Hypocalcemia, Autosomal Dominant 1

A number sign (#) is used with this entry because of evidence that autosomal dominant hypocalcemia-1 (HYPOC1) is caused by heterozygous mutation in the CASR gene (601199) on chromosome 3q21.

Description

Autosomal dominant hypocalcemia-1 is associated with low or normal serum parathyroid hormone concentrations (PTH). Approximately 50% of patients have mild or asymptomatic hypocalcemia; about 50% have paresthesias, carpopedal spasm, and seizures; about 10% have hypercalciuria with nephrocalcinosis or kidney stones; and more than 35% have ectopic and basal ganglia calcifications (summary by Nesbit et al., 2013).

Thakker (2001) noted that patients with gain-of-function mutations in the CASR gene, resulting in generally asymptomatic hypocalcemia with hypercalciuria, have low-normal serum PTH concentrations and have often been diagnosed with hypoparathyroidism because of the insensitivity of earlier PTH assays. Because treatment with vitamin D to correct the hypocalcemia in these patients causes hypercalciuria, nephrocalcinosis, and renal impairment, these patients need to be distinguished from those with other forms of hypoparathyroidism (see 146200). Thakker (2001) suggested the designation 'autosomal dominant hypocalcemic hypercalciuria' for this CASR-related disorder.

Genetic Heterogeneity of Autosomal Dominant Hypocalcemia

Autosomal dominant hypocalcemia-2 (HYPOC2; 615361) is caused by mutation in the GNA11 gene (139313) on chromosome 19p13.

Clinical Features

Pollak et al. (1994) reported a family in which 16 members over 4 generations had autosomal dominant hypocalcemia. Parathyroid hormone levels were normal in affected individuals, and serum phosphate levels were normal or mildly elevated. Affected family members did not exhibit the usual signs and symptoms of hypocalcemia, with the exception of 1 who experienced intermittent overt tetany. Bone films of this patient were normal, and target organ responsiveness to PTH was also normal.

Baron et al. (1996) studied 2 families and 1 sporadic patient with hypocalcemia. 'Family N' had 5 affected individuals over 3 generations who all had low serum calcium concentrations, elevated serum phosphate concentrations, and low serum levels of PTH. Most of the affected members presented in childhood with seizures or tetany, and all required treatment with calcium and vitamin D. Other features included paresthesias, basal ganglia calcification, and nephrolithiasis. The affected mother and daughter of 'family B' had milder symptoms, primarily muscle cramps; the daughter presented for medical attention in adolescence and the mother in adulthood. Serum PTH levels were low despite low serum calcium concentrations. Both pedigrees suggested autosomal dominant transmission. In addition, Baron et al. (1996) reported a female patient who presented in infancy with hypocalcemic seizures. The patient also had muscle cramps and/or tetany and laryngospasm, and exhibited hypercalciuria even during hypocalcemia. Her twin sister, 3 other sibs, and her parents were unaffected.

Pearce et al. (1996) studied 20 affected and 17 unaffected members of 6 kindreds originally diagnosed with isolated hypoparathyroidism, but in whom hypocalcemia was associated with normal serum PTH concentrations. Of the 20 affected individuals, 11 had carpopedal spasm or childhood seizures, 2 of whom had calcification of basal ganglia in addition to seizures; in 1 patient, the seizures continued into adult life. The remaining 9 affected individuals had asymptomatic hypocalcemia; 16 patients also had hypomagnesemia. Urinary calcium excretion was either inappropriately within the normal range or high at the time of diagnosis. Of 19 patients treated with oral vitamin D, serum PTH levels became low or undetectable in 16 of them, and 9 had hypercalciuria. Renal calcification developed in 8 of the 9 hypercalciuric patients, and renal impairment in 7 of them; renal calcification and renal impairment also developed in 7 other patients during vitamin D therapy. Bone mineral density of the lumbar spine was normal in 4 patients from 2 families but increased in 3 patients from another family. Pearce et al. (1996) noted the importance of differentiating patients with familial hypercalciuric hypocalcemia from those with hypoparathyroidism because treatment with vitamin D to correct hypocalcemia in the former may cause hypercalciuria, nephrocalcinosis, and renal impairment.

De Luca et al. (1997) described a 25-year-old woman who presented with fatigue and depression at 18 years of age and was found to be hypocalcemic and hyperphosphatemic, with an inappropriately low-normal serum PTH level. She had a history of a generalized seizure of unknown etiology at 2 weeks of age. Examination at 20 years of age was normal except for short stature, and she had minimal basal ganglia calcifications on CT scan. The authors also reported a 23-year-old woman who had a hypocalcemic seizure at 7 months of age, at which time hyperphosphatemia and low PTH levels were detected. Despite oral calcium and vitamin D analogs, she was repeatedly hospitalized for hypocalcemia and was treated with anticonvulsants for recurrent seizures. At 14 years of age, her CT scan showed calcifications of the frontal cortex and basal ganglia. Both patients had nephrocalcinosis on CT scan but normal renal function.

