Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 405, 93372; DO: 0060700;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q13.33-q21.1 | Hypocalciuric hypercalcemia, type I | 145980 | Autosomal dominant | 3 | CASR | 601199 |
A number sign (#) is used with this entry because of evidence that hypocalciuric hypercalcemia type I (HHC1) is caused by heterozygous loss-of-function mutations in the CASR gene (601199), which encodes the calcium-sensing receptor, on chromosome 3q13-q21.
Loss-of-function mutations in the CASR gene can also result in neonatal severe hyperparathyroidism (NSHPT; 239200), whereas gain-of-function mutations in CASR result in autosomal dominant hypocalcemia (HYPOC1; 601198).
Familial hypocalciuric hypercalcemia (HHC) is a heritable disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. HHC is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone (PTH; 168450) level. Hypermagnesemia is typically present. Individuals with HHC are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults (summary by Hannan et al., 2010).
Characteristic features of familial hypocalciuric hypercalcemia include mild to moderate hypercalcemia, nonsuppressed parathyroid hormone, relative hypocalciuria while hypercalcemic (calcium/creatinine clearance ratio less than 0.01, or 24-hr urine calcium less than 6.25 mmol), almost 100% penetrance of hypercalcemia from birth, absence of complications, persistence of hypercalcemia following subtotal parathyroidectomy, and normal parathyroid size, weight, and histology at surgery. However, atypical presentations with severe hypercalcemia, hypercalciuria with or without nephrolithiasis or nephrocalcinosis, kindreds with affected members displaying either hypercalciuria or hypocalciuria, postoperative normocalcemia, and pancreatitis have all been described in FHH (Warner et al., 2004).
Genetic Heterogeneity of Hypocalciuric Hypercalcemia
Familial hypocalciuric hypercalcemia type II (HHC2; 145981) is caused by mutation in the GNA11 gene (139313) on chromosome 19p13, and HHC3 (600740) is caused by mutation in the AP2S1 gene (602242) on chromosome 19q13.
From studies of the families of 25 index patients with primary parathyroid hyperplasia, Marx et al. (1977) identified 2 autosomal dominant disorders: type I multiple endocrine neoplasia (MEN1; 131100) and one that they termed familial hypocalciuric hypercalcemia. The latter was present in the families of 2 of the patients. Among offspring of affected persons in the kindreds with FHH, as distinct from MEN1, the prevalence of hypercalcemia approached the expected 50% during the first 2 decades. Nephrolithiasis and peptic ulcer were uncommon. Moderate hypercalcemia occurred without hypercalciuria. Subtotal parathyroidectomy did not abolish hypercalcemia. Concentrations of peptide hormones other than parathyroid hormones were common in patients with FHH.
Marx et al. (1978) and Marx et al. (1981) contrasted FHH with primary hyperparathyroidism (HRPT; see 145000). Patients with FHH had higher creatinine clearance values than patients with HRPT but higher serum magnesium levels than both normals and HRPT patients. Elevated magnesium level was proportional to elevated calcium level in FHH but was inversely related in HRPT. Urinary excretion of both calcium and magnesium was significantly lower in FHH than in HRPT. Abnormal serum protein binding of calcium and magnesium in FHH was excluded. In 2 (kindreds A and L) of the 15 FHH families studied by Marx et al. (1981), at least 1 affected individual exhibited hypercalciuria. The authors suggested that these individuals had FHH in combination with an unidentified cause for hypercalciuria.
Attie et al. (1980) stated that familial hypocalciuric hypercalcemia, which was first reported by Foley et al. (1972) as familial benign hypercalcemia, is the first-to-be-described parathormone-independent renal tubular defect in calcium reabsorption. Menko et al. (1984) presented the hypothesis that the abnormality may involve the 'setting of the parathyroid gland,' a process that seems to occur in the perinatal period, and that the fundamental defect may be in renal calcium handling.
