Fisiopatologia Renal, Centre D'Investigacions en Bioquímica I Biologia Molecular (CIBBIM), Institut de Recerca Vall D'Hebron (VHIR), Barcelona, Spain.
Unidad de Investigación, Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.
J Nephrol. 2021 Dec;34(6):2053-2062. doi: 10.1007/s40620-021-01054-6. Epub 2021 Apr 30.
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare tubulopathy caused by mutations in the CLDN16 or CLDN19 genes. Patients usually develop hypomagnesemia, hypercalciuria, nephrocalcinosis and renal failure early in life. Patients with CLDN19 mutations may also have ocular abnormalities. Despite clinical variability, factors associated with kidney function impairment, especially in patients with CLDN19 mutations, have not been addressed.
Retrospective multicenter study of 30 genetically confirmed FHHNC Spanish patients. We analyzed kidney function impairment considering as outcomes chronic kidney disease (CKD) stage 3 and annual estimated glomerular filtration rate (eGFR) decline, to identify factors associated with the different phenotypes.
Of thirty patients, 27 had mutations in the CLDN19 gene (20 homozygous for the p.G20D mutation) and 3 in the CLDN16. Age at diagnosis was 1.71 (0.67-6.04) years and follow-up time was 8.34 ± 4.30 years. No differences in CKD stage 3-free survival based on CLDN19 mutation (p.G20D homozygous vs. other mutations) or gender were found, although females seemed to progress faster than males. Patients with more pronounced eGFR decline had higher PTH levels at diagnosis than those with stable kidney function, despite similar initial eGFR. Approximately 60% of CLDN19 patients presented ocular abnormalities. Furthermore, we confirmed high phenotypic intrafamilial variability.
In a contemporary cohort of FHHNC patients with CLDN19 mutations, females seemed to progress to CKD-stage 3 faster than males. Increased PTH levels at baseline may indicate a more severe renal course. There was high phenotype variability among patients with CLDN19 mutations and kidney function impairment differed even between siblings.
家族性低镁血症伴高钙尿和肾钙质沉着症（FHHNC）是一种由 CLDN16 或 CLDN19 基因突变引起的罕见肾小管病。患者通常在生命早期就会出现低镁血症、高钙尿症、肾钙质沉着症和肾衰竭。CLDN19 基因突变的患者也可能有眼部异常。尽管临床表现存在差异，但与肾功能损害相关的因素，尤其是 CLDN19 基因突变患者的肾功能损害相关因素尚未得到解决。
对 30 名经基因证实的西班牙 FHHNC 患者进行回顾性多中心研究。我们分析了肾功能损害，将慢性肾脏病（CKD）3 期和估算肾小球滤过率（eGFR）年下降率作为结局，以确定与不同表型相关的因素。
30 名患者中，27 名患者的 CLDN19 基因突变（20 名纯合子 p.G20D 突变），3 名患者的 CLDN16 基因突变。诊断时的年龄为 1.71（0.67-6.04）岁，随访时间为 8.34±4.30 年。未发现 CLDN19 基因突变（p.G20D 纯合子与其他突变）或性别与 CKD3 期无差异相关，但女性似乎比男性进展更快。尽管初始 eGFR 相似，但 eGFR 下降更明显的患者在诊断时甲状旁腺激素（PTH）水平更高。大约 60%的 CLDN19 患者有眼部异常。此外，我们还证实了该疾病存在高表型家族内变异性。
在 CLDN19 基因突变的 FHHNC 患者当代队列中，女性似乎比男性更早进展到 CKD3 期。基线时 PTH 水平升高可能表明更严重的肾脏病程。CLDN19 基因突变患者的表型变异性很大，即使是兄弟姐妹之间，肾功能损害也不同。