Mapping

In a 3-generation family segregating autosomal dominant hypocalcemia, Finegold et al. (1994) demonstrated probable linkage to marker D3S1303 on 3q13 by multipoint linkage analysis (maximum lod = 2.71 at theta = 0). Affected family members had low serum calcium, high serum phosphorus, and PTH levels that were low or undetectable; no family member was disabled by symptoms of hypocalcemia.

By use of dinucleotide markers and RFLP analysis in a large Norwegian family with isolated autosomal dominant hypoparathyroidism, Lovlie et al. (1996) excluded the loci for the PTH gene (168450), the PTH receptor gene (168468), and the RET protooncogene (164761) as sites of causative mutations. They found complete cosegregation of this trait with chromosome 3q13 and subsequently identified a missense mutation in the CASR gene (601199.0012).

Molecular Genetics

In a family in which at least 16 members over 4 generations had autosomal dominant hypocalcemia, Pollak et al. (1994) found a missense mutation in the CASR gene (601199.0004). The authors hypothesized that, in contrast to familial hypocalciuric hypercalcemia (145980) in which mild hypercalcemia is caused by mutations in CASR 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 had been described in other G protein-coupled receptors. Xenopus oocytes expressing the mutant receptor exhibited a larger increase in inositol 1,4,5-triphosphate in response to Ca(2+) than did oocytes expressing the wildtype receptor.

In 2 families with autosomal dominant hypoparathyroidism, Baron et al. (1996) identified heterozygous missense mutations in the CASR gene (601199.0009 and 601199.0010, respectively) that were not found in normal controls. In addition, a female infant with hypocalcemic seizures and severe sporadic hypoparathyroidism was found to carry a de novo heterozygous missense mutation in the CASR gene (601199.0011). Baron et al. (1996) suggested that these were activating mutations of the CASR gene. Because the receptor negatively regulates calcium resorption by kidney cells, receptor activation leads to hypercalciuria even in the presence of low serum calcium concentrations, and because the receptor participates in a negative feedback loop regulating parathyroid function, CASR activation is accompanied by hypoparathyroidism.

Pearce et al. (1996) sequenced the CASR gene in probands from 6 families with hypercalciuric hypocalcemia and identified heterozygous missense mutations in 5 probands (601199.0012-601199.0014 and 601199.0016-601199.0017) that cosegregated with hypocalcemia in the respective families and were not found in 55 controls. Transfection studies in HEK293 cells confirmed that the mutant receptors were active at lower extracellular calcium concentrations than wildtype receptors, consistent with a gain of function.

In 2 patients with sporadic isolated hypoparathyroidism, one who was severely symptomatic from infancy and another who presented with mild symptoms at 18 years of age, De Luca et al. (1997) identified de novo heterozygous gain-of-function mutations in the CASR gene (601199.0013 and 601199.0019, respectively). The authors noted that these patients demonstrated that CASR mutations can cause severe disease presenting in infancy or mild disease occurring in adulthood, and that even patients presenting in adulthood without affected relatives should not be assumed to have an autoimmune etiology.

Watanabe et al. (1998) reported a Japanese family with severe autosomal dominant hypocalcemia in which the proband presented with a seizure at 6 days of age and her older brother and mother also experienced seizures and tetany, respectively. However, some patients in the family did not experience seizures despite their severe hypocalcemia. A heterozygous missense mutation (601199.0027) was identified in the fifth transmembrane domain of the CASR protein and was shown to cosegregate with the disease. The mutation was absent in DNA from 50 control subjects. Functional analysis in transiently transfected HEK293 cells demonstrated that the mutant receptor was more sensitive than normal to activation by cytosolic calcium. The authors stated that this condition needs to be differentiated from other causes of hypoparathyroidism.

In a 41-year-old man who had asymptomatic hypocalcemia with a history of recurrent nephrolithiasis, Okazaki et al. (1999) identified heterozygosity for a missense mutation in the CASR gene (601199.0028). The mutation was present in his father, who also had asymptomatic hypocalcemia, but was not found in his normocalcemic mother.

In 5 affected members of a 3-generation family segregating autosomal dominant hypocalcemia, short stature, and premature osteoarthritis, Stock et al. (1999) identified heterozygosity for a missense mutation in the CASR gene (601199.0029).

