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      Calcimimetic Use in Familial Hypocalciuric Hypercalcemia—A Perspective in Endocrinology

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      1 ,
      The Journal of Clinical Endocrinology and Metabolism
      Endocrine Society

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          Abstract

          Context:

          Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia that even persists after subtotal parathyroidectomy. Symptoms are usually mild. Past recommendations have often been for monitoring and against surgical or pharmacologic treatments.

          Methods:

          Review of publications about FHH, calcium-sensing receptors (CaSRs), and calcimimetics.

          Results:

          FHH reflects heterozygous germline mutation of CASR, GNA11, or AP2S1. These mutations inactivate the CaSRs in the parathyroid cell. Thereby, they shift the serum calcium set point to higher values and cause hypercalcemia. Calcimimetic drugs enhance the effects of calcium on the CaSRs and thereby inhibit the parathyroid cell. Calcimimetic drugs are indicated in adults with primary hyperparathyroidism without a good surgical option. Calcimimetic safety and efficacy are not established in children younger than age 18 years. Recent case reports have described treatment of FHH with calcimimetics. Success was classified as combinations of subjective improvements and decreases of serum calcium levels, but not necessarily into the normal range. Treatment was successful in 14 of 16 cases (88%).

          Conclusion:

          Deductions based on these case reports have limitations. For example, failures of therapy may not have been reported. Cost of the drug might be rate limiting. Calcimimetics can be offered to adults with FHH and those in whom the serum calcium level is >0.25 mM (1 mg/dL) beyond the upper limit of normal or with possible symptoms of hypercalcemia. Calcimimetics can now be offered to more adults with FHH.

          Abstract

          Treatment with a calcimimetic was successful in 14 of 16 reported cases of FHH. Calcimimetics can be used in more cases of FHH.

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          Most cited references21

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          Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid.

          Maintenance of a stable internal environment within complex organisms requires specialized cells that sense changes in the extracellular concentration of specific ions (such as Ca2+). Although the molecular nature of such ion sensors is unknown, parathyroid cells possess a cell surface Ca(2+)-sensing mechanism that also recognizes trivalent and polyvalent cations (such as neomycin) and couples by changes in phosphoinositide turnover and cytosolic Ca2+ to regulation of parathyroid hormone secretion. The latter restores normocalcaemia by acting on kidney and bone. We now report the cloning of complementary DNA encoding an extracellular Ca(2+)-sensing receptor from bovine parathyroid with pharmacological and functional properties nearly identical to those of the native receptor. The novel approximately 120K receptor shares limited similarity with the metabotropic glutamate receptors and features a large extracellular domain, containing clusters of acidic amino-acid residues possibly involved in calcium binding, coupled to a seven-membrane-spanning domain like those in the G-protein-coupled receptor superfamily.
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            Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis

            The extracellular calcium (Ca2+ o)-sensing receptor (CaSR) is a family C G protein-coupled receptor, which detects alterations in Ca2+ o concentrations and modulates parathyroid hormone secretion and urinary calcium excretion. The central role of the CaSR in Ca2+ o homeostasis has been highlighted by the identification of mutations affecting the CASR gene on chromosome 3q21.1. Loss-of-function CASR mutations cause familial hypocalciuric hypercalcaemia (FHH), whereas gain-of-function mutations lead to autosomal dominant hypocalcaemia (ADH). However, CASR mutations are only detected in ≤70% of FHH and ADH cases, referred to as FHH type 1 and ADH type 1, respectively, and studies in other FHH and ADH kindreds have revealed these disorders to be genetically heterogeneous. Thus, loss- and gain-of-function mutations of the GNA11 gene on chromosome 19p13.3, which encodes the G-protein α-11 (Gα11) subunit, lead to FHH type 2 and ADH type 2, respectively; whilst loss-of-function mutations of AP2S1 on chromosome 19q13.3, which encodes the adaptor-related protein complex 2 sigma (AP2σ) subunit, cause FHH type 3. These studies have demonstrated Gα11 to be a key mediator of downstream CaSR signal transduction, and also revealed a role for AP2σ, which is involved in clathrin-mediated endocytosis, in CaSR signalling and trafficking. Moreover, FHH type 3 has been demonstrated to represent a more severe FHH variant that may lead to symptomatic hypercalcaemia, low bone mineral density and cognitive dysfunction. In addition, calcimimetic and calcilytic drugs, which are positive and negative CaSR allosteric modulators, respectively, have been shown to be of potential benefit for these FHH and ADH disorders.
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              Deficiency of the calcium-sensing receptor in the kidney causes parathyroid hormone-independent hypocalciuria.

              Rare loss-of-function mutations in the calcium-sensing receptor (Casr) gene lead to decreased urinary calcium excretion in the context of parathyroid hormone (PTH)-dependent hypercalcemia, but the role of Casr in the kidney is unknown. Using animals expressing Cre recombinase driven by the Six2 promoter, we generated mice that appeared grossly normal but had undetectable levels of Casr mRNA and protein in the kidney. Baseline serum calcium, phosphorus, magnesium, and PTH levels were similar to control mice. When challenged with dietary calcium supplementation, however, these mice had significantly lower urinary calcium excretion than controls (urinary calcium to creatinine, 0.31±0.03 versus 0.63±0.14; P=0.001). Western blot analysis on whole-kidney lysates suggested an approximately four-fold increase in activated Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). In addition, experimental animals exhibited significant downregulation of Claudin14, a negative regulator of paracellular cation permeability in the thick ascending limb, and small but significant upregulation of Claudin16, a positive regulator of paracellular cation permeability. Taken together, these data suggest that renal Casr regulates calcium reabsorption in the thick ascending limb, independent of any change in PTH, by increasing the lumen-positive driving force for paracellular Ca(2+) transport.
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                Author and article information

                Journal
                J Clin Endocrinol Metab
                J. Clin. Endocrinol. Metab
                jcem
                jcem
                The Journal of Clinical Endocrinology and Metabolism
                Endocrine Society (Washington, DC )
                0021-972X
                1945-7197
                01 November 2017
                18 September 2017
                : 102
                : 11
                : 3933-3936
                Affiliations
                [1 ]Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892
                Author notes
                Correspondence and Reprint Requests:  Stephen J. Marx, MD, 5402 Trent Street, Chevy Chase, Maryland 20815. E-mail: Stephen1.Marx1@ 123456gmail.com .
                Article
                jcem_201701606
                10.1210/jc.2017-01606
                5673268
                28945857
                04a98195-3bb4-4d1b-91a3-698e1f4a2cf5
                History
                : 17 July 2017
                : 13 September 2017
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 31, Pages: 4
                Categories
                Perspectives in Endocrinology

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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