Familial hypomagnesemia with hypercalciuria and nephrocalcinosis

Abstract

Very few patients with familial hypomagnesemia, hypercalciuria and nephrocalcinosis have been described. Information about clinical course, familial studies or evolution after renal transplantation is very scant. We have studied eight patients with this syndrome who belong to five different families. The mean age at diagnosis was 15 +/- 7 years (5 to 25 years). The primary clinical data were polyuria-polydipsia (8 cases), ocular abnormalities (5), recurrent urinary tract infections (5) and recurrent renal colics with stone passage (2). Bilateral nephrocalcinosis was observed in all cases. Every patient showed hypomagnesemia (1.1 +/- 0.2 mg/dl) with inappropriately high urinary magnesium (Mg) excretions (70 +/- 17 mg/day), Mg clearances (4.4 +/- 1.2 ml/m) and Mg fractional excretions (16.2 +/- 7.1%). Hypercalciuria was present in every case except in those with advanced renal insufficiency. Serum parathormone levels were abnormally high. Serum calcium (Ca), phosphorus and potassium, and urinary excretions of uric acid and oxalate were normal. Neither chronic oral Mg administration nor thiazide diuretics normalized serum Mg levels or urinary Ca excretions, respectively. Follow-up was 6 +/- 4.5 years. Renal function worsened in every case with six patients starting on chronic dialysis after 4.3 +/- 3.8 years. The progression rate of renal insufficiency correlated with the severity of nephrocalcinosis. Five patients have received a kidney graft, and their serum Mg and urinary Ca have always been within normal values after transplantation. Twenty-six members of four of the affected families were studied: none of them showed hypomagnesemia, renal insufficiency or nephrocalcinosis. However, eleven cases (42%) had hypercalciuria and four of them presented with recurrent renal stones. Two family members had medullary sponge kidneys. In conclusion, progression to renal insufficiency is common in this syndrome; oral Mg and thiazide diuretics are ineffective to correct abnormalities. After kidney graft, tubular handling of Mg and Ca was normal. A striking incidence (42%) of hypercalciuria was found in the familial study.

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis maps to chromosome 3q27 and is associated with mutations in the PCLN-1 gene

“…It was speculated that isolated hypercalciuria might appear as a milder phenotype of the disease, consistent with an autosomal dominant mode of inheritance with variable phenotypic expression. 6 Accepting an autosomal recessive mode of inheritance of FHHNC, as supported by the results of linkage and mutational analysis, family members with hypercalciuria and/or nephrolithiasis seem to be symptomatic heterozygotes -a phenomenon not commonly seen in autosomal recessive diseases.…”

“…2,7 Some authors report elevated serum PTH levels early during the course of disease, independent of reduced GFR and therefore probably reflecting chronic calcium depletion. 6 Ocular abnormalities, such as corneal calcifications, chorioretinitis, horizontal nystagmus and severe myopia have been described as inconsistent findings in families affected by FHHNC. 6,8 In family members not affected by FHHNC, history of hypercalciuria and kidney stones is frequent.…”

“…6 Ocular abnormalities, such as corneal calcifications, chorioretinitis, horizontal nystagmus and severe myopia have been described as inconsistent findings in families affected by FHHNC. 6,8 In family members not affected by FHHNC, history of hypercalciuria and kidney stones is frequent. 6 FHHNC has to be differentiated from other forms of familial hypomagnesaemia.…”

“…6,8 In family members not affected by FHHNC, history of hypercalciuria and kidney stones is frequent. 6 FHHNC has to be differentiated from other forms of familial hypomagnesaemia. The autosomal dominant form of isolated renal magnesium loss (MIM 154020) has recently been mapped to chromosome 11q23 in two large Dutch families probably sharing a common ancestor.…”

“…[1][2][3][4][5][6] The mode of inheritance is autosomal recessive. Besides marked hypomagnesaemia the affected individuals present with polyuria, hyposthenuria, hypercalciuria, advanced nephrocalcinosis, low citrate excretion and impaired glomerular filtration rate (GFR).…”