Escola Paulista de Medicina
Postgraduate in Clinical Endocrinology

Hypomagnesemia with Hypercalciuria Leading to Nephrocalcinosis, Amelogenesis Imperfecta, and Short Stature in a Child Carrying a Homozygous Deletion in the CLDN16 Gene (2020)

Vanessa Radonsky1 · Marina Malta Letro Kizys1 · Renata Pires Dotto1 · Priscila Ligeiro Gonçalves Esper2 ·
Ita Pfeferman Heilberg2 · Magnus Regios Dias‑da‑Silva1,3 · Marise Lazaretti‑Castro1
1 Division of Endocrinology, Escola Paulista de Medicina,
Universidade Federal de São Paulo (UNIFESP), São Paulo,
2 Division of Nephrology, Department of Medicine, Escola
Paulista de Medicina, Universidade Federal de São Paulo
(UNIFESP), São Paulo, Brazil
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
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 wholeexome
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.
Keywords Case report · Hypomagnesemia · Hypercalciuria · Nephrocalcinosis · Amelogenesis

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