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

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Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disease caused by mutations in the CLDN16 or CLDN19 gene; 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 the CLDN16 and absence of the other exons [c.325_c918*? (E2_E5del)]. We confirmed a CLDN16 E2_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 the CLDN16 or CLDN19 gene, 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 in CLDN16.

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Data Availability

Genetic test available on manuscript and WES files on request.

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Funding

This work was supported by The São Paulo Research Foundation—FAPESP Grant for M.R.D.S [14/06570-6], and Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq for the scholarships to M.M.L.K. (2012/01628-0, 2014/15948-2), R.P.D. (160044/2013-8) and M.R.D.S (312746/2017-2).

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Authors and Affiliations

  1. Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil

    Vanessa Radonsky, Marina Malta Letro Kizys, Renata Pires Dotto, Magnus Regios Dias-da-Silva & Marise Lazaretti-Castro

  2. Division of Nephrology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil

    Priscila Ligeiro Gonçalves Esper & Ita Pfeferman Heilberg

  3. Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, 11° andar, São Paulo, SP, 04039-032, Brazil

    Magnus Regios Dias-da-Silva

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  1. Vanessa Radonsky
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  2. Marina Malta Letro Kizys
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Correspondence to Magnus Regios Dias-da-Silva.

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Conflict of interest

Vanessa Radonsky, Marina Malta Letro Kizys, Renata Pires Dotto, Priscila Ligeiro Gonçalves Esper, Ita Pfeferman Heilberg, Magnus Regios Dias-da-Silva, Marise Lazaretti-Castro declare that they have no conflict of interest.

Ethical Approval

CEP/UNIFESP nº 0307/2014.

Human and Animal Rights

Our case report is in accordance with the ethical standards of the national and institutional committee on human study.

Informed Consent

Proband’s parents signed the informed consent to participate in this study after the protocol was properly approved by the Ethics Committee in Research (research number nº 0307/2014).

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Radonsky, V., Kizys, M.M.L., Dotto, R.P. et al. Hypomagnesemia with Hypercalciuria Leading to Nephrocalcinosis, Amelogenesis Imperfecta, and Short Stature in a Child Carrying a Homozygous Deletion in the CLDN16 Gene. Calcif Tissue Int 107, 403–408 (2020). https://doi.org/10.1007/s00223-020-00726-y

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