Hypomagnesemia 3, Renal

A number sign (#) is used with this entry because of evidence that hypomagnesemia-3 (HOMG3) is caused by homozygous or compound heterozygous mutation in the claudin-16 gene (CLDN16; 603959) on chromosome 3q28.

Description

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a progressive renal disorder characterized by excessive urinary Ca(2+) and Mg(2+) excretion. There is progressive loss of kidney function, and in about 50% of cases, the need for renal replacement therapy arises as early as the second decade of life (summary by Muller et al., 2006). Amelogenesis imperfecta may also be present in some patients (Bardet et al., 2016).

A similar disorder with renal magnesium wasting, renal failure, and nephrocalcinosis (HOMG5; 248190) is caused by mutations in another tight-junction gene, CLDN19 (610036), and is distinguished by the association of severe ocular involvement.

For a discussion of phenotypic and genetic heterogeneity of familial hypomagnesemia, see HOMG1 (602014).

Clinical Features

Friedman et al. (1967) described convulsions in infants in the neonatal period. Primary hypomagnesemia, thought to be due to a defect in intestinal absorption, was present. Associated hypocalcemia was corrected by administration of magnesium alone. The genetic basis of the defect was suggested by its persistence over a period of months and by the fact that the parents were first cousins. Salet et al. (1970) reported the disorder in brother and sister.

Manz et al. (1978) described 2 sisters with polyuria, hyposthenuria, hypomagnesemia, hypercalciuria, advanced nephrocalcinosis, low citrate excretion, and low glomerular filtration rates. Acid loading showed incomplete distal tubular acidosis. Hypomagnesium was due to renal magnesium wasting. Their hypothesis that the primary defect was one in renal tubular transport of magnesium was supported by the report by Passer (1976) of 2 adult patients with hypomagnesemia due to intestinal malabsorption combined with incomplete renal tubular acidosis. Both patients responded to Mg supplementation with correction of the renal acidification defect. Manz et al. (1978) suggested that the same disorder was present in the sibs reported by Michelis et al. (1972). Five pairs of affected sibs have been reported (see, e.g., Geven et al., 1987), including 2 instances of affected brother and sister (Evans et al., 1981). A parent (Paunier and Sizonenko, 1976) and a child (Freeman and Pearson, 1966) of a patient were said to be affected in other reports.

Hennekam and Donckerwolcke (1983) observed Chinese brother and sister with primary hypomagnesemia. The 5-year-old sister, the proband, was admitted to hospital because of tetany following gastroenteritis for several days. She had never before had spasms. Intravenous calcium gluconate had no effect, but after magnesium chloride intravenously, the tetany stopped at once. The affected 17-year-old brother was discovered on family screening. He complained of muscle weakness for more than 2 years and had paresthesias of the fingers and spontaneous spasms. During venipuncture, Trousseau sign was elicited. In the sister and brother, serum magnesium was 0.56 and 0.49 nmol/l, respectively (normal, 0.7-1.0), and serum calcium was 2.09 and 2.31 nmol/l, respectively (normal, 2.25-2.75). The parents denied consanguinity. These authors found a total of 32 reported cases of primary hypomagnesemia of which 10 were in females. Although symptoms usually began in the first 3 months of life, they were delayed to the 36th year in the extreme. Consanguineous parents were reported by Becker et al. (1979) and by Friedman et al. (1967).

Secondary magnesium-losing kidney can be caused by diuretics, gentamicin, mercury-containing laxatives, transplanted kidney, urinary tract obstruction, and the diuretic phase of acute renal failure. The disorder may be incorrectly diagnosed as primary hypoparathyroidism because of tetany and hypocalcemia, or as Bartter syndrome because of secondary renal potassium wasting. The diagnosis is made by finding hypomagnesemia with inappropriately high urinary magnesium excretion. Nephrocalcinosis is frequent. Chondrocalcinosis with arthritis is a recognized complication of magnesium depletion. Evans et al. (1981) reported 2 brothers, aged 39 and 29, with infertility and severe oligospermia but normal endocrine function. One of the brothers had sensorineural deafness. Neither deafness nor male infertility had been reported previously in this disorder. Dudin and Teebi (1987) described primary hypomagnesemia with secondary hypocalcemia as a cause of infantile tetany and convulsions in an Arab girl of consanguineous parentage.