Among 67 patients referred after unsuccessful surgery for presumed primary hyperparathyroidism, Marx et al. (1980) found that 6 were members of kindreds with familial hypocalciuric hypercalcemia. This disorder achieves greater practical importance as routine biochemical screening becomes widely practiced. Marx (1980) estimated that about 25 patients with this disorder undergo unsuccessful parathyroidectomy in the United States each year. Furthermore, their hypercalcemic relatives are usually not recognized or informed of the mild nature of their disorder. Unlike primary hyperparathyroidism, hypercalcemia of this origin begins before age 10 years and is not accompanied by urinary stone or renal damage. The only complications attributable to the hypercalcemia are pancreatitis and chondrocalcinosis. Parathyroid hyperplasia is found in most cases, but hypercalcemia usually persists after parathyroidectomy. Both the kidneys and the parathyroid glands seem insensitive to chronic hypercalcemia. In some cases circulating parathormone levels are elevated and can lead to neonatal severe 'primary hyperparathyroidism' (239200) in offspring of affected women. A simple diagnostic test is the ratio of renal calcium clearance to creatinine clearance; a value below 0.01 suggests familial hypocalciuric hypercalcemia. The finding of hypercalcemia in first-degree relatives supports the diagnosis, particularly when found in children under age 10 years. Lipomas may be a pleiotropic effect of the FHH gene (Levine, 1980).
Paterson and Gunn (1981) found this disorder in at least 10 members of 4 generations of a large kindred. Parathyroid exploration had been performed in 3 members (twice in 1) before it was realized that they did not have primary hyperparathyroidism. The relation to neonatal severe primary hyperparathyroidism was discussed further by Marx et al. (1982). In some instances, NSPH may represent the homozygous state of FHH. Menko et al. (1983) identified 27 hypercalcemic persons in 3 generations of a large kindred. Five had had parathyroid surgery. The patients tend to have hypermagnesemia as opposed to the hypomagnesemia of hyperparathyroidism. Increased renal tubular calcium reabsorption and persistent normal functioning of the parathyroid glands in the face of hypercalcemia remain the sole definite abnormalities of the syndrome. Steinmann et al. (1984) and Marx et al. (1985) presented evidence that FHH can show only intermittent and very mild hypercalcemia in heterozygotes and that in the homozygous state the gene can cause neonatal severe primary hyperparathyroidism. This hypothesis was proven by Pollak et al. (1994). The kindred on which Marx et al. (1985) based this conclusion was first reported by Hillman et al. (1964) as an instance of autosomal recessive neonatal severe primary hyperparathyroidism. Two offspring of first-cousin parents were affected. Only later was FHH described and was it realized that most cases of neonatal severe primary hyperparathyroidism occur in families with FHH.
Marx et al. (1985) concluded that of 22 reported cases of NSPH, 9 were in kindreds with definite or probable FHH. In 3 kindreds, because of normocalcemia in both parents and, in 2 of them, parental consanguinity, autosomal recessive inheritance was suggested. It was one of these 3 kindreds that Marx et al. (1985) restudied. The mild and intermittent nature of hypercalcemia in heterozygotes was responsible for the earlier misinterpretation. The frequency of gallstones is increased; indeed, this is the only discernible increase in medical problems. Skeletal mass is normal and fractures do not occur with increased frequency (Law and Heath, 1985).
Clinical Variability
Pasieka et al. (1990) studied a 3-generation family with familial benign hypercalcemia in which the female proband and her affected son were hypercalciuric, whereas her affected daughter and that daughter's affected son were hypocalciuric. The 66-year-old proband underwent parathyroidectomy, with detection of 4 normal-sized glands and removal of the 3 largest of the 4. Postoperatively, she remained hypercalcemic with a PTH in the normal range. Histologic examination of the parathyroid glands revealed a larger proportion of stromal fat than in normal glands, consistent with previous findings in parathyroid glands from patients with familial benign hypercalcemia. The authors concluded that the presence of hypercalciuria in a patient with hypercalcemia does not exclude the diagnosis of familial benign hypercalcemia.
