ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد ایتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia

Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia
Author:
Michael Mannstadt, MD
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jun 2022. | This topic last updated: Nov 11, 2020.

INTRODUCTION — The demonstration that the rare disorder, familial hypocalciuric hypercalcemia (FHH, now called FHH1), was caused by inactivating mutations in the gene for the calcium-sensing receptor (CaSR) had two major consequences; it explained the phenotypic expression of the disease, and it initiated an ongoing effort to comprehend the normal physiologic functions of the receptor. This topic will briefly review our understanding of the function of the CaSR in the parathyroid glands and kidneys and then describe conditions caused by mutations in this gene, particularly FHH and autosomal dominant hypocalcemia (table 1). There is also increasing evidence that abnormalities of the CaSR can be an acquired defect in hyperparathyroidism and hypoparathyroidism.

FUNCTIONS OF THE CALCIUM-SENSING RECEPTOR — The calcium-sensing receptor (CaSR) is expressed in the parathyroid glands and kidneys where it plays a key role in the regulation of calcium balance [1-3]. The CaSR can detect even minor changes in the serum ionized calcium concentration. The subsequent changes in intracellular signaling lead to responses in the parathyroid glands and kidneys directed at normalizing serum calcium concentration. This receptor is also activated by magnesium and certain amino acids, inhibited by phosphate, and therefore may have a role in the cellular response to changes in other constituents of the extracellular environment [4-6]. The CaSR is also expressed in cells and tissues unrelated to calcium homeostasis, such as pancreas, airway epithelium, bone marrow, osteoclasts and osteoblasts, breast, thyroid C-cells, gastrin-secreting cells in the stomach, intestine, some areas of the brain, and others [1,2,7-11].

Parathyroid gland — The CaSR is highly expressed on the surface of the chief cells of the parathyroid glands [1,2]. It permits the parathyroid gland to sense variations in the serum calcium concentration, leading to the desired changes in parathyroid hormone (PTH) secretion. A fall in serum calcium concentration is a potent stimulus to the release of PTH (figure 1). This is an appropriate physiologic response since, via its effects to increase bone resorption, to increase the formation of calcitriol in the kidney, and to reduce renal calcium excretion, PTH acts to raise the serum calcium concentration toward normal. Chronic hypocalcemia, acting via the CaSR, has other homeostatically appropriate effects on parathyroid function, including increasing PTH gene expression and stimulating parathyroid cellular proliferation. Conversely, when serum calcium concentration is high, synthesis and secretion of PTH are inhibited. (See "Parathyroid hormone secretion and action", section on 'Biological actions of PTH'.)

There are clearly PTH-independent roles for the CaSR in maintaining the normally exquisitely tight regulation of serum calcium concentration. Mice lacking both the PTH and CaSR genes develop marked hypercalcemia in response to oral calcium loads, while those lacking only PTH can mount an effective defense against hypercalcemia via the CaSR by upregulating renal calcium excretion and calcitonin secretion [12]. In addition, polymorphisms of the CaSR may underlie some of the variability observed in the serum calcium concentrations in normal subjects [13-15], and genome-wide association studies showed that the CaSR locus is strongly associated with serum calcium and PTH concentrations in the population [16-18].

Kidney

Urine calcium excretion — The CaSR is an important regulator of urinary calcium excretion [19-23]. It explains why hypercalcemia reduces calcium and sodium transport in the loop of Henle, with an associated decrease in urinary concentrating ability. Receptors expressed on the basolateral membrane on the cells of the thick ascending limb of the loop of Henle appear to be the major site where this occurs [3,24,25].

A brief review of normal function in this segment is required to understand the mechanism by which the CaSR acts. Filtered sodium chloride enters the cells in the thick ascending limb of the loop of Henle via Na-K-2Cl cotransporters in the luminal (or apical) membrane (figure 2) [26]. Although this process is electrically neutral, most of the potassium reabsorbed by the cotransporter leaks back into the lumen to drive further inward sodium chloride transport. This movement of cationic potassium into the lumen plus the movement of reabsorbed chloride (via a chloride channel) out of the basolateral surface of the cells generates a net trans-epithelial potential difference. That is, the tubular lumen is positive with respect to the interstitial fluid and capillaries at the basolateral cell surface. The resulting lumen electropositivity drives the passive reabsorption of cations (sodium and, to a lesser degree, calcium and magnesium) via the paracellular pathway between the cells [27].

When calcium intake is increased, some of the excess calcium is absorbed, enters the systemic circulation, and slightly raises the serum calcium concentration. Suppression of PTH release with subsequent reduction in distal tubular calcium reabsorption increases calcium excretion. This appropriate change may be augmented by direct effects of hypercalcemia on the CaSR in the ascending limb of Henle's loop, which include the following sequence [3]:

Calcium binding to the receptor leads to the generation of an arachidonic acid metabolite (which may be 20-hydroxyeicosatetraenoic acid [20-HETE] [28]) that then inhibits the potassium channel in the luminal membrane [29] and the sodium-potassium ATPase pump in the basolateral membrane [30].

Inhibition of potassium recycling via the potassium channel reduces sodium chloride reabsorption via the Na-K-2Cl transporter, diminishing the generation of the lumen-positive electrical gradient and therefore passive reabsorption of calcium and magnesium.

Inhibition of the sodium pump reduces the driving force for sodium and chloride entry from the tubular fluid by the Na-K-2Cl cotransporter.

An additional action of the CaSR reduces cellular cyclic adenosine monophosphate (cAMP) levels, thereby diminishing the increase in lumen positive potential that is stimulated by PTH through activation of adenylate cyclase [31].

Another action of the CaSR is to reduce the permeability of the paracellular pathway for reabsorption of calcium and magnesium cations that is created by claudins 16 and 19 between the tubular epithelial cells of the thick ascending limb by upregulating the inhibitory claudin 14 [32,33].

Urinary concentration — There is increasing evidence that calcium-induced activation of the CaSR impairs concentrating ability. Two sites appear to be involved: first, interference with sodium chloride reabsorption in the thick ascending limb directly impairs generation of the medullary osmotic gradient that is essential for urinary concentration; second, activation of calcium-sensing receptors expressed on the luminal membrane of the cells of the inner medullary collecting duct reduces antidiuretic hormone-induced increases in water permeability [34].

Acutely, the CaSR-mediated reduction in concentrating ability allows calcium excretion to increase while minimizing the risk of crystallization of calcium salts and the resultant possibility of stone formation owing to dilution of the calcium in a larger volume of urine. Chronically, it may be responsible for the nephrogenic diabetes insipidus associated with chronic hypercalcemia (see "Clinical manifestations and causes of nephrogenic diabetes insipidus"). This action of the CaSR on urinary concentrating ability may be augmented by CaSR-mediated activation of proton secretion in the intercalated cells of the outer medullary collecting duct, which further increases the solubility of calcium salts, particularly the calcium-phosphate in mouse models [35].

Bone — The CaSR is expressed in chondrocytes, osteoblasts, osteoclast precursors, and some osteoclasts. Experiments in CaSR-knockout mice suggest that the CaSR plays a role in the embryonic development of the skeleton, postnatal bone formation, and osteoblast differentiation [36-38]. Additional studies are required to clarify further the role of the CaSR in skeletal homeostasis, including how it relates to mineral ion homeostasis.

