Interpretive Handbook

The extracellular G-protein-coupled calcium sensing receptor (CASR) is an essential component of calcium homeostasis. CASR is expressed at particularly high levels in the parathyroid glands and kidneys. It forms stable homodimeric cell-membrane complexes, which signal upon binding of extracellular calcium-ions (Ca[++]). In the parathyroid glands, this results in downregulation of gene expression of the main short-term regulator of calcium homeostasis, parathyroid hormone (PTH), as well as diminished secretion of already synthesized PTH. At the same time, renal calcium excretion is upregulated and sodium-chloride excretion is downregulated. Ca(++) binding to CASR is highly cooperative within the physiological Ca(++) concentration range, leading to a steep dose-response curve, which results in tight control of serum calcium levels.

To date over 100 different alterations in the CASR gene have been described. Many of these cause diseases of abnormal serum calcium regulation. Inactivating mutations result in undersensing of Ca(++) concentrations and consequent PTH overproduction and secretion. This leads to either familial hypocalciuric hypercalcemia (FHH) or neonatal severe primary hyperparathyroidism (NSPHT), depending on the severity of the functional impairment.

Except for a very small percentage of cases with no apparent CASR mutations, FHH is due to heterozygous inactivating CASR mutations. Serum calcium levels are mildly-to-moderately elevated. PTH is within the reference range or modestly elevated, phosphate is normal or slightly low, and urinary calcium excretion is low for the degree of hypercalcemia. Unlike patients with primary hyperparathyroidism (PHT), which can be difficult to distinguish from FHH, the majority of FHH patients do not seem to suffer any adverse long-term effects from hypercalcemia and elevated PTH levels. They should therefore generally not undergo parathyroidectomy.

NSPHT is usually due to homozygous or compound heterozygous inactivating CASR mutations, but can occasionally be caused by dominant-negative heterozygous mutations. The condition presents at birth, or shortly thereafter, with severe hypercalcemia requiring urgent parathyroidectomy.

Activating mutations lead to oversensing of Ca(++), resulting in suppression of PTH secretion and consequently hypoparathyroidism. All activating mutations described are functionally dominant and disease inheritance is therefore autosomal dominant. However, sporadic cases also occur. Autosomal dominant hypoparathyroidism may account for many cases of idiopathic hypoparathyroidism. Disease severity depends on the degree of gain of function, spanning the spectrum from mild hypoparathyroidism, which is diagnosed incidentally, to severe and early onset disease. In addition, while the majority of patients suffer only from hypoparathyroidism, a small subgroup with extreme gain of function mutations suffer from concomitant inhibition of renal sodium-chloride transport. These individuals may present with additional symptoms of hypokalemic metabolic alkalosis, hyperreninemia, hyperaldosteronism, and hypomagnesemia, consistent with type V Bartter's syndrome.

Confirming or ruling out a suspected diagnosis of familial hypocalciuric hypercalcemia in family members of affected individuals with known mutations

Confirming or ruling out a suspected diagnosis of neonatal severe primary hyperparathyroidism in family members of affected individuals with known mutations

Confirming or ruling out a suspected diagnosis of autosomal dominant hypoparathyroidism in family members of affected individuals with known mutations

Once a mutation is identified in an affected family member, predictive testing is then available for at-risk relatives. Presence of the known mutation(s) in family members of affected individuals essentially confirms familial hypocalciuric hypercalcemia (FHH), neonatal severe primary hyperparathyroidism (NSPHT), or autosomal dominant hypoparathyroidism (ADH), respectively.

If a mutation has been identified in an affected family member, the absence of it in another family member essentially excludes FHH, NSPHT, or ADH, respectively.

The identification of a disease-causing mutation in an affected family member is necessary before predictive testing for other family members can be offered. If a familial mutation has not been previously identified, order CSRMS/83703 Calcium Sensing Receptor (CASR) Gene, Mutation Screen.

Analysis is performed for the familial mutation(s) provided only. This assay does not rule out the presence of other mutations within this gene or within other genes that may be associated with familial hypocalciuric hypercalcemia (FHH), neonatal severe primary hyperparathyroidism (NSPHT), or autosomal dominant hypoparathyroidism (ADH).

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Any error in the diagnosis or in the pedigree provided to us, including false-paternity, could lead to an erroneous interpretation of results.

A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

An interpretive report will be provided.

1. Hendy GN, D'Souza-Li L, Yang B, et al: Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hypocalciuric hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 2000 Oct;16(4):281-296. The authors maintain a CASR polymorphism/mutation database: http://www.casrdb.mcgill.ca/

2. Lienhardt A, Bai M, Lgarde JP, et al: Activating mutations of the calcium-sensing receptor: management of hypocalcemia. J Clin Endocrinol Metab 2001 Nov;86(1):5313-5323

3. Hu J, Spiegel AM: Naturally occurring mutations of the extracellular Ca2+ -sensing receptor: implications for its structure and function. Trends Endocrinol Metab 2003 Aug;14(6):282-288

4. Naesens M, Steels P, Verberckmoes R, et al: Bartter's and Gitelman's syndromes: from gene to clinic. Nephron Physiol 2004;96(3):65-78

5. Egbuna OI, Brown EM: Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol 2008;22:129-148