Caner Alparslan, Belde Kasap-Demir, Fatma Mutlubaş, Önder Yavaşcan, Elif Perihan Öncel, Demet Alaygut, Martin Konrad, Sinem Akbay, Mansur Tatlı

A novel homozygous W99G mutation in CLDN-16 gene causing familial hypomagnesemic hypercalciuric nephrocalcinosis in Turkish siblings

Familial hypomagnesemic hypercalciuric nephrocalcinosis (FHHNC)(OMIM: 248250) is characterized by hypomagnesemia, hypercalciuria andnephrocalcinosis. FHHNC inevitably progresses to end-stage renal diseasein decades. Mutations in CLDN-16 and CLDN-19 genes are associated withdisrupted magnesium handling in the thick ascending limp of Henle’s loop.Patients with mutations in these genes share similar clinical features, andthose with CLDN-19 gene mutations have ocular findings in addition.A 2-month-old boy, was admitted to our clinic with the complaints of upperrespiratory tract infection. He was the first-born child of consanguineousparents. Laboratory findings revealed hypocalcemia and hypomagnesemia.Bilateral medullary nephrocalcinosis was detected on abdominal ultrasound.His ophthalmologic examination was unremarkable. With hypomagnesemia,hypercalciuria and nephrocalcinosis, the patient was considered to have FHHNC.Oral magnessium supplementation was initiated. Four years of follow-up hasbeen completed uneventfully.When 6-days-old the brother of the case above was admitted with seizure.The patient was resistant to calcium and anticonvulsant drugs and the seizureactivity could only be controlled after magnesium infusion. Biochemistry profilerevealed hypocalcemia and hypomagnesemia. Urinary calcium extraction was11 mg/kg/day. Medullary nephrocalcinosis was reported on renal ultrasound.His eye examination, echocardiography, transfontanel ultrasound andelectroencephalography were normal. Due to the triad of hypomagnesemia,hypercalciuria and nephrocalcinosis, and the medical history of his elderbrother, he was diagnosed with FHHNC. After correction of the electrolyteabnormalities, he was discharged from hospital and is currently being followedup without any problem.In this manuscript, we shared our experience about a novel homozygousmutation (W99C) in CLDN-16 gene causing FHHNC in a couple of Turkishsiblings.

PDF

___

1. Tasic V, Dervisov D, Koceva S, Weber S, Konrad M. Hypomagnesemia with hypercalciuria and nephrocalcinosis: case report and a family study. Pediatr Nephrol 2005; 20: 1003-1006.
2. Nadarajah L, Khosravi M, Dumitriu S, et al. A novel claudin-16 mutation, severe bone disease, and nephrocalcinosis. Lancet 2014; 383: 98.
3. Kasap B, Alparslan C, Bal A, et al. Ocular involvement in a child with medullary nephrocalcinosis. Pediatr Nephrol 2013; 28: 627-630.
4. Konrad M, Hou J, Weber S, et al. CLDN16 genotype predicts renal decline in familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol 2008; 19: 171-181.
5. Godron A, Harambat J, Boccio V, et al. Familial h y p o m a g n e s e m i a w i t h h y p e r c a l c i u r i a a n d nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations. Clin J Am Soc Nephrol 2012; 7: 801-809.
6. Cole DE, Quamme GA. Inherited disorders of renal magnesium handling. J Am Soc Nephrol 2000; 11:1937- 1947.
7. Abdulrazzaq YM, Smigura FC, Wettrell G. Primary infantile hypomagnesaemia; report of two cases and review of literature. Eur J Pediatr 1989; 148: 459-461.
8. Thomas TC, Smith JM, White PC, Adhikari S. Transient neonatal hypocalcemia: presentation and outcomes. Pediatrics 2012; 129: e1461-1467.
9. Shulman R, O’Gorman CS, Sochett EB. Case 1: Neonate with seizures and hypocalcemia. Paediatr Child Health 2008; 13:197-200.
10. Camadoo L, Tibbott R, Isaza F. Maternal vitamin D deficiency associated with neonatal hypocalcaemic convulsions. Nutr J 2007; 6: 23.
11. Deeb A, Abood SA, Simon J, Dastoor H, Pearce SH, Sayer JA. A novel CLDN16 mutation in a large family with familial hypomagnesaemia with hypercalciuria and nephrocalcinosis. BMC Res Notes 2013; 6: 527.
12. Hampson G, Konrad MA, Scoble J. Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC): compound heterozygous mutation in the claudin 16 (CLDN16) gene. BMC Nephrol 2008; 9: 12.
13. Kang JH, Choi HJ, Cho HY, et al. Familial h y p o m a g n e s e m i a w i t h h y p e r c a l c i u r i a a n d nephrocalcinosis associated with CLDN16 mutations. Pediatr Nephrol 2005; 20: 1490-1493.
14. Peru H, Akin F, Elmas S, Elmaci AM, Konrad M. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: report of three Turkish siblings. Pediatr Nephrol 2008; 23: 1009-1012.
15. Kari JA, Farouq M, Alshaya HO. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Pediatr Nephrol 2003; 18: 506-510.
16. Weber S, Schneider L, Peters M, et al. Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol 2001; 12:1872-1881.