CaSR MUTATIONS — Activating or inactivating mutations in the calcium-sensing receptor (CaSR) gene result in altered calcium sensing and therefore inappropriate parathyroid hormone (PTH) release with respect to the serum calcium concentration (table 1).

An inactivating (or loss-of-function) mutation causes familial hypocalciuric hypercalcemia (FHH1; also called familial benign hypercalcemia). The decrease in sensitivity to calcium shifts the calcium-PTH curve to the right and produces hypercalcemia since higher concentrations of calcium are required to suppress PTH release, in effect "resetting" the serum calcium concentration to a higher than normal level (figure 1). (See 'Inactivating mutations' below.)

An activating (or gain-of-function) mutation causes autosomal dominant hypocalcemia (ADH; sometimes called autosomal dominant hypoparathyroidism). The increase in sensitivity to calcium shifts the calcium-PTH curve to the left and decreases the set-point of the CaSR, so that PTH is not released at serum calcium concentrations that normally trigger PTH release, thereby causing hypocalcemia (figure 1). (See 'Activating mutations' below.)

Mutations in some residues of the CaSR can be inactivating if mutated to one specific amino acid and activating if mutated to a different one (so-called "switch" mutations) [39].

Inactivating mutations — Inactivating mutations of the CaSR gene have been reported in inherited hypercalcemic disorders, eg, FHH1 and neonatal severe primary hyperparathyroidism (NSHPT) [40-44]. The degree of hypercalcemia in these two disorders reflects a gene dose effect [41-43]. FHH heterozygotes usually have mild hypercalcemia because of partial loss of CaSR function. In contrast, most patients who are homozygous for the CaSR gene defect have more marked disease, presenting with NSHPT and hypercalcemia that is often severe (>15 mg/dL). [40,41,43,44]. In unusual cases, however, the mutation produces only mild inactivation of the receptor [45], resulting in moderate hypercalcemia in homozygotes that is more similar to that in FHH, while heterozygotes can be normocalcemic, resulting in an autosomal recessive clinical presentation of hypercalcemia [46].

These differences have been confirmed in mice lacking the CaSR gene [47]. Heterozygotes have a syndrome similar to FHH, while homozygotes have the murine equivalent of NSHPT. The number of CaSR molecules on the surface of the parathyroid glands may be a major determinant of the serum calcium concentration in normal subjects. However, some mutations exert a dominant negative action, thereby interfering with the function of the wild-type receptor in wild-type-mutant heterodimers and hypercalcemia in heterozygotes that is higher than is typically seen in FHH [48].

Familial hypocalciuric hypercalcemia — FHH is a benign cause of hypercalcemia that is characterized by autosomal dominant inheritance with high penetrance. Affected heterozygous patients typically present in childhood with the incidental discovery of mild hypercalcemia, hypocalciuria, a normal PTH level, and high-normal to frankly elevated serum magnesium levels [45,49-51]. In most cases, FHH results from inactivating mutations in the CaSR, whose gene resides on the long arm of chromosome 3 (3q21.1) [40-44]; this form of FHH is now called FHH1. In addition, a few families have been described in whom their conditions are linked to either the short arm (19p13.3) [52] or the long arm of chromosome 19 (19q13.3) [53]. The form of FHH (FHH2) arising from the short arm of chromosome 19 results from inactivating mutations in G alpha 11, one of the guanine nucleotide binding (G) proteins linking the CaSR to activation of phospholipase C, which contributes to inhibition of PTH release at elevation of extracellular calcium concentrations [54]. The form of FHH (FHH3) that is linked to the long arm of chromosome 19 results from missense mutations of adaptor-related protein complex 2, sigma 1 subunit (AP2S1) [55,56], which participates in clathrin-mediated endocytosis of G protein-coupled receptors and signal transduction. Mutations in AP2S1 decrease the sensitivity of the CaSR-expressing cells to extracellular calcium and modify the receptor's endocytosis.

Several hundred different mutations of the CaSR have been identified [51,57]. Most result in receptors that have a change in a single amino acid (missense mutation) that reduces the receptor's function or, less commonly, that produce a truncated, inactive CaSR; in both cases, the result is fewer normally functioning receptors on the parathyroid or renal cell surface [41,44,51].

The inactivating mutations of the CaSR in FHH make the parathyroid glands less sensitive to calcium. This defect means that a higher than normal serum calcium concentration is required to reduce PTH release [48,51,58]. In the kidney, this defect leads to an increase in tubular calcium and magnesium reabsorption [45,49]. The net effect is hypercalcemia, hypocalciuria, and frequently high normal levels of serum magnesium or frank hypermagnesemia. Thus, the relative insensitivity of the CaSR to calcium effectively "resets" not only parathyroid but also kidney to maintain mild to moderate hypercalcemia.

Clinical findings — In FHH, serum PTH concentrations are typically inappropriately normal or high (in approximately 20 percent of cases) in the presence of mild hypercalcemia. One cause of a frankly high serum PTH level in FHH is the presence of coexistent vitamin D deficiency [59]. Patients with FHH have few (if any) symptoms or signs of hypercalcemia (eg, constipation, polyuria, renal insufficiency, or neuropsychiatric disease), although occasional cases have exhibited pancreatitis or chondrocalcinosis [45,49,60,61]. The CaSR gene is one of several genes that, when mutated, can confer increased susceptibility to pancreatitis [62]. The usual absence of high serum PTH concentrations may contribute to the benign clinical course of FHH, as compared with primary hyperparathyroidism [45,49,60]. In the latter disorder, excess PTH is directly responsible for the bone disease that occurs in some patients. Only a handful of cases of FHH2 have been described [54,63,64] and appear to have a clinical presentation similar to that of FHH1. Individuals with FHH3 comprise 20 to 25 percent of patients thought to have FHH on clinical grounds [55], and they can have higher levels of serum calcium and lower levels of urinary calcium excretion than in FHH1 or FHH2, as well as cognitive and behavioral disorders [65,66].

Urinary calcium excretion is low in patients with FHH. The 24-hour urinary calcium excretion is typically below 200 mg/day (5 mmol/day) [45,49]. In contrast, approximately 40 percent of patients with primary hyperparathyroidism have hypercalciuria (24-hour calcium excretion above 250 mg [6.2 mmol] in women and 300 mg [7.5 mmol] in men) [67]. When evaluating patients suspected of having FHH, it is important to exclude other factors causing hypocalciuria in the setting of PTH-dependent hypercalcemia. These include vitamin D deficiency and/or very low calcium intake, mild renal insufficiency, and treatment with thiazides or lithium (both of which are hypocalciuric). (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Differential diagnosis'.)

Calculation of the Ca/Cr (calcium/creatinine) clearance ratio, which is equivalent to the fractional excretion of calcium, is felt by most authorities to be preferable to simply measuring 24-hour excretion of calcium for diagnosing FHH [45,49,51]. This ratio is calculated from the results of a 24-hour urine collection and simultaneously measured total serum calcium and creatinine concentrations, using the following formula:

 Ca/Cr clearance ratio  =  [24-hour urine Ca  x  serum Cr]  ÷  [serum Ca  x  24-hour urine Cr]

The data establishing the value of the Ca/Cr clearance ratio in differentiating FHH from primary hyperparathyroidism are based primarily on 24-hour urine collections [45,49]. While there are insufficient data available to prove that Ca/Cr ratios calculated from fasting spot urines are equivalent to those determined from 24-hour urines, in principle, the two should reflect renal calcium handling similarly.

