IllnessHypomagnesiämie, hyperkalziurisch; Differentialdiagnose

NGS +

[Sanger]

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; OMIM 248250) is a progressive kidney disease characterized by hypomagnesemia, hypercalciuria and nephrocalcinosis due to a renal absorption disorder of magnesium and calcium. The disease manifests itself in childhood with polyuria, polydipsia, recurrent urinary tract infections, vomiting, abdominal pain and failure to thrive and leads to chronic kidney failure as it progresses. Although the clinical picture is usually severe, the clinical manifestations can also be subject to a certain degree of variability in affected siblings. In some cases (so-called FHHNCOI), ocular involvement is also present (e.g. myopia, nystagmus, retinal dysplasia).

The disease is heterogeneous and is inherited in an autosomal recessive manner. Pathogenic variants have been detected in the CLDN16 and CLDN19 (FHHNCOI) genes. CASR gene-related hypocalciuric hypercalcemia (hypocalcemia (or hypercalcemia), familial hypocalciuric hypercalcemia and hyperparathyroidism in newborns) is an important differential diagnosis due to similar clinical symptoms and is also covered in the panel. This disease is inherited in an autosomal dominant manner.

There is currently no specific therapy available for FHHNC. Symptomatic treatment with fluid intake, magnesium salts, thiazide diuretics and citrates can delay the progression of kidney failure. By knowing the genetic cause, the course of the disease can be better assessed, but in most cases a kidney transplant is the only treatment option.

If FHHNC/FHHNCOI or CASR-related kidney disease has been confirmed in an affected person by the detection of (one of) the pathogenic variants, relatives can be offered predictive testing for the familially identified variants as part of genetic counseling.

Literature

Vall-Palomar et al. 2021, PMID: 33595712; https://pubmed.ncbi.nlm.nih.gov/33595712/

Daan H H M Viering et al. 2017, PMID:27234911; https://pubmed.ncbi.nlm.nih.gov/27234911/

• ALias: Familial hypomagnesemia with secondary hypocalcemia
• Alias: Familial primary hypomagnesemia with hypercalciuria + nephrocalcinosis (CLDN16, CLDN19)
• Alias: Michellis-Castrillo syndrome
• Allelic: Epilepsy idiopathic generalized, susceptibility to, 8 (CASR)
• Allelic: Hyperparathyroidism, neonatal (CASR)
• Allelic: Hypocalcemia, AD (CASR)
• Allelic: Hypocalciuric hypercalcemia, type I (CASR)
• Bartter syndrome, type 3 (CLCNKB)
• Hypocalcemia, AD, with Bartter syndrome (CASR)
• Hypomagnesemia 3, renal (CLDN16)
• Hypomagnesemia 5, renal, with ocular involvement (CLDN19)