Carling et al. (2000) studied a large Swedish family in which 20 members had hypercalcemia. Of 10 extensively studied members, 3 had calcium-clearance to creatinine-clearance ratios consistent with a diagnosis of FHH, whereas 7 had values exceeding the upper limit for FHH. Two of the hypercalcemic individuals had a history of renal stones. Parathyroid surgery in 9 affected family members revealed parathyroid gland enlargement, with chief cell hyperplasia of the diffuse or nodular type in 7 patients, a single parathyroid adenoma in 1 patient, and equivocal findings in 1 patient. Radical subtotal parathyroidectomy reversed the hypercalcemia and hypercalciuria in 7 patients, whereas 2 had postoperative recurrence of hypercalcemia, albeit ameliorated. The authors stated that this family displayed characteristics that were atypical for FHH, but noted that FHH patients previously had been reported with high urinary calcium levels.
Simonds et al. (2002) provided detailed analysis of 36 kindreds with a provisional diagnosis of familial isolated hyperparathyroidism (see 145000). They identified 5 kindreds with CASR-associated disease, 3 of which had at least 1 affected member with hypercalciuria. The probands were all asymptomatic, and hypercalcemia was diagnosed at ages ranging from 21 to 53 years. Findings typical of FHH that were present in at least 1 affected family member included hypercalcemia before 10 years of age, relative hypocalciuria, hypermagnesemia, and/or persistent hyperparathyroidism following subtotal parathyroidectomy. Features atypical for FHH included hypercalciuria and nephrolithiasis; in addition, 2 probands presented with intact PTH levels greater than 150 pg/mL, more than 2 times above the value reported to discriminate between FHH and forms of hyperparathyroidism.
Warner et al. (2004) studied 22 unrelated patients with a clinical diagnosis of FHH and identified 4 probands with heterozygous mutations in the CASR gene. All 4 exhibited atypical FHH phenotypes, including 1 with hypercalciuria, 1 with pancreatitis, and 1 whose offspring had hypercalcemia, hypercalciuria, and nephrolithiasis. The authors suggested that there might be many families with hypercalcemia due to as yet unidentified CASR mutations manifesting atypical or variable phenotypes, in whom considerations for parathyroid surgery would differ from those for patients with typical FHH.
Brachet et al. (2009) studied a family of Turkish origin in which a 16-year-old boy presented with abdominal pain, fatigue, and intermittent polyuria and polydipsia. He was found to have hypocalciuric hypercalcemia with markedly elevated PTH, and a parathyroid adenoma was removed. Postoperatively, his serum calcium level remained slightly elevated with marked hypocalciuria, unsuppressed PTH in the upper-normal range, and low vitamin D level. Screening of family members revealed mild hypercalcemia, unsuppressed serum PTH, and marked hypocalciuria in 2 sibs, his father, and his paternal grandmother. The grandmother had a parathyroid adenoma surgically removed at age 55 years.
Guarnieri et al. (2010) studied a 3-year series of 185 Italian patients presenting with hypercalcemia, including 165 with a clinical diagnosis of sporadic primary hyperparathyroidism, 17 with FHH, and 3 with familial hyperparathyroidism. Inactivating CASR variants were found in 7 of the FHH patients and in 1 sporadic patient from the sporadic hyperparathyroidism cohort; no variants were identified in the 3 patients with familial HRPT. The sporadic patient was a 56-year-old woman with a history of renal stones 20 years previously, who was hypercalcemic with an elevated PTH level and hypercalciuria. After removal of a parathyroid adenoma detected by ultrasound, her serum calcium was 9.8 mg/dL and calcium excretion was 100 mg/day. The authors stated that although clinically overt hyperparathyroidism is not observed in the vast majority of FHH cases, this patient could be classified among previously reported FHH patients with parathyroid adenomas.
Mastromatteo et al. (2014) reported a 68-year-old man with fatigue, intermittent polyuria, and a history of recurrent nephrolithiasis, who was found to be hypercalcemic with an inappropriately normal PTH level. He also showed hypercalciuria on several occasions, with a calcium to creatinine clearance ratio of 0.031. Evaluation of his neck by ultrasound, NMR, and tomoscintigraphy did not reveal parathyroid gland hyperplasia or adenoma. He was heterozygous for an inactivating mutation in the CASR gene, and screening of his 3 asymptomatic sons revealed 1 carrier, a 41-year-old man with an ionized calcium level at the upper limit of normal and normal PTH and urinary calcium levels. The authors concluded that the inactivating mutation of the CASR gene results in an atypical presentation of FHH with hypercalciuria.