The Ca/Cr clearance ratio is less than 0.01 in approximately 80 percent of patients with the various forms of FHH, indicating that more than 99 percent of the filtered calcium has been reabsorbed despite the presence of hypercalcemia. In patients with primary hyperparathyroidism, however, the Ca/Cr clearance ratio is most often >0.02, although in some cases, it can overlap sufficiently with the range seen in FHH to cause diagnostic confusion (see 'Distinction from primary hyperparathyroidism' below). In a study that re-evaluated the discriminative power of the Ca/Cr clearance ratio, a value of 0.0115, similar to that proposed earlier [45,49], provided optimal discrimination between FHH and primary hyperparathyroidism [68]. Other tools to discriminate the two disorders on biochemical grounds have been published (eg, [69,70]).

Distinction from primary hyperparathyroidism — It is important to distinguish asymptomatic primary hyperparathyroidism from FHH because FHH in most cases is a benign, inherited condition that typically does not require parathyroidectomy, nor will it be routinely cured by it. Although it is not difficult to differentiate patients with typical biochemical findings of either FHH or primary hyperparathyroidism, it can be challenging to differentiate patients with atypical presentations of either disease.

Hypercalcemia with "normal" serum PTH concentrations occurs in approximately 10 percent of patients with primary hyperparathyroidism, which is a much more common cause of hypercalcemia than FHH, and 15 to 20 percent of patients with FHH may have a mildly elevated PTH concentration, especially in those with FHH3 [65,66].

In addition, there may be overlap in urinary calcium excretion. In patients with primary hyperparathyroidism, the Ca/Cr clearance ratio is usually between 0.01 and 0.05 and most often >0.02. However, the Ca/Cr clearance ratio may be less than 0.01 in approximately 20 percent of patients with primary hyperparathyroidism, particularly those with concomitant vitamin D deficiency. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Serum vitamin D'.)

In contrast, affected family members in occasional FHH families are hypercalciuric [71]. As an example, in some families with what was thought by experienced clinicians to be familial isolated hyperparathyroidism or sporadic primary hyperparathyroidism, inactivating mutations of the CaSR have been identified [72,73]. In these patients, the clinical presentation is similar to that of primary hyperparathyroidism (hypercalcemia and hypercalciuria). Furthermore, in one family with an atypical presentation of FHH (including hypercalciuria and even renal stone disease), which was confirmed by mutational analysis to be due to an inactivating mutation in the CaSR, subtotal parathyroidectomy was effective in reversing the biochemical abnormalities [74]. It should be emphasized, however, that parathyroidectomy is neither desirable nor curative in most typical cases of FHH. (See "Pathogenesis and etiology of primary hyperparathyroidism", section on 'Familial hyperparathyroidism'.)

Establishing the diagnosis of FHH biochemically is more difficult in these atypical patients. Mutational analysis of the CaSR and, in some cases, of G alpha 11 (GNA11) and AP2S1, may be of benefit in distinguishing FHH from primary hyperparathyroidism in the following clinical settings [68]:

Families with familial isolated hyperparathyroidism

Patients with overlap in the Ca/Cr clearance ratio, namely between 0.01 and 0.02

Patients with the phenotype of FHH whose parents are both normocalcemic (ie, FHH1 possibly caused by a de novo CaSR mutation)

Atypical cases where no family members are available for testing

Infants or children under 10 years of age in whom NSHPT, neonatal hyperparathyroidism (NHPT, a milder condition described below), and FHH are the most common causes of PTH-dependent hypercalcemia

This genetic test of the CaSR gene is by no means infallible. As many as one-third of families with FHH linked to chromosome 3 do not have a detectable mutation within the coding region of the gene or its intron-exon boundaries. Some of these cases may harbor mutations in regulatory regions of the gene affecting its level of expression or be caused by FHH2, FHH3, or some as-yet-undiscovered form(s) of FHH.

Genetic testing by mutational analysis is also available for the two more recently discovered forms of FHH, FHH2 and FHH3. In FHH3, most mutations reside in codon 15 of APS2S1, simplifying the initial genetic screening for this form of FHH. However, mutations in other residues in AP2S1 have been identified [56], potentially impacting this approach. Given the relative frequency of FHH (FHH1 and FHH3 more common than FHH2), it has been suggested that sequencing of the CaSR and AP2S1 genes (perhaps only codon 15 of the latter) should be performed first and sequencing of GNA11 only carried out if the other two genes are unrevealing for pathogenic mutations [75]. Single-gene testing might be replaced by gene panels, exome sequencing, or other next-generation testing modalities [76]. There is no firm consensus, however, in this regard, and the discovery of additional cases of FHH2 and FHH3 will be useful in refining the diagnostic approach to the three forms of FHH (and perhaps others yet to be identified) [66].

In most circumstances, the diagnosis of FHH, particularly its distinction from primary hyperparathyroidism, is primarily based upon the absence of symptoms, as well as laboratory findings typical of FHH in the proband (PTH-dependent, hypocalciuric hypercalcemia). A history of familial hypercalcemia with hypocalciuria, sometimes with previously unsuccessful parathyroid surgery, in other affected family members, including young children, is helpful in diagnosing FHH. Even if the family history is reportedly negative, this does not rule out familial involvement in this typically asymptomatic condition, and serum and urinary calcium determination should be performed in several first-degree relatives, if possible. Penetrance is high, and typical findings in the proband, combined with family screening that yields biochemical findings characteristic of FHH, is often the most reliable method of confirming the diagnosis. In most cases, however, mutational analysis is being carried out and provides the definitive diagnosis assuming the mutation, if identified, is pathogenic and not simply a polymorphism.

The laboratory findings that help to distinguish FHH from primary hyperparathyroidism are also discussed in more detail elsewhere. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Familial hypocalciuric hypercalcemia' and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Urinary calcium excretion'.)

Course and management — Because of the usually benign natural history of FHH and because subtotal parathyroidectomy does not cure the disorder, the great majority of these patients should not undergo neck exploration or any other aggressive intervention [45,49-51,61]. Affected family members should be identified and counseled on the benign nature of this condition and, consequently, the importance of avoiding parathyroid surgery, sometimes undertaken because of a mistaken diagnosis of primary hyperparathyroidism.

While typically ineffective in curing hypercalcemia in FHH, subtotal parathyroidectomy may be appropriate in occasional kindreds with atypical features (pancreatitis, hypercalciuria, and/or overt hyperparathyroidism) [74,77]. Rare patients with FHH develop a parathyroid adenoma and benefit from removal of the parathyroid tumor, which reduces serum calcium concentration but only to the level presumed to be present prior to development of the adenoma [78].

The natural histories of FHH2 and FHH3 are yet to be studied in detail. Cinacalcet, by sensitizing the CaSR to calcium, can reduce or normalize the serum calcium concentration in approximately three-quarters of patients with all three forms of FHH [79]. It may, therefore, represent a potentially useful medical treatment of FHH in cases, for example, with unusually high serum calcium concentrations (eg, FHH3) who might otherwise be considered for surgery, or as a therapeutic trial to investigate whether symptoms that could result from hypercalcemia are improved by cinacalcet-induced lowering of serum calcium concentration toward normal. (See 'Calcimimetics and calcilytics' below.)