Lienhardt et al. (2000) reported a 3-generation family with autosomal dominant hypocalcemia caused by a large in-frame deletion of 181 amino acids in the C-terminal tail of CASR (601199.0030). The affected grandfather was homozygous for the deletion but was not more severely affected than the heterozygous affected individuals. Functional studies in transiently transfected HEK293 cells demonstrated a gain of function with the mutant receptor, but there was no difference between cells transfected with mutant cDNA alone or cotransfected with mutant and wildtype cDNAs, consistent with the similar phenotypes of heterozygous and homozygous family members.

In 6 affected members of a 3-generation Japanese family with autosomal dominant hypocalcemia, Nagase et al. (2002) identified heterozygosity for an activating missense mutation in the CASR gene (601199.0038). Five of the 6 patients were asymptomatic; 1 patient had a history of seizures.

In 2 sibs with hypocalcemia, Hendy et al. (2003) identified a heterozygous missense mutation in exon 7 of the CASR gene (601199.0039). Both parents and a third sib were clinically unaffected and were found to be genotypically normal by direct sequencing. However, the mother was mosaic for the mutation as shown by sequence analysis of multiple subclones as well as by denaturing HPLC of the CASR exon 7 leukocyte PCR product. The authors stated that this was the first report of mosaicism for an activating CASR mutation and suggested that care should be exercised in counseling for risks of recurrence in a situation where a de novo mutation appears likely.

In affected members of a 3-generation family with autosomal dominant hypocalcemia, Tan et al. (2003) identified heterozygosity for an activating missense mutation in the CASR gene (601199.0041). Although all affected individuals had marked hypocalcemia, some cases with untreated hypocalcemia exhibited seizures in infancy, whereas others were largely asymptomatic from birth into adulthood.

Hypocalcemia, Autosomal Dominant 1, With Bartter Syndrome

In a 19-year-old man and an unrelated 26-year-old woman, both of whom presented soon after birth with tetany and hypocalcemia and demonstrated features of Bartter syndrome (see 607364), including hypomagnesemia, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronemia, Watanabe et al. (2002) identified heterozygous missense mutations in the CASR gene (601199.0034 and 601199.0035, respectively). The authors noted that in rats it had been shown that activation of this calcium-sensing receptor by higher concentrations of extracellular calcium ions inhibits the activity of the renal outer-medullary potassium channel (KCNJ1; 600359) (see Brown and MacLeod, 2001); the KCNJ1 gene is mutated in type 2 Bartter syndrome (241200). Watanabe et al. (2002) suggested that other molecules that inhibit activity of Bartter syndrome-associated genes might be additional causes of Bartter and related syndromes.

Vargas-Poussou et al. (2002) reported a boy who had severe autosomal dominant hypocalcemia associated with Bartter syndrome-like features, characterized by a decrease in the distal tubular fractional chloride reabsorption rate and negative NaCl balance with secondary hyperaldosteronism and hypokalemia. At 3 weeks of age he was found to have severe hypocalcemia and hyperphosphatemia with an inappropriately low serum PTH; he was diagnosed with neonatal hypoparathyroidism and treated with calcium and vitamin D. At 7 years of age, during an episode of severe hypocalcemia with seizures and electrocardiographic disturbances, he also had polyuria; increased doses of vitamin D resulted in marked hypercalciuria, and he was diagnosed with Bartter syndrome. Renin levels normalized and there was improvement of plasma ion abnormalities and polyuria while on treatment with indomethacin and magnesium, calcium, and potassium supplementation. Metabolic analysis in the absence of indomethacin therapy at age 9 years showed low levels of plasma potassium, calcium, magnesium, and chloride, elevated levels of phosphorus, renin, and aldosterone, and undetectable PTH. Renal ultrasound showed a small stone in the right kidney, without nephrocalcinosis. The patient was negative for mutation in the CLCNKB gene (602023), but sequencing of the CASR gene identified a de novo missense mutation (L125P; 601199.0037) that was not present in his unaffected parents or sister or in 50 unrelated controls. Functional analysis in transfected HEK293 cells revealed that the L125P mutation was more potent than any previously reported gain-of-function mutation, with an EC50 value approximately one-third that of wildtype; Vargas-Poussou et al. (2002) proposed that mutant L125P CASR may reduce NaCl reabsorption in the cortical thick ascending limb of the loop of Henle sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia.