In a linkage study in an extensively affected Dutch family with FHH, Menko et al. (1984) excluded linkage with several markers; low positive lod scores were observed with Duffy. On the basis of linkage studies, Heath et al. (1992) concluded that HHC is not related to the multiple endocrine neoplasia syndromes (131100, 171400, 162300). They also excluded basic fibroblast growth factor (134920), parathyroid hormone (168450), and several other candidate loci.
In each of 4 unrelated families with FHH, Chou et al. (1992) demonstrated linkage of the disease phenotype with DNA markers on 3q; combined maximum multipoint lod score = 20.67. The FHH locus lies within 15 cM of RHO (180380) (99% confidence interval). The FHH gene presumably lies in the 3q21-q24 region. Chou et al. (1992) suggested that the gene defect perturbs the ability of the parathyroid gland and kidney to recognize and/or respond to changes in extracellular calcium concentration.
In a further study of 5 families, Heath et al. (1993) found that HHC mapped to 3q in 4, but to 19p12.2 in 1 (see 145981), thus indicating locus heterogeneity.
Finegold et al. (1994) presented evidence for linkage of a form of autosomal dominant hypoparathyroidism to a region of 3q13 flanking marker D3S1303 and suggested that it may be caused in this family by an inactivating mutation in the Ca(2+)-sensing receptor suppressing PTH secretion and lowering the 'set point' for serum calcium levels.
In a large Swedish family with hypercalcemia in which some affected members were hypocalciuric and others hypercalciuric, Carling et al. (2000) identified linkage to chromosome 3q, between markers D3S1303 (maximum lod score, 4.25) and D3S1269 (maximum lod score, 5.39). Linkage to other loci was excluded by haplotype analysis.
Parathyroid cells respond to decreases in extracellular calcium concentration by means of the calcium-sensing receptor (601199), a cell surface receptor that alters phosphatidylinositol turnover and intracellular calcium, ultimately effecting an increase in PTH secretion. The 'set point' of parathyroid cells is defined as that calcium concentration at which PTH secretion is half-maximal. Parathyroid glands from FHH patients have an increase in this set point, and in vitro studies of parathyroid tissue from neonatal severe hyperparathyroidism patients show a still greater increase in this set point. Calcium handling by the kidney is also abnormal in individuals with FHH, who fail to show a hypercalciuric response to hypercalcemia. Brown et al. (1993) identified a putative bovine parathyroid cell Ca(2+)-sensing receptor cDNA by expression cloning in Xenopus laevis oocytes. The cDNA encoded a predicted 120-kD polypeptide containing a large extracellular domain and 7 membrane-spanning regions characteristic of G protein-coupled cell surface receptors. In addition to parathyroid tissue, the receptor was also expressed in regions of the kidney involved in Ca(2+)-regulated Ca(2+) and Mg(2+) reabsorption.
The Ca(2+)-sensing receptor belongs to the superfamily of 7-membrane-spanning G protein-coupled receptors. Pollak et al. (1993) demonstrated that mutations in the human Ca(2+)-sensing receptor gene cause both familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. They discovered 3 nonconservative missense mutations, 2 in the extracellular N-terminal domain of the receptor (601199.0002 and 601199.0003) and 1 in the final intracellular loop (601199.0001). The wildtype receptor expressed in Xenopus laevis oocytes elicited large inward currents in response to perfused polyvalent cations; in contrast, a markedly attenuated response was observed with the protein expressed by 1 of the mutations.
Clapham (1993) pointed out that familial hypocalciuric hypercalcemia joins the list of disorders due to defective G protein receptors, others being defects in the thyrotropin receptor (603372), the luteinizing hormone receptor (152790), the V2 vasopressin receptor (AVPR2; 300538), rhodopsin (180380), the ACTH receptor (202200), and the cone opsin receptors (see 300821). Diseases have been related to defects in G protein itself in the case of the alpha subunit of Gs (139320) and to mutations in the alpha subunit of Gi found in pituitary, adrenal cortex, ovary, and thyroid tumors (Lyons et al., 1990)--the GIP oncogene.
