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Familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement
Familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement (FHHN) is a form of familial primary hypomagnesemia (FPH; see this term), characterized by recurrent urinary tract infections, nephrolithiasis, bilateral nephrocalcinosis, renal magnesium (Mg) wasting, hypercalciuria and kidney failure.
ORPHA:31043Classification level: Disorder
- FHHNC without severe ocular involvement
- Renal hypomagnesemia type 3
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Childhood
- ICD-10: E83.4
- OMIM: 248250
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
To date, more than 110 individuals have been reported in the literature.
FHHN has an onset in childhood and the clinical manifestations are recurrent urinary tract infections, polyuria, polydipsia, enuresis, hematuria, nephrolithiasis and bilateral nephrocalcinosis. Some patients fail to thrive during early childhood and experience seizures, vomiting, abdominal pain, tetany and rarely rickets. Ocular involvement is rare and when observed it is relatively mild (myopia, hypermetropia, astigmatism and strabism). Approximately one third of patients progress to renal failure or end-stage renal disease (ESRD) during adolescence.
FHHN is characterized by impaired tubular reabsorption of Mg and calcium (Ca) in the thick ascending limb of Henle's loop due to mutations in CLDN16 (3q27), which encodes claudin-16 (previously known as paracellin 1). A significant residual function is observed in several missense mutations, whereas a complete loss of claudin-16 function appears to be more severe (disease presenting earlier and often progressing to kidney failure at a significantly younger age).
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.