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.

家族性低镁血症伴高钙尿症和肾钙化病（FHHNC）是由CLDN16或CLDN19突变引起的罕见的常染色体隐性遗传疾病基因; 然而，很少有病例发展出经典的牙釉质不全。在本文中，我们报道了一个男孩的早期临床表现，该疾病始于1岁，并表现出牙齿发育不全和生长延迟。该患者出现呕吐，多尿和多饮。除了复发性的无菌白细胞增多症（被误认为是传染性的）外，他是正常的，除了身材矮小和牙釉质发育不全，牙齿逐渐变色。实验室检查在24小时尿液检查中发现甲状旁腺功能亢进，低镁血症，严重的高钙尿症和高镁尿症。螺旋CT检查证实肾钙化。我们进行了全外显子测序（WES），以测试FHHNC的假说和釉形成的寡聚遗传。CLDN16和其他外显子的缺失[c.325_c918 *？（E2_E5del）]。我们通过多重连接依赖性探针扩增和聚合酶链反应分析证实了CLDN16 E2_E5纯合缺失。尽管大多数导致FHHNC的突变是CLDN16或CLDN19中的错义和无义突变基因，大的缺失发生并可能被WES所误导，WES通常用于遗传性筛查寡聚性疾病。患者接受胆钙化固醇，氧化镁和柠檬酸钾。后来，开具氢氯噻嗪加阿米洛利的处方，在随访期间反应良好。我们的报告拓宽了FHHNC的表型，包括严重的早发性成年和身材矮小，并增强了CLDN16中发现的大缺失的表型与基因型的相关性。