Clinical feature: 

Definition: 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.

History: The first family as described by Michelis in 1972 exhibited renal magnesium wasting and a distal renal tubular acidosis.

Clinical picture: 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.
   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.

Diagnostics: 

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.  » » » 

Differential: The most important differential is the cousin disorder with ocular findings that closely resembles as it is caused by the same pathogenetic mechanism.  » » » 
   Patients with hypomagnesemia and secondary hypocalcemia (HSH) have normal renal calcium excretion. Their hypocalcemia is treated with magnesium supplemetation, but does not respond well to calcium or vitamin D supplementation.  » » » 
   Isolated hypomagnesemias (IDH/IRH) go without hypocalcemia and hypercalciuria.  » » » 

Literature: 

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.
Weber S et al. (2001) Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.
Müller D et al. (2003) A novel claudin 16 mutation associated with childhood hypercalciuria abolishes binding to ZO-1 and results in lysosomal mistargeting.
Schmitz C et al. (2007) Molecular components of vertebrate Mg2+-homeostasis regulation.
Vargas-Poussou R et al. (2008) Report of a family with two different hereditary diseases leading to early nephrocalcinosis.
Vezzoli G et al. (2008) Hypercalciuria revisited: one or many conditions?
Ikari A et al. (2008) Activation of a polyvalent cation-sensing receptor decreases magnesium transport via claudin-16.
Konrad M et al. (2008) CLDN16 genotype predicts renal decline in familial hypomagnesemia with hypercalciuria and nephrocalcinosis.
Hou J et al. (2008) Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex.
Vezzoli G et al. (2008) Update on primary hypercalciuria from a genetic perspective.
Alexander RT et al. (2008) Molecular determinants of magnesium homeostasis: insights from human disease.
Günzel D et al. (2009) Function and regulation of claudins in the thick ascending limb of Henle.
Hampson G et al. (2008) Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC): compound heterozygous mutation in the claudin 16 (CLDN16) gene.
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).