Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Hypomagnesemia with hypercalciuria and nephrocalcinosis

FHHNC without ocular involvement is an autosomal recessive disorder with hypomagnesemia, hypercalciuria and nephrocalcinosis often complicated by progressive chronic renal failure during childhood or adolescence. Loss of function mutations in the CLDN16 gene are the underlying genetic cause.

Historical Aspects

The first family as described by Michelis in 1972 exhibited renal magnesium wasting and a distal renal tubular acidosis.[Error: Macro 'ref' doesn't exist]

Clinical Findings

Signs and Symptoms

The first typical symptom is nephrocalcinosis, which becomes apparent in childhood or adolescence. if not a sibling is affected or consanguinity present family history is not instructice as with all recessive disorders. Although the prevailing symptoms are renal and every so often end-stage renal failure develops, it is an multiorgan disorder. Symptoms include tetany, seizures, hypertension, gout, deafness, chondrocalcinosis, and rickets. if ocular symptoms present, the cousin disorder FHHNC with ocular abnormalities should be considered.

Laboratory Findings

Plasma magnesium is 0.59 ± 0.06 mmol/l. Renal magnesium excretion is inaprpriatly high 2.07 ± 0.073mmol/d. The same holds true for fractional magnesium excretion 12.5 ± 4.7%. Of note, trenal calcium excretion is also elevated. Urinary calcium creatinin ratio is 1.88 ± 0.67.

Diagnosis

Often the patients present with urinary tract infections and carful sultrasound examination then reveals nephrocalcinosis. The diagnosis is further confirmed by laboratory findings and finally proved by molecular genetic tests of CLDN16.

Management

It is only a symptomatic therapy available for this disorder, which includes substitution of renal mineral losses, urinary dilution by increase water intake, the complex care for recurrent kidney stones, and antibiotics if urinary tract infections occur. Unfortunately these measures exert minimal effect on the progression of renal failure, so the ultimate therapie is a renal transplant after which the disease is definitely cured.

Symptoms

Hypomagnesaemia
Hypomagnesemia is a cardinal symptom of FHHNC without ocular involvement. Typical of this disorder is further hypocalcemia, due to excessive renal losses of divalent cations; nephrocalcinosis; recurrent kidney stones; and progressive renal failure.
Hypocalcemia
Hypocalcemia is typical of FHHNC without ocular involvement though hypomagnesemia is essential. Other crucial symptoms are nephrocalcinosis, recurrent kidney stones, and progressive renal failure.
Nephrocalcinosis
Nephrocalcinosis in FHHNC without ocular involvement is accompanied by hypomagnesemia and hypocalemia due to excessive renal losses. By contrast to other diseases with nephrocalcinosis, progressive renal failure is typical.
Hypercalciuria
Hypercalciuria in FHHNC is accompanied by hypomagnesemia and nephrocalcinosis.

Systematic

Hypomagnesemia
EGFR
Gitelman syndrome
Hereditary myokymia type 1
Hypomagnesemia with hypercalciuria and nephrocalcinosis
CLDN16
Hypomagnesemia with hypercalciuria and nephrocalcinosis with ocular involvement
Hypomagnesemia with normocalciuria
Intestinal hypomagnesemia with secondary hypocalcemia
Isolated dominant hypomagnesemia
Renal cysts and diabetes (RCAD)
Renal hypomagnesemia 6
TRPM7

References:

1.

Weber S et al. (2000) Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis maps to chromosome 3q27 and is associated with mutations in the PCLN-1 gene.

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2.

Vezzoli G et al. (2008) Hypercalciuria revisited: one or many conditions?

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3.

Hou J et al. (2008) Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex.

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4.

Vezzoli G et al. (2008) Update on primary hypercalciuria from a genetic perspective.

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5.

Alexander RT et al. (2008) Molecular determinants of magnesium homeostasis: insights from human disease.

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6.

Günzel D et al. (2009) Function and regulation of claudins in the thick ascending limb of Henle.

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7.

Michelis MF et al. (1972) Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis. (Evaluation of the pathophysiological role of parathyroid hormone).

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8.

Weber S et al. (2001) Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

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9.

Müller D et al. (2003) A novel claudin 16 mutation associated with childhood hypercalciuria abolishes binding to ZO-1 and results in lysosomal mistargeting.

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10.

Schmitz C et al. (2007) Molecular components of vertebrate Mg2+-homeostasis regulation.

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11.

Vargas-Poussou R et al. (2008) Report of a family with two different hereditary diseases leading to early nephrocalcinosis.

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12.

Ikari A et al. (2008) Activation of a polyvalent cation-sensing receptor decreases magnesium transport via claudin-16.

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13.

Konrad M et al. (2008) CLDN16 genotype predicts renal decline in familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

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14.

Hampson G et al. (2008) Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC): compound heterozygous mutation in the claudin 16 (CLDN16) gene.

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Update: Sept. 26, 2018