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 ... 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). - 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 ... 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 (HP). Patients with FHH had higher creatinine clearance values than HP patients but higher serum magnesium levels than both normals and HP patients. Elevated magnesium level was proportional to elevated calcium level in FHH but was inversely related in HP. Urinary excretion of both calcium and magnesium was significantly lower in FHH than in HP. Abnormal serum protein binding of calcium and magnesium in FHH was excluded. 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).
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 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 (601199.0002). 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. In addition to familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, mutation in the CASR gene can cause autosomal dominant hypocalcemia. Pollak et al. (1994) hypothesized that, in contrast to familial hypocalciuric hypercalcemia in which mild hypercalcemia is caused by mutations that reduce the activity of the Ca(2+)-sensing receptor, mild hypocalcemia might be caused by a mutation that inappropriately activates the receptor at subnormal Ca(2+) levels. Such activating mutations have been described in other G protein-coupled receptors. In 1 of 2 probands with hypocalcemia, they indeed found a missense mutation (glu128ala; see 601199.0004) in the CASR gene, which they symbolized PCAR1. 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 an HHC1 mutation by PCR and SSCP. Nucleotide sequencing showed a G-to-C transversion at nucleotide 118 that resulted in a pro40-to-ala amino acid substitution. 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) did a mutation search of the CASR gene in 9 unrelated kindreds with a total of 39 affected members with familial benign hypercalcemia and in 3 unrelated children with sporadic NHPT. In 6 of 9 FBH kindreds, heterozygosity for a novel mutation (1 missense and 5 missense) were found; in the 3 children with NHPT, 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 FBH from mild primary hyperparathyroidism which otherwise can be clinically difficult. These results indicated that NHPT 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 NHPT were normocalcemic. All 3 children with NHPT 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 NHPT children, who all became hypocalcemic and required vitamin D replacement postoperatively. The clinical features of 2 of the cases had been previously reported by Meeran et al. (1994) and Dezateux et al. (1984). 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. 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 NHPT resulting from a de novo, heterozygous missense mutation in the CASR gene. 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). The proband's CASR gene showed a missense mutation (R185Q) at codon 185 (601199.0003). 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 NHPT 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 NHPT 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 NHPT and one of them, patient A-26, inherited the abnormal CASR from her father. Miyashiro et al. (2004) reported 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. She carried a leu13-to-pro mutation in homozygosity (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 mutation found in the very beginning N-terminal portion of the CASR may be associated with this phenotype. - 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.