Neonatal severe hyperparathyroidism — NSHPT is usually caused by a homozygous inactivating mutation in the CaSR gene [40,41,43,44], although a compound heterozygote harboring a different mutation from each parent has been described [80]. It is most commonly an autosomal recessive condition. A milder condition has also been described, termed neonatal hyperparathyroidism (NHPT), that is usually caused by inherited or de novo heterozygous inactivating mutations of the CaSR [44,48,81]. In some cases, NHPT may be the result of the mutant receptor exerting a dominant negative action on its wild-type partner, thereby leading to a greater elevation in set-point for PTH secretion and, as a consequence, more severe hypercalcemia [48]. Such cases may revert to the clinical and biochemical picture of FHH if managed medically with careful monitoring.

Infants who are homozygous for the CaSR defect present with NSHPT (serum PTH concentrations as much as 10-fold higher than normal), usually severe hypercalcemia (serum calcium concentration often above 15 mg/dL [3.75 mmol/L]), and relative hypocalciuria [40-43,51,82,83]. Rachitic changes often occur, and bone radiographs may reveal marked demineralization and subperiosteal resorption with multiple fractures. This disorder can be fatal without immediate parathyroidectomy, although case reports have described the use of pamidronate and cinacalcet as a "rescue" therapy to stabilize infants with NSHPT prior to surgery or after failed surgery [84,85].

Activating mutations — An activating (or gain-of-function) mutation of the CaSR gene shifts the calcium-PTH curve to the left and decreases the set-point of the CaSR, so that PTH is not released at serum calcium concentrations that normally trigger PTH release, thereby causing hypocalcemia (figure 1 and table 1).

The first form of autosomal dominant hypocalcemia identified (ADH; sometimes called autosomal dominant hypoparathyroidism), which is termed ADH1, is caused by an activating mutation in the CaSR [51,86,87]. Another genetic cause of ADH, termed ADH2, has been identified in families with activating mutations in G alpha 11 [54,88,89]. As a result, a low serum calcium concentration is perceived as normal, leading to a downward resetting of the PTH-calcium relationship [58]. In patients with ADH, serum PTH concentrations are low or inappropriately normal despite the presence of mild to moderate and occasionally severe hypocalcemia. In contrast to other causes of hypocalcemia, urinary calcium excretion is normal or frankly high in the untreated state, presumably due to increased activation of the CaSR in the kidney. (See 'Kidney' above.)

Some patients also have potassium wasting, hypokalemia, and metabolic alkalosis, creating a phenotype similar to Bartter syndrome [90,91]. These patients appear to have a more marked gain-of-function in the CaSR than those without hypokalemia. The presumed mechanism, as described above, is that activation of the CaSR inhibits the outer medullary luminal potassium channel, thereby diminishing potassium reabsorption [3,29]. Bartter syndrome is reviewed separately. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)

Autosomal dominant hypocalcemia — ADH is commonly caused by an activating mutation of the CaSR gene (ADH type 1) [51,86,87,92-99]. Most reported mutations occur in the extracellular domain of the CaSR, although some occur in the transmembrane domain [51,83,92,93]. As noted earlier, so-called "switch" mutations can cause FHH or ADH depending on the residues to which the wild-type residue is mutated [39]. In addition to point mutations, a large 181 amino acid deletion from the carboxyl terminal tail of the CaSR has been reported in a French family [96]. This is not invariably true, however, as an ADH family has recently been described with an autosomal recessive pattern of inheritance [100]. Interestingly, a homozygous member of the family had a similar phenotype to heterozygous individuals, implying that one mutated allele is enough to cause a maximal shift of calcium sensitivity [96]. Sporadic de novo mutations in the CaSR have also been identified [97,98]. Such patients are often labeled as having idiopathic hypoparathyroidism, unless their CaSR gene is subjected to mutational analysis. The second, rare form of ADH is caused by gain-of-function mutations in GNA11, the gene encoding G alpha 11, a key mediator of CASR signaling (ADH type 2) [54,89].

These findings have been confirmed in mouse models of activating mutations in the CaSR [101,102] and GNA11 [103,104].

Clinical manifestations — The majority of patients with ADH are asymptomatic and therefore are not diagnosed until adulthood, when hypocalcemia is incidentally noted. A few patients, however, have symptomatic hypocalcemia [51]. Children in particular may become symptomatic with seizures and neuromuscular irritability during periods of stress, such as a febrile illness, and may be mislabeled as having febrile seizures. Two reports found that affected members of families with ADH2 have short stature [105,106].

The biochemical features are as follows:

Serum calcium concentration usually in the range of 6 to 8 mg/dL (1.5 to 2.0 mmol/L), but as low as 5 mg/dL in occasional families

Normal (or low but clearly measurable) serum PTH concentrations

High or high normal urinary calcium excretion rather than the expected low excretion in the presence of hypocalcemia

Recurrent nephrolithiasis and nephrocalcinosis, particularly during treatment with vitamin D and calcium supplementation

No previous normal serum calcium values

Low serum magnesium concentration (in some)

The usual biochemical tests do not reliably discriminate this disorder from other forms of PTH-deficient hypoparathyroidism [51,107,108]. In addition to the features listed above, the major clinical clue to this syndrome is its familial nature and the tendency of patients to develop renal complications during treatment with calcium and vitamin D supplementation [77,107]. The diagnosis can be confirmed by analysis for mutations in the CaSR gene [77,83], or if necessary, in the G alpha 11 gene.

Treatment — Once the diagnosis is established, attempts to raise the serum calcium concentration should be considered only in patients who are symptomatic, and they should only be treated to the point where symptoms disappear [77,96,107,108]. In addition to the lack of need for therapy in asymptomatic patients, there is a high potential for adverse effects from raising the serum calcium with calcium and vitamin D supplementation. As the serum calcium concentration increases, the activating mutation in the CaSR in the loop of Henle will lead to a marked increase in urinary calcium excretion, which can cause renal stones, nephrocalcinosis, and renal insufficiency [77,107]. A similar phenomenon occurs in hypoparathyroidism (although usually to a lesser degree), in which lack of the calcium-conserving effect of PTH results in hypercalciuria well before normocalcemia is achieved. (See "Hypoparathyroidism", section on 'Preventing hypercalciuria'.)

Patients with ADH requiring therapy can be treated with cautious calcium and vitamin D supplementation with monitoring of urinary calcium excretion [77,96,107,108]. A possible adjunct in patients who remain symptomatic despite hypercalciuria is to give a thiazide diuretic to reduce urinary calcium excretion and raise the serum calcium concentration. This approach, which has been effective in patients with hypoparathyroidism, has been successfully used in rare cases of hypercalciuric hypocalcemia due to sporadic activating mutations of the CaSR [109]. (See "Hypoparathyroidism", section on 'Preventing hypercalciuria'.)

The administration of recombinant PTH, which is available for the treatment of hypoparathyroidism unrelated to CaSR mutations, holds promise as a treatment for patients with ADH and refractory hypercalciuria. In clinical trials that included patients with ADH, recombinant PTH increased serum calcium while maintaining a normal level of urinary calcium excretion [110]. The treatment of hypoparathyroidism with recombinant human PTH is reviewed elsewhere. (See "Hypoparathyroidism", section on 'Recombinant human PTH'.)

Alternatively, calcilytics, a class of drugs in development that inhibit the CaSR, may provide a useful therapeutic approach in the future by blocking the calciuric action of elevating serum calcium on the distal tubule. (See 'Calcimimetics and calcilytics' below.)

