Hypomagnesemia with Hypercalciuria Leading to Nephrocalcinosis, Amelogenesis Imperfecta, and Short Stature in a Child Carrying a Homozygous Deletion in the CLDN16 Gene

Author(s)

Radonsky, Vanessa ; Kizys, Marina Malta Letro ; Dotto, Renata Pires ; Esper, Priscila Ligeiro Goncalves ; Heilberg, Ita Pfeferman ; Dias-da-Silva, Magnus Regios ; Lazaretti-Castro, Marise

• Document type: Journal article
• Source: CALCIFIED TISSUE INTERNATIONAL; v. 107, n. 4, p. 6-pg., 2020-07-24.

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disease caused by mutations in theCLDN16orCLDN19gene; however, few cases develop classical amelogenesis imperfecta. Herein, we report the case of a boy with early clinical renal manifestations that started at 1 year of age and presenting with dental hypoplasia and growth delay. The patient presented with vomiting, polyuria, and polydipsia. Apart from recurrent sterile leukocyturia, erroneously treated as infectious, he was normal, except for short stature and amelogenesis imperfecta with gradually discolored teeth. Laboratory tests revealed hyperparathyroidism, hypomagnesemia, severe hypercalciuria, and hypermagnesuria on 24-h urine testing. Helical computed tomography confirmed nephrocalcinosis. We performed whole-exome sequencing (WES) to test the hypothesis of FHHNC and oligogenic inheritance of amelogenesis. Analysis of the WES binary sequence alignment/map file revealed the presence of exon 1 of theCLDN16and absence of the other exons [c.325_c918*? (E2_E5del)]. We confirmed aCLDN16E2_E5 homozygous deletion by multiplex ligation-dependent probe amplification and polymerase chain reaction assays. Although most mutations causing FHHNC are missense and nonsense mutations in theCLDN16orCLDN19gene, large deletions occur and may be misled by WES, which is generally used for genetic screening of oligogenic disorders. The patient received cholecalciferol, magnesium oxide and potassium citrate. Later, the combination with hydrochlorothiazide plus amiloride was prescribed, with a good response during follow-up. Our report broadens the phenotype of FHHNC, including severe early-onset amelogenesis and short stature, and reinforces the phenotype-genotype correlation of the large deletion found inCLDN16. (AU)

• FAPESP's process: 14/06570-6 - Comprehensive whole exome, paired-end RNA and genome sequencing: new insights into genetic bases of thyroid carcinoma in pediatric and adult ages and applications in clinical practice
• Grantee: Janete Maria Cerutti
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/01628-0 - Thyroid dysgenesis: molecular analysis and functional studies of mutations in candidate genes discovered by next generation sequence in a cohort of 268 cases
• Grantee: Marina Malta Letro Kizys Polisel
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 14/15948-2 - Congenital hypothyroidism: in vivo functional validation of the new candidate-gene CCDC for thyroid hemiagenesis
• Grantee: Marina Malta Letro Kizys Polisel
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)