Chou et al. (1995) reported 5 novel mutations (see 601199.0022) in the CASR gene (called PCAR1 by them) in FHH or neonatal severe hyperparathyroidism: arg228gln, thr139met, gly144glu, arg63met, and arg67cys. Each resulted in a nonconservative amino acid alteration and each was predicted to be in the large extracellular domain of the Ca(2+)-sensing receptor. In the case of the probands from 3 other families with FHH linked to 3q, no mutations were identified in PCAR1.
In a Japanese FHH family, Aida et al. (1995) identified a CASR mutation (P39A; 601199.0021) by PCR and SSCP. The proband was homozygous and the consanguineous parents were heterozygous for the mutation. The parents showed borderline elevations of serum calcium.
Pearce et al. (1995) analyzed the CASR gene in 9 unrelated kindreds with a total of 39 affected members with familial benign hypercalcemia as well as in 3 unrelated children with sporadic NSHPT, 2 of whom had previously been described by Meeran et al. (1994) and Dezateux et al. (1984). In 6 of 9 HHC kindreds, heterozygosity for novel mutations (1 missense and 5 missense) were found; in the 3 children with NSHPT, 2 de novo heterozygous missense mutations and 1 homozygous frameshift mutation were identified (see 601199.0006, 601199.0007, and 601199.0008). SSCP analysis was found by the authors to be a sensitive and specific mutational screening method that detected more than 85% of these CASR gene mutations. Pearce et al. (1995) noted that the identification of CASR mutations may help distinguish HHC from mild primary hyperparathyroidism which otherwise can be clinically difficult. In addition, these results indicated that NSHPT is not exclusively the result of homozygosity for a mutation that causes familial benign hypercalcemia in the heterozygous state but rather can be due to heterozygosity for mutations at the CASR locus. Indeed, the parents and sibs of the 3 children with NSHPT were normocalcemic. All 3 children with NSHPT presented with neonatal hypercalcemia that was associated with marked bony undermineralization. Parathyroidectomy and histologic examination revealed T-cell hyperplasia of all 4 parathyroid glands in the 3 NSHPT children, who all became hypocalcemic and required vitamin D replacement postoperatively.
Janicic et al. (1995) studied family members of a Nova Scotian deme in which both FHH and NSHPT were segregating and found, by PCR amplification of CASR exons, that FHH individuals were heterozygous and NSHPT individuals were homozygous for an abnormally long exon 7. This was due to an insertion at codon 877 of an Alu-repetitive element of the predicted-variant/human-specific-1 subfamily (601199.0005). The Alu insertion was in the opposite orientation to the PCAR1 gene and contained an exceptionally long poly(A) tract. Stop signals were found in all reading frames within the Alu sequence, leading to a predicted shortening of the Ca(2+)-sensing receptor protein. Janicic et al. (1995) observed that the loss of most of the carboxy-terminal intracellular domain of the protein would dramatically impair its signal transduction capability. Identification of the specific mutation in this community will allow rapid testing of at-risk individuals. Clinical features of affected members of the kindred had previously been reported by Pratt et al. (1947), Goldbloom et al. (1972), and Cole et al. (1990). This was a common ancestry that dated back at least 11 generations to settlement of the area by New England fishing families in the mid-1700s. Bai et al. (1997) demonstrated that insertion of this Alu element resulted in the production of a nonfunctional protein of molecular weight 30 kD less than wildtype with decreased cell surface expression. They also showed that transcription of the Alu-containing CASR produced both a full-length product and a product that was truncated due to stalling at the poly(T) tract. Subsequent in vitro translation produced 3 truncated proteins due to termination in all reading frames as predicted.