ACQUIRED DISORDERS OF THE CALCIUM-SENSING RECEPTOR — There is increasing recognition of acquired changes in the calcium-sensing receptor (CaSR) in patients with hyperparathyroidism and hypoparathyroidism. The following observations illustrate the range of findings:

Hyperparathyroidism

Expression of the CaSR protein is commonly reduced in adenomas from patients with primary hyperparathyroidism [111,112] and/or severe secondary or so-called "tertiary" (eg, hypercalcemic) hyperparathyroidism due to chronic kidney disease [112]. Although the pathogenetic importance of this change is uncertain, it would make parathyroid hormone (PTH) secretion less responsive to suppression by calcium, as occurs in familial hypocalciuric hypercalcemia (FHH).

Some patients have antibodies that inactivate the CaSR, resulting in acquired hypocalciuric hypercalcemia [113-115]. Some of them have a history of multiple autoimmune disorders. Hypercalcemia and elevated PTH levels may respond to corticosteroids in occasional patients with this condition. (See 'Familial hypocalciuric hypercalcemia' above.)

Hypoparathyroidism

Occasional patients with apparently sporadic idiopathic hypoparathyroidism have an activating mutation of the CaSR [77,97,98]. The hypocalcemia in these cases ranges from mild to severe. (See 'Autosomal dominant hypocalcemia' above.)

Autoimmune hypoparathyroidism is a common feature of polyglandular autoimmune syndrome type I, which is a familial disorder (see "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 1'). In several studies of patients with hypoparathyroidism, autoantibodies directed at the CaSR's extracellular domain have been identified [116-120]. In two such studies, the anti-CaSR antibodies in patients with autoimmune hypoparathyroidism activated the CaSR in vitro, presumably inhibiting PTH secretion and producing hypoparathyroidism in vivo by this mechanism [116,121]. In one of these studies, the anti-CaSR antibodies were apparently not cytotoxic to parathyroid cells in vivo, since the hypoparathyroidism remitted spontaneously in one patient, while a histologically normal parathyroid gland was identified in the other at the time of thyroidectomy long after the onset of the hypoparathyroidism [116].

CALCIMIMETICS AND CALCILYTICS — Calcium-sensing receptor (CaSR) modulators that function as agonists (calcimimetics) or antagonists (calcilytics) are in development for the treatment of select disorders of calcium and parathyroid hormone (PTH) regulation [122,123].

Calcimimetics – One calcimimetic agent (cinacalcet) is approved in the United States for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease receiving dialysis, for the treatment of hypercalcemia in patients with parathyroid carcinoma, and for the treatment of severe hypercalcemia in patients with primary hyperparathyroidism unable to undergo parathyroidectomy. It has also been approved for use in other forms of primary hyperparathyroidism in Europe. In mild primary hyperparathyroidism, the calcimimetic cinacalcet has been shown to normalize the serum calcium concentration in approximately three-quarters of the patients receiving it. (See "Parathyroid carcinoma", section on 'Calcimimetics' and "Management of secondary hyperparathyroidism in adult dialysis patients", section on 'Calcimimetics' and "Primary hyperparathyroidism: Management", section on 'Calcimimetics'.)

The orally active calcimimetic agent, cinacalcet, like other drugs of this class, modulates the CaSR by sensitizing it to activation by calcium, such that PTH secretion is reduced, thereby effectively lowering serum calcium concentration. Although not approved for other indications, calcimimetics may prove useful in the treatment of neonatal severe primary hyperparathyroidism (NSHPT), familial hypocalciuric hypercalcemia (FHH) [124,125], and additional forms of PTH-dependent hypercalcemia other than primary hyperparathyroidism, such as tertiary or lithium-induced hyperparathyroidism. In addition to demonstrating utility in reducing serum calcium concentration in patients with FHH1, cinacalcet has shown efficacy in cases of FHH2 [63] and FHH3 [126]. Calcimimetics might be useful, for example, in FHH patients with symptoms suggestive of hypercalcemia or hyperparathyroidism to assess their impact on such symptoms as a diagnostic and/or therapeutic trial. In the occasional FHH1 patients with unusually severe biochemical findings or in FHH3 patients, who might otherwise be considered for surgery, calcimimetic therapy might be a useful alternative to parathyroid surgery [79]. An injectable calcimimetics, etelcalcetide, has recently been approved for use in patients with severe hyperparathyroidism receiving dialysis treatment for renal insufficiency [127]. It is long-acting and has the advantage of being administered only at the time of dialysis. (See "Management of secondary hyperparathyroidism in adult dialysis patients", section on 'Calcimimetics'.)

Calcilytics – Oral CaSR antagonists (calcilytics) were initially developed for the treatment of osteoporosis [128]. Administration leads to a transient rise in endogenous PTH [129], but three different calcilytics failed in clinical trials because of a lack in efficacy [130].

Calcilytics likely will have a role in the treatment of autosomal dominant hypocalcemia (ADH) and in some patients with autoimmune hypoparathyroidism caused by activating CaSR antibodies. By inhibiting the action of calcium on the CaSR, calcilytics can reset the abnormally low set-point of the CaSR in the parathyroid and kidney in these two conditions. In fact, in naturally occurring and engineered mouse models of ADH1 [131] and ADH2 [103], administration of a calcilytic (NPS2143) substantially raised the serum calcium concentration toward normal. A calcilytic could be particularly useful in ADH as it would be predicted to "reset" the abnormal calcium sensing in both parathyroid and kidney. A calcilytic suitable for this application, however, is not yet available for human use. A clinical trial showed safety and dose-dependent increase in PTH in patients with ADH1 [132].

SUMMARY AND RECOMMENDATIONS

The calcium-sensing receptor (CaSR) senses small changes in the serum ionized calcium concentration. In response to these changes, the CaSR allows functional changes in the parathyroid glands and kidneys, which are directed at normalizing serum calcium concentrations. (See 'Functions of the calcium-sensing receptor' above.)

Inactivating mutations of the CaSR cause familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism (NSHPT), a milder form of neonatal hyperparathyroidism (NHPT), and occasionally familial isolated hyperparathyroidism. Inactivating mutations of G alpha 11 or AP2S1 cause a similar clinical picture. (See 'Inactivating mutations' above.)

In most cases of FHH, parathyroid surgery is neither curative nor appropriate, although in the uncommon cases with atypical features, such as pancreatitis, hypercalciuria, and/or overt hyperparathyroidism, subtotal parathyroidectomy has in some cases corrected these clinical and biochemical abnormalities. In NSHPT due to homozygous inactivating CaSR mutations, total parathyroidectomy is usually the therapy of choice. Treatment of these patients prior to surgery with a bisphosphonate or cinacalcet may be helpful in stabilizing them medically. (See 'Course and management' above and 'Neonatal severe hyperparathyroidism' above.)

Activating mutations of the CaSR or of G alpha 11 cause autosomal dominant hypocalcemia (ADH) and a form of ADH with features of Bartter syndrome. (See 'Activating mutations' above.)

Autoimmune activation of the CaSR can cause autoimmune hypoparathyroidism, whereas blocking antibodies can cause autoimmune hypocalciuric hypercalcemia. (See 'Acquired disorders of the calcium-sensing receptor' above.)

The CaSR activator cinacalcet, a calcimimetic, is already in clinical use for various forms of hyperparathyroidism. Calcimimetics and calcilytics (CaSR antagonists) also hold promise for pharmacologically improving defective calcium sensing in the various forms of FHH and ADH, respectively, as well as in other inherited or acquired disorders of the CaSR.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Edward M Brown, MD, who contributed to earlier versions of this topic review.