Praga et al. (1995) used the designation 'familial hypomagnesemia with hypercalciuria and nephrocalcinosis' and cited the patients reported by Michelis et al. (1972), Manz et al. (1978), Evans et al. (1981), Ulmann et al. (1985), and Rodriguez-Soriano et al. (1987) as examples of this disorder. They studied 8 patients from 5 different families. Mean age at diagnosis was 15 years with a range from 5 to 25. All 8 patients had polyuria-polydipsia; 5 had ocular abnormalities (corneal calcifications, chorioretinitis, nystagmus, myopia); 5 had recurrent urinary tract infections; and 2 had recurrent renal colic with passage of stones. Bilateral nephrocalcinosis was observed in all cases. The mean serum magnesium was 1.1 mg/dl with inappropriately high urinary magnesium excretions (70 mg/day). Hypercalciuria was present in every case except in those with advanced renal insufficiency. Serum parathormone levels were abnormally high. Serum Mg and urinary Ca became normal after renal transplantation in 5 patients. None of the 26 members of 4 of the affected families showed hypomagnesemia, renal insufficiency, or nephrocalcinosis; however, 11 (42%) had hypercalciuria and 4 of them presented with recurrent renal stones. Two family members had medullary sponge kidneys. In 1 family, 2 affected individuals were double first cousins. The daughters of 2 sisters married 2 brothers. In another family, the affected brother and sister in one sibship were cousins of an affected female in a first-cousin sibship. Praga et al. (1995) speculated that isolated hypercalciuria might be a heterozygous manifestation.

Challa et al. (1994) described 2 female sibs with primary idiopathic hypomagnesemia, born to consanguineous parents. Both presented at 6 weeks of age, with convulsions and persistent hypocalcemia, which could not be controlled with anticonvulsants and/or calcium gluconate. Serum magnesium values of the mother and father were just below the normal range with normal serum calcium.

Shalev et al. (1998) described the clinical presentation and long-term outcomes of 15 patients with autosomal recessive primary familial hypomagnesemia. The most common (67%) presenting events were generalized hypocalcemic-hypomagnesemic seizures at a mean age of 4.9 weeks. Thirteen infants who were treated soon after diagnosis with high-dose enteral magnesium developed normally. Their serum calcium returned to normal concentrations, but serum magnesium could not be maintained at normal concentrations. Delay in establishing a diagnosis led to a convulsive disorder with permanent neurologic impairment in 2 infants. Reported complications of prolonged hypomagnesemia such as renal stones, hypertension, arrhythmias, sudden death, or dyslipidemia were not observed.

Bardet et al. (2016) examined 5 unrelated patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis due to CLDN16 mutations. The patients were from diverse geographic backgrounds and ranged in age from 6 to 45 years. Detailed dental examination revealed enamel defects characteristic of amelogenesis imperfecta, including demarcated and diffuse opacities, reduced amount of enamel with pitted defects, and/or horizontal grooves. Several permanent teeth failed to erupt in 2 patients, with persistence of deciduous teeth in one. Cone beam computed tomography in these 2 patients revealed tooth ankylosis. No gingival hyperplasia was observed in any of the patients.

Childhood Hypercalciuria, Self-Limiting

Muller et al. (2003) studied a Scandinavian family in which 3 of 5 sibs had self-limiting childhood hypercalciuria. The proband came to attention because of nocturnal enuresis and was found to have marked hypercalciuria and renal medullary nephrocalcinosis. The mother reported nocturnal enuresis and urinary tract infections in 2 older sibs who were found to be similarly affected. During a 6-year follow-up period, urinary Ca(2+) excretion decreased in each consecutive year in the affected children and, despite their age differences, there was a clear linear decrease over time in all patients. In the oldest affected sib, normal values for Ca(2+) excretion were found at the time of last examination, although nephrocalcinosis was still detectable on renal ultrasound. Glomerular filtration rate remained normal in all 3 affected children, with no evidence of further progression of medullary nephrocalcinosis. In all affected members, Mg(2+) levels were within the low normal range, although they were consistently lower than in the unaffected members of the family and urinary Mg(2+) excretion was slightly elevated.