Hu et al. (2004) described monozygotic twin sisters of Italian origin who presented in the neonatal period with apnea, tremors, tonic contractions of the limbs, and seizures, and were found to be severely hypocalcemic, with hyperphosphatemia and undetectable serum PTH. Follow-up at 20 months of age showed low serum calcium, high serum phosphorus, and high urinary calcium excretion. Despite treatment to reduce the hypercalciuria, both sibs developed nephrocalcinosis in early childhood and nephrolithiasis in the second decade of life, although renal function remained normal and neither developed cataract. Low-normal magnesium levels were a constant finding as well. Sequence analysis of the CASR gene revealed a heterozygous de novo gain-of-function missense mutation (K29E; 601199.0053) in the affected twins that was not present in their unaffected parents and sister. In a follow-up study, Vezzoli et al. (2006) reported that the twins developed Bartter syndrome-like features at 22 years of age, with mild hypokalemia, mild hyperreninemia and hyperaldosteronism, but no alkalosis; the authors designated the disorder 'type 5 Bartter syndrome.' Vezzoli et al. (2006) noted that all 4 CASR mutations causing hypocalcemia associated with Bartter syndrome-like features were highly activating, with EC50 values less than 1.5 mmol/L, whereas the EC50 values for other CASR mutations causing autosomal dominant hypocalcemia but not Bartter syndrome ranged between 1.5 and 3 mmol/L.

Clinical Management

Pearce et al. (1996) and Baron et al. (1996) reported that patients with activating CASR mutations generally show a milder degree of hypocalcemia before treatment and more profound hypercalciuria during treatment than those with idiopathic hypoparathyroidism. To test the validity of this generalization, Yamamoto et al. (2000) analyzed the data of serum and urinary calcium collected from 85 patients with idiopathic hypoparathyroidism and 15 with activating CASR mutations. The mean serum calcium concentration before treatment was significantly higher in patients with activating CASR mutations than in those with idiopathic hypoparathyroidism, but there was substantial overlap in the range of hypocalcemia between the 2 groups. The mean urinary calcium/creatinine ratio (Ca/Cr) in patients with activating CASR mutations before treatment was almost equal to that in normocalcemic controls and markedly higher than in patients with idiopathic hypoparathyroidism. In contrast to pretreatment findings, however, the degree of hypercalciuria during treatment was not different between the 2 disorders. The data points of urinary Ca/Cr plotted as a function of serum calcium were not separable between 15 patients with CASR mutations and 40 with idiopathic hypoparathyroidism. Comparison of urinary Ca/Cr between 2 patients with a CASR mutation and 7 with idiopathic hypoparathyroidism over a wide range of serum calcium concentrations measured during 4 to 8 years of treatment also indicated that the 2 disorders were inseparable. The authors suggested that inappropriately normal urinary Ca/Cr in patients with untreated hypocalcemia, mostly of mild degree, might be a better biochemical clue than the development of severe hypercalciuria during treatment to suspect gain-of-function mutations in the CASR.

Because thiazide diuretics have been used successfully to treat patients with hypercalciuria and hypoparathyroidism, they are theoretically useful in reducing urine calcium excretion and maintaining serum calcium levels in patients with gain-of-function mutations of the CASR gene. Sato et al. (2002) reported on the clinical course, molecular analysis, and effects of hydrochlorothiazide therapy in 2 Japanese patients with gain-of-function mutations of the CASR gene (601199.0034 and 601199.0037). Within a few weeks after birth, they developed generalized tonic seizures due to hypocalcemia. Despite treatment with the standard dose of 1,25-dihydroxyvitamin D3 in one patient and 1-alpha-hydroxyvitamin D3 in the other, acceptable serum calcium levels near the lower limit of normal were not established, and their urinary calcium excretion inappropriately increased. Addition of hydrochlorothiazide (1 mg/kg) reduced their urinary calcium excretion and maintained their serum calcium concentrations near the lower limit of normal, allowing the 1,25-dihydroxyvitamin D3 and 1-alpha-hydroxy vitamin D3 doses to be reduced, and alleviated their symptoms.

In an infant presenting with hypocalcemia at 3 weeks of age who was found to have an activating mutation in the CASR gene (601199.0045), Mittelman et al. (2006) demonstrated short-term efficacy of treatment with PTH(134). During treatment, the patient had no further serious hypocalcemic episodes, and his urinary calcium excretion declined remarkably. The authors concluded that PTH should be evaluated further as a treatment of autosomal dominant hypocalcemia in young patients.

Animal Model

Hough et al. (2004) described a mouse model of autosomal dominant hypocalcemia, named Nuf, originally identified by having opaque flecks in the nucleus of the lens in a screen for eye mutants. Nuf mice displayed ectopic calcification, hypocalcemia, hyperphosphatemia, cataracts, and inappropriately reduced levels of plasma parathyroid hormone. These features are similar to those observed in patients with autosomal dominant hypocalcemia. An activating missense mutation in the Gprc2a gene, the mouse ortholog of human CASR, was identified as the cause of the phenotype. Ectopic calcification and cataract formation tended to be milder in the heterozygous Nuf mice, indicating that an evaluation for such abnormalities in autosomal dominant hypocalcemia patients who have activating CASR mutations is required.