  1. Brown EM, Hebert SC. Calcium-receptor-regulated parathyroid and renal function. Bone 1997; 20:303.
  2. Brown EM, Hebert SC. A cloned extracellular Ca(2+)-sensing receptor: molecular mediator of the actions of extracellular Ca2+ on parathyroid and kidney cells? Kidney Int 1996; 49:1042.
  3. Hebert SC. Extracellular calcium-sensing receptor: implications for calcium and magnesium handling in the kidney. Kidney Int 1996; 50:2129.
  4. Tfelt-Hansen J, Brown EM. The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 2005; 42:35.
  5. Hofer AM, Curci S, Doble MA, et al. Intercellular communication mediated by the extracellular calcium-sensing receptor. Nat Cell Biol 2000; 2:392.
  6. Centeno PP, Herberger A, Mun HC, et al. Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion. Nat Commun 2019; 10:4693.
  7. Cheng I, Klingensmith ME, Chattopadhyay N, et al. Identification and localization of the extracellular calcium-sensing receptor in human breast. J Clin Endocrinol Metab 1998; 83:703.
  8. Ray JM, Squires PE, Curtis SB, et al. Expression of the calcium-sensing receptor on human antral gastrin cells in culture. J Clin Invest 1997; 99:2328.
  9. Kameda T, Mano H, Yamada Y, et al. Calcium-sensing receptor in mature osteoclasts, which are bone resorbing cells. Biochem Biophys Res Commun 1998; 245:419.
  10. Hebert SC, Cheng S, Geibel J. Functions and roles of the extracellular Ca2+-sensing receptor in the gastrointestinal tract. Cell Calcium 2004; 35:239.
  11. Geibel J, Sritharan K, Geibel R, et al. Calcium-sensing receptor abrogates secretagogue- induced increases in intestinal net fluid secretion by enhancing cyclic nucleotide destruction. Proc Natl Acad Sci U S A 2006; 103:9390.
  12. Kantham L, Quinn SJ, Egbuna OI, et al. The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion. Am J Physiol Endocrinol Metab 2009; 297:E915.
  13. Cole DE, Peltekova VD, Rubin LA, et al. A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations. Lancet 1999; 353:112.
  14. Cole DE, Vieth R, Trang HM, et al. Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene. Mol Genet Metab 2001; 72:168.
  15. Scillitani A, Guarnieri V, De Geronimo S, et al. Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor. J Clin Endocrinol Metab 2004; 89:5634.
  16. Kapur K, Johnson T, Beckmann ND, et al. Genome-wide meta-analysis for serum calcium identifies significantly associated SNPs near the calcium-sensing receptor (CASR) gene. PLoS Genet 2010; 6:e1001035.
  17. O'Seaghdha CM, Wu H, Yang Q, et al. Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. PLoS Genet 2013; 9:e1003796.
  18. Robinson-Cohen C, Lutsey PL, Kleber ME, et al. Genetic Variants Associated with Circulating Parathyroid Hormone. J Am Soc Nephrol 2017; 28:1553.
  19. Kos CH, Karaplis AC, Peng JB, et al. The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. J Clin Invest 2003; 111:1021.
  20. Tu Q, Pi M, Karsenty G, et al. Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. J Clin Invest 2003; 111:1029.
  21. Houillier P, Paillard M. Calcium-sensing receptor and renal cation handling. Nephrol Dial Transplant 2003; 18:2467.
  22. Frick KK, Bushinsky DA. Molecular mechanisms of primary hypercalciuria. J Am Soc Nephrol 2003; 14:1082.
  23. Gambaro G, Vezzoli G, Casari G, et al. Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am J Kidney Dis 2004; 44:963.
  24. Riccardi D, Lee WS, Lee K, et al. Localization of the extracellular Ca(2+)-sensing receptor and PTH/PTHrP receptor in rat kidney. Am J Physiol 1996; 271:F951.
  25. Hebert SC. Calcium and salinity sensing by the thick ascending limb: a journey from mammals to fish and back again. Kidney Int Suppl 2004; :S28.
  26. Haas M. The Na-K-Cl cotransporters. Am J Physiol 1994; 267:C869.
  27. Friedman PA, Gesek FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181.
  28. Amlal H, Legoff C, Vernimmen C, et al. Na(+)-K+(NH4+)-2Cl- cotransport in medullary thick ascending limb: control by PKA, PKC, and 20-HETE. Am J Physiol 1996; 271:C455.
  29. Wang WH, Lu M, Hebert SC. Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL. Am J Physiol 1996; 271:C103.
  30. Schwartzman M, Ferreri NR, Carroll MA, et al. Renal cytochrome P450-related arachidonate metabolite inhibits (Na+ + K+)ATPase. Nature 1985; 314:620.
  31. de Jesus Ferreira MC, Héliès-Toussaint C, Imbert-Teboul M, et al. Co-expression of a Ca2+-inhibitable adenylyl cyclase and of a Ca2+-sensing receptor in the cortical thick ascending limb cell of the rat kidney. Inhibition of hormone-dependent cAMP accumulation by extracellular Ca2+. J Biol Chem 1998; 273:15192.
  32. Gong Y, Renigunta V, Himmerkus N, et al. Claudin-14 regulates renal Ca⁺⁺ transport in response to CaSR signalling via a novel microRNA pathway. EMBO J 2012; 31:1999.
  33. Sato T, Courbebaisse M, Ide N, et al. Parathyroid hormone controls paracellular Ca2+ transport in the thick ascending limb by regulating the tight-junction protein Claudin14. Proc Natl Acad Sci U S A 2017; 114:E3344.
  34. Sands JM, Naruse M, Baum M, et al. Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. J Clin Invest 1997; 99:1399.
  35. Renkema KY, Velic A, Dijkman HB, et al. The calcium-sensing receptor promotes urinary acidification to prevent nephrolithiasis. J Am Soc Nephrol 2009; 20:1705.
  36. Yamaguchi T, Sugimoto T. [Impaired bone mineralization in calcium-sensing receptor (CaSR) knockout mice : the physiological action of CaSR in bone microenvironments]. Clin Calcium 2007; 17:1567.
  37. Brown EM, Lian JB. New insights in bone biology: unmasking skeletal effects of the extracellular calcium-sensing receptor. Sci Signal 2008; 1:pe40.
  38. Chang W, Tu C, Chen TH, et al. The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development. Sci Signal 2008; 1:ra1.
  39. Gorvin CM, Frost M, Malinauskas T, et al. Calcium-sensing receptor residues with loss- and gain-of-function mutations are located in regions of conformational change and cause signalling bias. Hum Mol Genet 2018; 27:3720.
  40. Pollak MR, Brown EM, Chou YH, et al. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993; 75:1297.
  41. Pollak MR, Chou YH, Marx SJ, et al. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest 1994; 93:1108.
  42. Bai M, Janicic N, Trivedi S, et al. Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. J Clin Invest 1997; 99:1917.
  43. Cole DE, Janicic N, Salisbury SR, Hendy GN. Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with an inactivating Alu insertion mutation of the calcium-sensing receptor gene. Am J Med Genet 1997; 71:202.
  44. Pearce SH, Trump D, Wooding C, et al. Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. J Clin Invest 1995; 96:2683.
  45. Marx SJ, Attie MF, Levine MA, et al. The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine (Baltimore) 1981; 60:397.
