CLDN16基因复合杂合突变致家族性低镁血症高钙尿症与肾钙质沉着症一例报告并文献复习

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis induced by compound heterozygous mutation of CLDN16： a case report and literature review

目的探讨家族性低镁血症高钙尿症与肾钙质沉着症（familial hypomagnesaemia with hypercalciuria and nephrocalcinosis，FHHNC）患者的临床特点和致病基因特征。方法2016年2月收治1例女性患者，年龄24岁。入院前1个月外院腹部X线片（KUB）检查示左肾结石，双肾钙质沉着。患者于外院行经皮肾镜取石术清除大部分左肾结石。本次入院后实验室检查：血镁0.65 mmol/L，24 h尿钙364.0 mg，血甲状旁腺激素187.4 pg/ml，血肌酐101.5μmol/L。行输尿管软镜碎石术清除左肾残余结石。考虑患者为FHHNC，对患者及其父母行外周血CLDN16和CLDN19基因测序分析。结果基因测序结果显示患者CLDN16基因的第2外显子第123密码子一个碱基缺失（c.368delA），第2外显子第139密码子发生错义突变[c.416C→T（p.A139V）]。患者母亲的第139密码子第2个碱基胞嘧啶变为胸腺嘧啶（c.416C→T）；患者父亲的第123密码子第2个碱基腺嘌呤缺失（c.368delA）。该患者确诊为FHHNC，口服氢氯噻嗪、枸橼酸钾、钙镁片治疗。随访6个月，复查血镁1.0 mmol/L，24 h尿钙156.0 mg，血甲状旁腺激素139.6 pg/ml，泌尿系结石无复发，双肾钙质沉着症及肾功能损伤无明显加重。结论CLDN16基因复合杂合突变致FHHNC的临床三联症为低镁血症、高钙尿症和肾钙质沉着症，确诊依靠CLDN16和CLDN19基因测序。肾功能严重受损前以对症治疗为主，给予氢氯噻嗪、枸橼酸钾、钙镁片治疗有可能明显改善低镁血症和高钙尿症。

Objective To investigate the clinical features and disease-causing mutations of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis. Methods In February 2016, a 24 year old female patient with left kidney stone and nephrocaleinosis in bilateral kidneys was admitted to our hospital. One month prior to this admission, she had been treated by PCNL to remove the most part of left kidney stone in other hospital. After admission, She was found hypomagnesaemia （serum magnesium 0. 65 mmol/ L） and hypercalciuria （24h urine calcium 364. 0 mg） but with normal renal function （serum creatinine 101.5μmol/L）. And the remained part of left kidney stone was removed by flexible ureteroseope. As she was considered probably with an autosomal recessive FHHNC, an analysis of CLDN16 and CLDN19 gene mutations was performed using her and her parents＇ peripheral white blood cells. Results Mutation analysis revealed this patient had two heterozygous mutations in the CLDN16. One is an one-base deletion mutation in the 123th codon in exon 2： 368delA. The other is a missense mutation in the 139th eodou in exon 2： 416C →T which resulted in an amino acid change Ala139Val. Her parents respectively had one of each heterozygous mutation. In the six months follow-up, an oral administration with hydrochlorothiazide, potassium citrate, and calcium magesium supplements significantly reduced her hypomagnesaemia （serum magnesium 1.0 mmol/L） and hyperealciuria （24-h urine calcium 156. 0 mg） , and no stone recurrenee and aggravation of nephroealcinosis and renal dysfunction occurred. Conclusions We diagnosed a patient with FHHNC who had a novel compound heterozygous mutation of CLDN16. This rare disease should be suspeeted if there are three constant elinieal features of hypomagnesaemia, hyperealeiuria and nephroealeinosis, and verified with CLDN16 and CLDN19 gene test. Currently the option for treatment of FHHNC is symptomatic treatment until severe deterioration of renal function. The hydrochlorothiazide, potassium citrate, and calcium magesium supplements may have considerable effeets on hypomagnesaemia aud hyperealciuria.