Kutluturk Faruk, Temel Berna, Uslu Bora, Aral Ferihan, Azezli Adil, Orhan Yusuf, Konrad Martin, Ozbey Nese
Department of Endocrinology and Metabolism, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Horm Res. 2006;66(4):175-81. doi: 10.1159/000094253. Epub 2006 Jun 27.
A 19-year-old female patient with hypercalciuria and recurrent nephrolithiasis/urinary tract infection unresponsive to thiazide type diuretics is presented. The patient first experienced nephrolithiasis at the age of 4 years. Afterwards, recurrent passages of stones and urinary tract infection occurred. On diagnostic evaluation at the age of 19 years, she also had hypocitraturia and hypomagnesemia. Her serum calcium concentrations were near the lower limit of normal (8.5-8.8 mg/dl; normal range: 8.5-10.5), her serum magnesium concentrations were 1.15-1.24 mg/dl (normal range: 1.4-2.5) and urinary calcium excretion was 900 mg/24 h. PTH concentrations were increased (110-156 pg/ml; normal range: 10-65). We tried to treat the patient with hydrochlorothiazide at a dose of 50 mg/day. During treatment with thiazide diuretics, PTH concentration remained high and the patient had recurrent urinary tract infections and passages of stones. Serum magnesium concentration did not normalize even under the parenteral magnesium infusion. Her mother had a history of nephrolithiasis 20 years ago. Severe hypomagnesemia in association with hypercalciuria/urinary stones is reported as a rare autosomal recessive disorder caused by impaired reabsorption of magnesium and calcium in the thick assending limp of Henle's loop. Recent studies showed that mutations in the CLDN16 gene encoding paracellin-1 cause the disorder. In exon 4, a homozygous nucleotide exchange (G679C) was identified for the patient. This results in a point mutation at position Glycine227, which is replaced by an Arginine residue (G227R). The mother was heterozygous for this mutation. G227 is located in the fourth transmembrane domain and is highly conserved in the claudin gene family. This case indicates the pathogenetic role of paracellin-1 mutation in familial hypomagnesemia with hypercalciuria and nephrocalcinosis and further underlines the risk of stone formation in heterozygous mutation carriers.
本文介绍了一名19岁女性患者，患有高钙尿症且复发性肾结石/尿路感染，对噻嗪类利尿剂无反应。该患者4岁时首次出现肾结石。此后，反复出现结石和尿路感染。19岁进行诊断评估时，她还存在低枸橼酸尿症和低镁血症。她的血清钙浓度接近正常下限（8.5 - 8.8mg/dl；正常范围：8.5 - 10.5），血清镁浓度为1.15 - 1.24mg/dl（正常范围：1.4 - 2.5），尿钙排泄量为900mg/24小时。甲状旁腺激素（PTH）浓度升高（110 - 156pg/ml；正常范围：10 - 65）。我们尝试以50mg/天的剂量用氢氯噻嗪治疗该患者。在使用噻嗪类利尿剂治疗期间，PTH浓度仍高，患者反复出现尿路感染和结石。即使静脉输注镁，血清镁浓度也未恢复正常。她的母亲20年前有肾结石病史。严重低镁血症伴高钙尿症/尿路结石被报道为一种罕见的常染色体隐性疾病，由亨利氏袢升支粗段镁和钙重吸收受损引起。最近的研究表明，编码紧密连接蛋白 - 1的CLDN16基因突变导致该疾病。在第4外显子中，为该患者鉴定出纯合核苷酸交换（G679C）。这导致甘氨酸227位点发生点突变，被精氨酸残基取代（G227R）。母亲是该突变的杂合子。G227位于第四个跨膜结构域，在紧密连接蛋白基因家族中高度保守。该病例表明紧密连接蛋白 - 1突变在家族性低镁血症伴高钙尿症和肾钙质沉着症中的致病作用，并进一步强调了杂合突变携带者形成结石的风险。
