Familial hypomagnesemia with hypercalciuria and nephrocalcinosis

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; OMIM 248250) is a rare autosomal recessive kidney disease caused by mutations in the CLDN16 or CLDN19 genes encoding the proteins claudin-16 and claudin-19, respectively. These are involved in paracellular magnesium and calcium transport in the thick ascending limb of Henle’s loop and account for most of the magnesium reabsorption in the tubules. FHHNC is characterized by hypomagnesaemia, hypercalciuria, and nephrocalcinosis, and progresses to kidney failure, requiring dialysis and kidney transplantation mainly during the second to third decades of life. Patients carrying CLDN19 mutations frequently exhibit associated congenital ocular defects leading to variable visual impairment. Despite this severe clinical course, phenotype variability even among siblings has been described in this disease, suggesting unidentified epigenetic mechanisms or other genetic or environmental modifiers. Currently, there is no specific therapy for FHHNC. Supportive treatment with high fluid intake and dietary restrictions, as well as magnesium salts, thiazides, and citrate, are commonly used in an attempt to retard the progression of kidney failure. A kidney transplant remains the only curative option for kidney failure in these patients. In this review, we summarize the current knowledge about FHHNC and discuss the remaining open questions about this disorder.

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Acknowledgements

We would like to acknowledge the FHHNC patient advocacy group Hipofam (Asociación para la Información y la Investigación de la Hipomagnesemia Familiar) (http://hipofam.org) for their valuable support and contribution to our research activity.

Funding

This work was funded by grants from the Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (PI14/01107 and PI18/01107), the Department of Health of the Basque Government (2017111014), and the patient advocacy group Hipofam (Asociación para la Información y la Investigación de la Hipomagnesemia Familiar).

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Correspondence to Gema Ariceta.

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1. d; 2. b; 3. d; 4. a; 5. d

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Vall-Palomar, M., Madariaga, L. & Ariceta, G. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Pediatr Nephrol (2021). https://doi.org/10.1007/s00467-021-04968-2

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Keywords

  • Hypomagnesemia-hypercalciuria-nephrocalcinosis
  • FHHNC
  • CLDN16
  • CLDN19
  • Claudin
  • Tight junctions
  • Macular colobomata