In addition to the family of Scandinavian origin with 3 affected sibs, Muller et al. (2003) also studied a Spanish family in which the parents were second-degree relatives and 1 of 4 brothers had childhood self-limiting hypercalciuria. The boy first came to attention at the age of 5 years for recurring urinary tract infections and nephrolithiasis. During follow-up, urinary Ca(2+) excretion decreased and was within normal range at the age of 20 years, and nephrocalcinosis did not show progression.

Mapping

Using whole genome scanning in 12 kindreds with typical recessive renal hypomagnesemia, Simon et al. (1999) demonstrated linkage to a segment of chromosome 3q with a lod score of 6.8. The trait was further localized to an approximately 1-cM interval flanked by loci 539-5 and D3S1288.

Weber et al. (2000) performed linkage analysis in 8 families with hypomagnesemia, including 3 with consanguineous marriages. They found linkage to microsatellite markers on 3q27 with a maximum 2-point lod score of 5.208 for D3S3530 without evidence for genetic heterogeneity. Haplotype analysis revealed crucial recombination events reducing the critical interval to 6.6 cM.

Molecular Genetics

By exon trapping, Simon et al. (1999) identified a gene at the chromosome 3q locus linked to recessive renal hypomagnesemia that they called paracellin-1 (CLDN16; 603959). By SSCP and sequencing, they found 10 different CLDN16 mutations (see, e.g., 603959.0001-603959.0009) in 10 of the kindreds with primary hypomagnesemia. The mutations were found in homozygous state in 8 kindreds and in compound heterozygous state in 2 others.

In 8 families with primary hypomagnesemia mapping to 3q27, including the family originally described by Manz et al. (1978), Weber et al. (2000) identified homozygosity or compound heterozygosity for mutations in the CLDN16 gene (see, e.g., 603959.0002 and 603959.0010-603959.0014).

In 2 sibs with familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Muller et al. (2006) identified homozygosity for a nonsense mutation in the CLDN16 gene (603959.0016). One of the sibs presented with hypocalcemic tetany, a phenomenon that had not previously been described in this disorder.

In a 2.5-year-old boy with hypomagnesemia and nephrocalcinosis, born of consanguineous Iranian parents, Muller et al. (2006) identified homozygosity for a nonsense mutation in the CLDN16 gene (603959.0017). The patient's development was normal until 9 months of age, when he began having recurrent urinary tract infections. Ultrasonography at 2.5 years of age revealed medullary nephrocalcinosis, and he was also found to have hypomagnesemia, hypercalciuria, and a reduced glomerular filtration rate.

In 5 unrelated patients with familial hypomagnesemia with hypercalciuria, nephrocalcinosis, and amelogenesis imperfecta, Bardet et al. (2016) identified mutations in the CLDN16 gene: homozygous mutations (see, e.g., 603959.0002) in 4 patients from consanguineous families and compound heterozygous mutations (603959.0018-603959.0019) in a Congolese patient with no family history of consanguinity.

Childhood Hypercalciuria, Self-Limiting

In affected members of a Scandinavian family and a Spanish family with self-limiting childhood hypercalciuria, Muller et al. (2003) identified homozygosity for a missense mutation in the CLDN16 gene (603959.0015).

Genotype/Phenotype Correlations

Godron et al. (2012) retrospectively reviewed 32 patients from 26 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis due to CLDN16 or CLDN19 mutations. Ocular abnormalities were found only in patients with CLDN19 mutations, who also displayed more severe renal impairment than patients with CLDN16 mutations.