CLDN16基因突变致家族性低镁血症高钙尿症伴肾钙质沉着症基因型与表型特点分析

doi:10.3969/j.issn.1673-8640.2020.10.011

摘要/Abstract

摘要：

目的探讨以严重佝偻病为主要表现的CLDN16基因突变致家族性低镁血症高钙尿症伴肾钙质沉着症（FHHNC）的基因型与临床表型特点。方法回顾性分析1例以严重佝偻病为主要表现的FHHNC患儿的临床资料及相关检查结果,并进行家系调查及基因测序。结果体格检查示患儿发育落后,特殊面容（鼻梁塌平、眼距宽、颈短）,鸡胸,四肢弯曲畸形,肘关节及膝关节膨大,被动盘腿坐位。实验室检测结果示血钙、血镁降低,尿钙升高,25-羟基维生素D降低。影像学检查结果示骨骼系统异常。全外显子基因测序提示患儿CLDN16基因存在“错义变异C.647G>A,p.Arg216His（纯合子）”,患儿父母携带该位点变异（杂合子）。结合相关检查结果明确诊断为FHHNC。结论 FHHNC由CLDN16/CLDN19基因突变引起,以低镁血症、高钙尿症、肾钙质沉着症以及进行性慢性肾功能衰竭为特征,可伴佝偻病等骨骼系统异常。全外显子基因测序可辅助诊断FHHNC。

关键词: CLDN16基因, 家族性低镁血症高钙尿症伴肾钙质沉着症, 佝偻病, 低镁血症, 高钙尿症, 肾钙质沉着症

Abstract:

Objective To investigate the genotype and phenotype characteristics of familial hypomagnesemia with hypercalciuria and nephrocalcinosis（FHHNC） caused by CLDN16 mutation. Methods The clinical data and laboratory determination results of a case of FHHNC were analyzed retrospectively,and pedigree survey and gene sequencing were performed. Results Physical examination showed backward development,special features（flat nose,wide eye space,short neck）,chicken breast,bent limbs,enlarged elbow and knee joints and passive cross-legged sitting. Laboratory determination results showed decreased blood calcium and magnesium,increased urinary calcium and decreased 25-hydroxyvitamin D. Imaging revealed skeletal system abnormalities. Whole exon gene sequencing indicated that the CLDN16 gene of the case had "missense variation c. 647G>A,p. arg216his（homozygous）",and the parents of the case carried this locus variation（heterozygous）. Combined with the results of relevant tests,the diagnosis was FHHNC clearly. Conclusions FHHNC is involved in CLDN16/CLDN19 gene mutations. FHHNC patients usually exhibit hypomagnesemia with hypercalciuria and nephrocalcinosis,and it can accompanied by ricket and other skeletal system abnormalities. Whole exon sequencing can be helpful for FHHNC diagnosis.

Key words: CLDN16 gene, Familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Ricket, Hypomagnesemia, Hypercalciuria, Nephrocalcinosis

中图分类号:

R446.7

热衣兰木·包尔汉, 李燕, 罗燕飞, 孙光辉, 迪丽胡麻·居来提, 米热古丽·买买提. CLDN16基因突变致家族性低镁血症高钙尿症伴肾钙质沉着症基因型与表型特点分析[J]. 检验医学, 2020, 35(10): 1013-1018.

BAOERHAN Reyilanmu, LI Yan, LUO Yanfei, SUN Guanghui, JULAITI Dilihuma, MAIMAITI Mireguli. Genotype and phenotype analysis of familial hypomagnesemia with hypercalciuria and nephrocalcinosis caused by CLDN16 mutation[J]. Laboratory Medicine, 2020, 35(10): 1013-1018.

图/表 7

图1 本例患儿体格检查特征注:（a）双上肢弯曲畸形;（b）双下肢弯曲畸形;（c）:踝关节畸形;（d）患儿全身正面图,鼻梁塌平,眼距宽,颈短,可见鸡胸

图2 本例患儿家系遗传系谱图注:Ⅰ2与Ⅰ3为表兄妹关系,Ⅱ3于6岁时因喉痉挛死亡; 为杂合子;为纯合子

图3 本例患儿四肢X线检查结果注:（a）~（c）为四肢X线检查结果,骨密度降低,皮质变薄,小梁稀疏,形态欠规整

图4 本例患儿泌尿系统B超图像注:双肾钙质沉着,多发结石

图5 本例患儿泌尿系统及骨骼三维重建注:（a）肾脏三维重建,双肾多发高密度填充,考虑结石;（b）骨骼三维重建,所及骨骼的骨密度增高,变性

图6 本例患儿及其父母全外显子基因测序图注:患儿CLDN16基因存在C.647G>A纯合错义突变,患儿父亲及母亲该位点存在C.647G>A杂合错义突变

表1 CLDN16基因C.647G>A突变导致的FHHNC患儿临床表型回顾

表型	纯合突变（6例）/例（%）	杂合突变（1例）	本例患儿
性别
男	4（66.7）	男
女	2（33.3）		女
低镁血症
有	5（83.3）		有
无	1（16.7）	无
低钙血症
有	5（83.3）		有
无	1（16.7）	无
高钙尿症
有	3（50）		有
无	3（50）	无
肾钙质沉着
有	6（100）		有
无	0（0）	无
肾结石
有	2（33.3）		有
无	4（66.7）	无
肾小球率过滤降低
有	5（83.3）
无	0（0）	无	无
不确定	1（16.7）
25-羟基维生素D降低
有	4（66.7）	有	有
无	0（0）
不确定	2（33.3）
泌尿系统症状
尿痛/腰痛	2（33.3）	无	无
血尿（肉眼/镜下）	4（66.7）	有	无
尿路感染	2（33.3）	有	有
其他表现			骨骼异常

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