Bai et al. (1997) characterized the in vivo, cellular and molecular pathophysiology of a case of NSHPT resulting from a de novo heterozygous missense mutation in the CASR gene (R185Q; 601199.0003). The female neonate was admitted to the hospital for suspected osteogenesis imperfecta. She presented with markedly undermineralized bones, multiple metaphyseal fractures, but moderately severe hypercalcemia. Subtotal parathyroidectomy was performed at 6 weeks; hypercalcemia recurred rapidly, but the bone disease improved gradually with reversion to an asymptomatic state resembling FHH. Dispersed parathyroid cells from the resected tissue showed a set-point (the level of Ca(2+) half maximally inhibiting PTH secretion) substantially higher than for normal human parathyroid cells (1.8 vs 1.0 mM Ca(2+), respectively). A similar increase in the calcium set-point was observed in vivo (serum calcium 3.2 vs 2.4 mM). Her normocalcemic parents were homozygous for the wildtype CASR sequence. While cotransfection of normal and mutant receptors showed a higher Ca(2+) level than for wildtype (6.3 vs 4.6 mM, respectively) for eliciting a half-maximal increase in inositol phosphates, transient expression of the mutant R185Q CASR in human embryonic kidney cells revealed a substantially attenuated Ca(2+)-evoked accumulation of total inositol phosphates, Bai et al. (1997) concluded that this de novo, heterozygous CASR mutation exerts a dominant-negative action on the normal CASR, producing NSHPT and more severe hypercalcemia than typically seen in FHH. Moreover, the authors presented evidence that normal maternal calcium homeostasis prompted additional secondary hyperparathyroidism in the fetus, thus contributing to the severity of the NSHPT in this patient with FHH. Of interest, the same R185Q mutation (601199.0003) had been described previously by Pollak et al. (1993) in a U.S. kindred (family A) reported by Marx et al. (1982). Affected family members had a degree of hypercalcemia (a mean of 3.08 mM with a range of 2.72 to 3.43 mM) that is similar to that of the proband described by Bai et al. (1997); 2 neonates in one branch of this family presented with NSHPT and one of them, patient A-26, inherited the abnormal CASR from her father.
In a large Swedish family with hypercalcemia mapping to the CASR locus on chromosome 3q, Carling et al. (2000) identified heterozygosity for a missense mutation in the CASR gene (F881L; 601199.0031) that segregated with disease. Of 10 affected family members who underwent detailed analysis, 3 were hypocalciuric and 7 were hypercalciuric. The authors stated that this family displayed characteristics that were atypical for FHH, but noted that FHH patients previously had been reported with high urinary calcium levels.
In a large kindred in which some members had HHC and others had NSHPT, which was previously studied by Philips (1948), Hillman et al. (1964), and Marx et al. (1985), D'Souza-Li et al. (2001) identified heterozygosity for a splice site mutation in the CASR gene (601199.0033) in 2 members of the family with HHC. The 2 brothers with NSHPT in this branch of the family and their consanguineous parents with HHC were not studied, thus their mutation status was unknown; however, D'Souza-Li et al. (2001) noted that previous reports had indicated that individuals who inherit 2 inactive copies of the CASR gene may have NSHPT.
From a cohort of 36 kindreds with a provisional diagnosis of familial isolated hyperparathyroidism, Simonds et al. (2002) identified 5 hypercalcemic families in which a heterozygous mutation in the CASR gene segregated with disease (see, e.g., 601199.0054). In 3 of the 5 families, at least 1 affected individual exhibited hypercalciuria.
In a 9-year-old Brazilian girl with hypocalciuric hypercalcemia, who presented with a 6-month history of headaches and emesis and was found to be severely hypercalcemic, Miyashiro et al. (2004) identified homozygosity for a L13P substitution in the CASR gene (601199.0044). The proband's consanguineous parents, who had mild asymptomatic hypercalcemia, carried the same mutation in heterozygous state. Miyashiro et al. (2004) concluded that patients with homozygous inactivation of the CASR gene may present with severe hypercalcemia in late phases of life and, based on their report and those of others (Aida et al., 1995; Chikatsu et al., 1999), suggested that homozygous mutations found in the very beginning N-terminal portion of the CASR may be associated with this phenotype.
In a 16-year-old boy of Turkish origin with HHC and a parathyroid adenoma, Brachet et al. (2009) identified heterozygosity for a missense mutation in the CASR gene (E297K; 601199.0002). His affected father and paternal grandmother were also heterozygous for the mutation, and the grandmother also had a parathyroid adenoma; the mutation status of the proband's affected brother and sister was not reported. The authors noted that the same mutation had been identified in homozygosity in a patient with NSHPT as well as in heterozygosity in patients with HHC (Pollak et al., 1993; Woo et al., 2006).