  46. Lietman SA, Tenenbaum-Rakover Y, Jap TS, et al. A novel loss-of-function mutation, Gln459Arg, of the calcium-sensing receptor gene associated with apparent autosomal recessive inheritance of familial hypocalciuric hypercalcemia. J Clin Endocrinol Metab 2009; 94:4372.
  47. Ho C, Conner DA, Pollak MR, et al. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 1995; 11:389.
  48. Bai M, Pearce SH, Kifor O, et al. In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia. J Clin Invest 1997; 99:88.
  49. Law WM Jr, Heath H 3rd. Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann Intern Med 1985; 102:511.
  50. Heath H 3rd. Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989; 18:723.
  51. Brown EM. Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocrinol Metab 2007; 3:122.
  52. Heath H 3rd, Jackson CE, Otterud B, Leppert MF. Genetic linkage analysis in familial benign (hypocalciuric) hypercalcemia: evidence for locus heterogeneity. Am J Hum Genet 1993; 53:193.
  53. Lloyd SE, Pannett AA, Dixon PH, et al. Localization of familial benign hypercalcemia, Oklahoma variant (FBHOk), to chromosome 19q13. Am J Hum Genet 1999; 64:189.
  54. Nesbit MA, Hannan FM, Howles SA, et al. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N Engl J Med 2013; 368:2476.
  55. Nesbit MA, Hannan FM, Howles SA, et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet 2013; 45:93.
  56. Gorvin CM, Metpally R, Stokes VJ, et al. Large-scale exome datasets reveal a new class of adaptor-related protein complex 2 sigma subunit (AP2σ) mutations, located at the interface with the AP2 alpha subunit, that impair calcium-sensing receptor signalling. Hum Mol Genet 2018; 27:901.
  57. Leach K, Hannan FM, Josephs TM, et al. International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function. Pharmacol Rev 2020; 72:558.
  58. Pearce SH, Bai M, Quinn SJ, et al. Functional characterization of calcium-sensing receptor mutations expressed in human embryonic kidney cells. J Clin Invest 1996; 98:1860.
  59. Zajickova K, Vrbikova J, Canaff L, et al. Identification and functional characterization of a novel mutation in the calcium-sensing receptor gene in familial hypocalciuric hypercalcemia: modulation of clinical severity by vitamin D status. J Clin Endocrinol Metab 2007; 92:2616.
  60. Marx SJ, Stock JL, Attie MF, et al. Familial hypocalciuric hypercalcemia: recognition among patients referred after unsuccessful parathyroid exploration. Ann Intern Med 1980; 92:351.
  61. Heath H III. The familial benign hypocalciuric hypercalcemia syndromes. In: Principles of Bone Biology, Bilezikian JP, Raisz LG, Rodan GA (Eds), Academic Press, San Diego, CA 1996. p.769.
  62. Whitcomb DC. Genetic aspects of pancreatitis. Annu Rev Med 2010; 61:413.
  63. Gorvin CM, Hannan FM, Cranston T, et al. Cinacalcet Rectifies Hypercalcemia in a Patient With Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) Caused by a Germline Loss-of-Function Gα11 Mutation. J Bone Miner Res 2018; 33:32.
  64. Gorvin CM, Cranston T, Hannan FM, et al. A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2). J Bone Miner Res 2016; 31:1200.
  65. Szalat A, Shpitzen S, Tsur A, et al. Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia. Endocrine 2017; 55:741.
  66. Lee JY, Shoback DM. Familial hypocalciuric hypercalcemia and related disorders. Best Pract Res Clin Endocrinol Metab 2018; 32:609.
  67. Silverberg SJ, Shane E, Jacobs TP, et al. Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am J Med 1990; 89:327.
  68. Christensen SE, Nissen PH, Vestergaard P, et al. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol (Oxf) 2008; 69:713.
  69. Stuckey BG, Kent GN, Gutteridge DH, et al. Fasting calcium excretion and parathyroid hormone together distinguish familial hypocalciuric hypercalcaemia from primary hyperparathyroidism. Clin Endocrinol (Oxf) 1987; 27:525.
  70. Bertocchio JP, Tafflet M, Koumakis E, et al. Pro-FHH: A Risk Equation to Facilitate the Diagnosis of Parathyroid-Related Hypercalcemia. J Clin Endocrinol Metab 2018; 103:2534.
  71. Pasieka JL, Andersen MA, Hanley DA. Familial benign hypercalcaemia: hypercalciuria and hypocalciuria in affected members of a small kindred. Clin Endocrinol (Oxf) 1990; 33:429.
  72. Warner J, Epstein M, Sweet A, et al. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J Med Genet 2004; 41:155.
  73. Simonds WF, James-Newton LA, Agarwal SK, et al. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) 2002; 81:1.
  74. Carling T, Szabo E, Bai M, et al. Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab 2000; 85:2042.
  75. Hovden S, Rejnmark L, Ladefoged SA, Nissen PH. AP2S1 and GNA11 mutations - not a common cause of familial hypocalciuric hypercalcemia. Eur J Endocrinol 2017; 176:177.
  76. Wang Y, Nie M, Wang O, et al. Genetic Screening in a Large Chinese Cohort of Childhood Onset Hypoparathyroidism by Next-Generation Sequencing Combined with TBX1-MLPA. J Bone Miner Res 2019; 34:2254.
  77. Egbuna OI, Brown EM. Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol 2008; 22:129.
  78. Brachet C, Boros E, Tenoutasse S, et al. Association of parathyroid adenoma and familial hypocalciuric hypercalcaemia in a teenager. Eur J Endocrinol 2009; 161:207.
  79. Marx SJ. Calcimimetic Use in Familial Hypocalciuric Hypercalcemia-A Perspective in Endocrinology. J Clin Endocrinol Metab 2017; 102:3933.
  80. Kobayashi M, Tanaka H, Tsuzuki K, et al. Two novel missense mutations in calcium-sensing receptor gene associated with neonatal severe hyperparathyroidism. J Clin Endocrinol Metab 1997; 82:2716.
  81. Obermannova B, Banghova K, Sumník Z, et al. Unusually severe phenotype of neonatal primary hyperparathyroidism due to a heterozygous inactivating mutation in the CASR gene. Eur J Pediatr 2009; 168:569.
  82. Marx SJ, Lasker RD, Brown EM, et al. Secretory dysfunction in parathyroid cells from a neonate with severe primary hyperparathyroidism. J Clin Endocrinol Metab 1986; 62:445.
  83. Hendy GN, D'Souza-Li L, Yang B, et al. Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 2000; 16:281.
  84. Waller S, Kurzawinski T, Spitz L, et al. Neonatal severe hyperparathyroidism: genotype/phenotype correlation and the use of pamidronate as rescue therapy. Eur J Pediatr 2004; 163:589.
  85. Wilhelm-Bals A, Parvex P, Magdelaine C, Girardin E. Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism. Pediatrics 2012; 129:e812.
  86. Pollak MR, Brown EM, Estep HL, et al. Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nat Genet 1994; 8:303.
  87. D'Souza-Li L, Yang B, Canaff L, et al. Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia. J Clin Endocrinol Metab 2002; 87:1309.
  88. Roszko KL, Bi RD, Mannstadt M. Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2. Front Physiol 2016; 7:458.
  89. Mannstadt M, Harris M, Bravenboer B, et al. Germline mutations affecting Gα11 in hypoparathyroidism. N Engl J Med 2013; 368:2532.
