normal PTH.

References

  1. Aida K, Koishi S, Inoue M, et al. Familial hypocalciuric hypercalcemia associated with mutation in the human Ca(2+)-sensing receptor gene. J Clin Endocrinol Metab. 1995 Sep;80(9):2594-8.
  2. Nesbit MA, Hannan FM, Howles SA, et al. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N Engl J Med. 2013 Jun 27;368(26):2476-86.
  3. Nesbit MA, Hannan FM, Howles SA, et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet. 2013 Jan;45(1):93-7.
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Nov;26(11):2717-8.
  5. http://www.omim.org