In a 68-year-old man with hypercalcemia, hypercalciuria, and recurrent nephrolithiasis, Mastromatteo et al. (2014) sequenced the candidate gene CASR and identified heterozygosity for a missense mutation (T972M; 601199.0055). Screening of his 3 asymptomatic sons revealed 1 carrier, a 41-year-old man with an ionized calcium level at the upper limit of normal and normal PTH and urinary calcium levels. Functional evaluation demonstrated strong impairment of signaling activity of the mutant receptor compared to wildtype. The authors concluded that T972M represents an inactivating mutation of the CASR gene causing an atypical presentation of FHH with hypercalciuria.
Acquired Hypocalciuric Hypercalcemia
Li et al. (1996) found that sera from 14 of 25 patients with acquired hypoparathyroidism reacted to the extracellular domain of the recombinantly expressed calcium-sensing receptor. Sera from 50 patients with other autoimmune disorders and 22 normal controls showed no reaction.
Kifor et al. (2003) studied sera from 4 patients with PTH-dependent hypercalcemia who also had other autoimmune manifestations. The patients' sera contained antibodies that reacted with several synthetic peptides derived from sequences within the calcium-sensing receptor's extracellular amino terminus; their sera also stimulated PTH release from dispersed human parathyroid cells. Kifor et al. (2003) concluded that a phenocopy of familial hypocalciuric hypercalcemia can be observed in patients with antibodies to the calcium-sensing receptor's extracellular domain, and suggested that the antibodies stimulate PTH release by inhibiting activation of the receptor by extracellular calcium.
Pallais et al. (2004) described a 66-year-old woman with acquired hypocalciuric hypercalcemia due to autoantibodies targeting the calcium-sensing receptor. ELISA analysis showed that the cognate epitopes for these autoantibodies, which were predominantly of the IgG4 subtype, corresponded to regions in the extracellular domain of the receptor. The patient's autoantibody titers showed a strong correlation with hypercalcemia and elevated parathyroid hormone levels. Rickels and Mandel (2004) noted that inappropriate elevation of serum parathyroid hormone is present in both acquired and familial hypocalciuric hypercalcemia. A low ratio of urinary calcium to creatine clearance separates these 2 disorders from primary hyperparathyroidism. Hypocalciuric hypercalcemia thus can be caused by either loss of function mutations in the calcium-sensing receptor or reduced function of the receptor resulting from autoantibodies. The distinction between the acquired and hereditary forms is important because glucocorticoids may control the acquired form and parathyroidectomy is rarely necessary for familial hypocalciuric hypercalcemia.
Using bioinformatics pathogenicity triage, mean serum calcium concentrations, and mode of inheritance to identify potential FHH1 or autosomal dominant hypocalcemia-1 (HYPOC1; 601198) variants in 51,289 individuals in the DiscovEHR cohort from a single health system, Dershem et al. (2020) identified 18 different loss-of-function CASR variants (nonsense, frameshift, and missense) in 38 unrelated individuals, 21 of whom were hypercalcemic, and 2 missense CASR variants in 2 unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. The genetic diagnosis of 38 individuals with FHH1 and 2 with HYPOC1 in a cohort of 51,289 persons gave a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for HYPOC1. A Sequence Kernel Association Test (SKAT) revealed associations with cardiovascular, neurologic, and other diseases. Dershem et al. (2020) concluded that FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas HYPOC1 is a major cause of nonsurgical hypoparathyroidism.
To examine the receptor's role in calcium homeostasis and to elucidate the mechanism by which inherited human CASR gene defects cause disease, Ho et al. (1995) created mice in which the Casr gene was disrupted by standard methods of homologous recombination. They found that the phenotype of heterozygous mice mimicked familial hypocalciuric hypercalcemia and homozygous deficient mice exhibited the phenotype of neonatal severe hyperparathyroidism. The findings suggested to the authors that human CASR mutations cause these disorders by reducing the number of functional receptor molecules on the cell surface.
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