  90. Watanabe S, Fukumoto S, Chang H, et al. Association between activating mutations of calcium-sensing receptor and Bartter's syndrome. Lancet 2002; 360:692.
  91. Konrad M, Weber S. Recent advances in molecular genetics of hereditary magnesium-losing disorders. J Am Soc Nephrol 2003; 14:249.
  92. CASRdb: Calcium-sensing receptor database. www.casrdb.mcgill.ca (Accessed on January 21, 2009).
  93. Watanabe T, Bai M, Lane CR, et al. Familial hypoparathyroidism: identification of a novel gain of function mutation in transmembrane domain 5 of the calcium-sensing receptor. J Clin Endocrinol Metab 1998; 83:2497.
  94. Conley YP, Finegold DN, Peters DG, et al. Three novel activating mutations in the calcium-sensing receptor responsible for autosomal dominant hypocalcemia. Mol Genet Metab 2000; 71:591.
  95. Tan YM, Cardinal J, Franks AH, et al. Autosomal dominant hypocalcemia: a novel activating mutation (E604K) in the cysteine-rich domain of the calcium-sensing receptor. J Clin Endocrinol Metab 2003; 88:605.
  96. Lienhardt A, Bai M, Lagarde JP, et al. Activating mutations of the calcium-sensing receptor: management of hypocalcemia. J Clin Endocrinol Metab 2001; 86:5313.
  97. Baron J, Winer KK, Yanovski JA, et al. Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism. Hum Mol Genet 1996; 5:601.
  98. De Luca F, Ray K, Mancilla EE, et al. Sporadic hypoparathyroidism caused by de Novo gain-of-function mutations of the Ca(2+)-sensing receptor. J Clin Endocrinol Metab 1997; 82:2710.
  99. Suzuki M, Aso T, Sato T, et al. A case of gain-of-function mutation in calcium-sensing receptor: supplemental hydration is required for renal protection. Clin Nephrol 2005; 63:481.
  100. Bastepe M. A Gain-of-Function CASR Mutation Causing Hypocalcemia in a Recessive Manner. J Clin Endocrinol Metab 2018; 103:3514.
  101. Hough TA, Bogani D, Cheeseman MT, et al. Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification. Proc Natl Acad Sci U S A 2004; 101:13566.
  102. Dong B, Endo I, Ohnishi Y, et al. Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH). J Bone Miner Res 2015; 30:1980.
  103. Roszko KL, Bi R, Gorvin CM, et al. Knockin mouse with mutant Gα11 mimics human inherited hypocalcemia and is rescued by pharmacologic inhibitors. JCI Insight 2017; 2:e91079.
  104. Gorvin CM, Hannan FM, Howles SA, et al. Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy. JCI Insight 2017; 2:e91103.
  105. Li D, Opas EE, Tuluc F, et al. Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization. J Clin Endocrinol Metab 2014; 99:E1774.
  106. Tenhola S, Voutilainen R, Reyes M, et al. Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation. Eur J Endocrinol 2016; 175:211.
  107. Pearce SH, Williamson C, Kifor O, et al. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med 1996; 335:1115.
  108. Burren CP, Curley A, Christie P, et al. A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges. J Pediatr Endocrinol Metab 2005; 18:689.
  109. Sato K, Hasegawa Y, Nakae J, et al. Hydrochlorothiazide effectively reduces urinary calcium excretion in two Japanese patients with gain-of-function mutations of the calcium-sensing receptor gene. J Clin Endocrinol Metab 2002; 87:3068.
  110. Winer KK, Ko CW, Reynolds JC, et al. Long-term treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium. J Clin Endocrinol Metab 2003; 88:4214.
  111. Kifor O, Moore FD Jr, Wang P, et al. Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab 1996; 81:1598.
  112. Gogusev J, Duchambon P, Hory B, et al. Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 1997; 51:328.
  113. Pallais JC, Kifor O, Chen YB, et al. Acquired hypocalciuric hypercalcemia due to autoantibodies against the calcium-sensing receptor. N Engl J Med 2004; 351:362.
  114. Kifor O, Moore FD Jr, Delaney M, et al. A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor. J Clin Endocrinol Metab 2003; 88:60.
  115. Makita N, Sato J, Manaka K, et al. An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations. Proc Natl Acad Sci U S A 2007; 104:5443.
  116. Kifor O, McElduff A, LeBoff MS, et al. Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 2004; 89:548.
  117. Li Y, Song YH, Rais N, et al. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 1996; 97:910.
  118. Gavalas NG, Kemp EH, Krohn KJ, et al. The calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 2007; 92:2107.
  119. Mayer A, Ploix C, Orgiazzi J, et al. Calcium-sensing receptor autoantibodies are relevant markers of acquired hypoparathyroidism. J Clin Endocrinol Metab 2004; 89:4484.
  120. Brown EM. Anti-parathyroid and anti-calcium sensing receptor antibodies in autoimmune hypoparathyroidism. Endocrinol Metab Clin North Am 2009; 38:437.
  121. Kemp EH, Gavalas NG, Krohn KJ, et al. Activating autoantibodies against the calcium-sensing receptor detected in two patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 2009; 94:4749.
  122. Hu J. Allosteric modulators of the human calcium-sensing receptor: structures, sites of action, and therapeutic potentials. Endocr Metab Immune Disord Drug Targets 2008; 8:192.
  123. Nemeth EF. Pharmacological regulation of parathyroid hormone secretion. Curr Pharm Des 2002; 8:2077.
  124. Timmers HJ, Karperien M, Hamdy NA, et al. Normalization of serum calcium by cinacalcet in a patient with hypercalcaemia due to a de novo inactivating mutation of the calcium-sensing receptor. J Intern Med 2006; 260:177.
  125. Howles SA, Hannan FM, Babinsky VN, et al. Cinacalcet for Symptomatic Hypercalcemia Caused by AP2S1 Mutations. N Engl J Med 2016; 374:1396.
  126. Tenhola S, Hendy GN, Valta H, et al. Cinacalcet Treatment in an Adolescent With Concurrent 22q11.2 Deletion Syndrome and Familial Hypocalciuric Hypercalcemia Type 3 Caused by AP2S1 Mutation. J Clin Endocrinol Metab 2015; 100:2515.
  127. Martin KJ, Bell G, Pickthorn K, et al. Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects. Nephrol Dial Transplant 2014; 29:385.
  128. Fitzpatrick LA, Dabrowski CE, Cicconetti G, et al. The effects of ronacaleret, a calcium-sensing receptor antagonist, on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab 2011; 96:2441.
  129. Kumar S, Matheny CJ, Hoffman SJ, et al. An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation. Bone 2010; 46:534.
  130. Nemeth EF, Van Wagenen BC, Balandrin MF. Discovery and Development of Calcimimetic and Calcilytic Compounds. Prog Med Chem 2018; 57:1.
  131. Hannan FM, Walls GV, Babinsky VN, et al. The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor (CaSR) Mutation: Relevance to Autosomal Dominant Hypocalcemia Type 1 (ADH1). Endocrinology 2015; 156:3114.
  132. Roberts MS, Gafni RI, Brillante B, et al. Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635). J Bone Miner Res 2019; 34:1609.
Topic 838 Version 23.0

References