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

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 highly 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 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 arginine vasopressin resistance (AVP-R, previously called nephrogenic diabetes insipidus) associated with chronic hypercalcemia (see "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Clinical manifestations and causes"). 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 type 1 (ADH1; 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 [65-67].

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) [68]. 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:

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 [69]. Other tools to discriminate the two disorders on biochemical grounds have been published (eg, [70,71]).

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 [72]. 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 [73,74]. 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 [75]. It should be emphasized, however, that parathyroidectomy is neither desirable nor curative in most typical cases of FHH. (See "Primary hyperparathyroidism: Pathogenesis and etiology", 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 the gene encoding G alpha 11 (GNA11) and AP2S1, may be of benefit in distinguishing FHH from primary hyperparathyroidism in the following clinical settings [69]:

●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, FHH possibly caused by a de novo 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 [76]. Single-gene testing might be replaced by gene panels, exome sequencing, or other next-generation testing modalities [77]. 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 variant, 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) [75,78]. 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 [79,80].

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 [81]. 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 [82]. 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 [44,48,83]. 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 [40-43,51,84,85]. 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 [86,87].

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 (table 2) [51,88,89]. Another genetic cause of ADH, termed ADH2, has been identified in families with activating mutations in G alpha 11 [54,90,91]. 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 [92,93]. 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) (table 2) [51,88,89,94-101]. Most reported mutations occur in the extracellular domain of the CaSR, although some occur in the transmembrane domain or intracellular tail [51,85,94,95]. 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 [98]. While most patients have a heterozygous mutation, this is not invariably true, however, as an ADH family has recently been described with an autosomal recessive pattern of inheritance [102]. 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 [98]. Sporadic de novo mutations in the CaSR have also been identified [99,100]. 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) [54,91].

These findings have been confirmed in mouse models of activating mutations in the CaSR [103,104] and GNA11 [105,106].

Clinical manifestations — In a systematic review of published reports of ADH type 1, 27 percent of patients were asymptomatic at presentation, whereas 32 percent had moderate and 41 percent severe symptoms, with the vast majority in the latter group presenting with seizures [107]. Most individuals (81 percent) were diagnosed with a hypocalcemia-related disorder when <18 years of age (median 4 years of age, range 0 to 66 years). The age at presentation was lower in those with severe symptoms (9 versus 19 years). The majority of patients (93 percent) were given an initial incomplete diagnosis, and a small number were mislabeled as having febrile seizures or other disorders.

Two reports found that affected members of families with ADH2 have short stature [108,109].

The biochemical features are as follows [107-109]:

●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 [51,110,111]. 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 [78,110]. The diagnosis can be confirmed by analysis for mutations in the CaSR gene [78,85], or if necessary, in the G alpha 11 gene. Several genetic testing companies offer gene panels for hypocalcemic disorders that include both candidate genes.

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 [78,98,110,111]. 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 [78,110]. 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 'Managing hypercalciuria'.)

Patients with ADH requiring therapy can be treated with cautious calcium and vitamin D supplementation with monitoring of urinary calcium excretion [78,98,110,111]. 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 [112]. (See "Hypoparathyroidism", section on 'Managing 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 [113]. In children with ADH1 and recurrent seizures despite treatment with calcium and calcitriol, continuous subcutaneous administration of PTH (1-34) proved to be effective in reducing seizure frequency and hospital admissions [114]. The treatment of hypoparathyroidism with recombinant human PTH is reviewed elsewhere. (See "Hypoparathyroidism", section on 'PTH-based therapies'.)

Alternatively, calcilytics, a class of drugs in development that inhibit the CaSR, may provide a useful therapeutic approach in the future by normalizing endogenous PTH production and 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 [115,116] and/or severe secondary or so-called "tertiary" (eg, hypercalcemic) hyperparathyroidism due to chronic kidney disease [116]. 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).

●Rare patients have antibodies that inactivate the CaSR, resulting in acquired hypocalciuric hypercalcemia [117-119]. 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

●Autoimmune hypoparathyroidism is a common feature of polyglandular autoimmune syndrome type I, which is a familial disorder (see "Causes of primary adrenal insufficiency (Addison disease)", section on 'Type 1 (monogenic)'). In several studies of patients with hypoparathyroidism, autoantibodies directed at the CaSR's extracellular domain have been identified [120-124]. 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 [120,125]. 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 [120].

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 [126,127].

●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 patients on dialysis", section on 'Calcimimetics' and "Primary hyperparathyroidism: Management", section on 'Severe hypercalcemia'.)

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) [128,129], 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 [130]. 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 [81]. An injectable calcimimetics, etelcalcetide, has recently been approved for use in patients with severe hyperparathyroidism receiving dialysis treatment for renal insufficiency [131]. It is long-acting and has the advantage of being administered only at the time of dialysis. (See "Management of secondary hyperparathyroidism in adult patients on dialysis", section on 'Calcimimetics'.)

●Calcilytics – Oral CaSR antagonists (calcilytics) were initially developed for the treatment of osteoporosis [132]. Administration leads to a transient rise in endogenous PTH [133], but three different calcilytics failed in clinical trials because of a lack in efficacy [134].

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 [135] and ADH2 [105], 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 [136].

SUMMARY AND RECOMMENDATIONS

●Functions of the CaSR – 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.)

●CaSR mutations

•Inactivating – 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.)

-FHH – 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. In most cases, 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. (See 'Familial hypocalciuric hypercalcemia' above.)

-NSHPT – NSHPT is most commonly an autosomal recessive condition. Infants who are homozygous for the CaSR mutation present with 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. Total parathyroidectomy is usually the therapy of choice. Treatment of these infants prior to surgery with a bisphosphonate or cinacalcet may be helpful in stabilizing them medically. (See 'Neonatal severe hyperparathyroidism' above.)

•Activating – Activating mutations of the CaSR or of G alpha 11 cause autosomal dominant hypocalcemia (ADH) and, in the rare patient with severe phenotype, a form of ADH with features of Bartter syndrome (table 2). (See 'Activating mutations' above.)

●Autoimmune disorders of CaSR – 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.)

●Calcimimetics and calcilytics – 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. (See 'Calcimimetics and calcilytics' above.)

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