Fang Lv1, Xiao-Jie Xu1, Jian-Yi Wang1, Yi Liu1, Yan Jiang1, Ou Wang1, Wei-Bo Xia1, Xiao-Ping Xing1, Mei Li2. 1. Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China. 2. Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China. Electronic address: limeilzh@sina.com.
Abstract
BACKGROUND: Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessively inherited disease characterized by excessive wasting of renal tubular magnesium and calcium. FHHNC is associated with various mutations in CLDN16 and CLDN19. CASES: Two children from a consanguineous family of Chinese Han origin demonstrated manifestations of rickets, polyuria, polydipsia, hematuria and failure to thrive. Hypomagnesaemia (0.49-0.50mmol/L), hypercalciuria or a trend to hypercalciuria (24hour urine calcium: 3.8-5.1mg/kg/day), and secondary hyperparathyroidism (serum PTH level: 94.7-200pg/mL) were revealed upon laboratory examination. Using targeted next-generation sequencing and subsequent confirmation by Sanger sequencing, a novel homozygous mutation was identified in the CLDN16 gene of both FHHNC patients. This specific mutation, a 16bp deletion followed by a 23bp insertion in exon 3, led to the generation of a premature termination codon. The parents and an unaffected sister were all heterozygous carriers of this mutation. CONCLUSIONS: We detected a novel mutation in CLDN16 for the first time. The clinical and genetic findings from this study will help to expand the understanding of this rare disease, FHHNC.
BACKGROUND:Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessively inherited disease characterized by excessive wasting of renal tubularmagnesium and calcium. FHHNC is associated with various mutations in CLDN16 and CLDN19. CASES: Two children from a consanguineous family of Chinese Han origin demonstrated manifestations of rickets, polyuria, polydipsia, hematuria and failure to thrive. Hypomagnesaemia (0.49-0.50mmol/L), hypercalciuria or a trend to hypercalciuria (24hour urine calcium: 3.8-5.1mg/kg/day), and secondary hyperparathyroidism (serum PTH level: 94.7-200pg/mL) were revealed upon laboratory examination. Using targeted next-generation sequencing and subsequent confirmation by Sanger sequencing, a novel homozygous mutation was identified in the CLDN16 gene of both FHHNC patients. This specific mutation, a 16bp deletion followed by a 23bp insertion in exon 3, led to the generation of a premature termination codon. The parents and an unaffected sister were all heterozygous carriers of this mutation. CONCLUSIONS: We detected a novel mutation in CLDN16 for the first time. The clinical and genetic findings from this study will help to expand the understanding of this rare disease, FHHNC.