Dataset Information

Case report: a Chinese girl with dent disease 1 and turner syndrome due to a hemizygous CLCN5 gene mutation and Isochromosome (Xq).

ABSTRACT: BACKGROUND:Female Dent disease 1 patients with low-molecular-weight proteinuria (LMWP) due to CLCN5 gene mutation were rarely reported, and these cases that the people were also with Turner syndrome (TS) were even hardly documented before. CASE PRESENTATION:Here we report a 3-year and 11-month old Chinese girl with short stature who had a karyotype of 46,X,i(X)(q10) and a de novo pathogenic variant in the CLCN5 gene on the short arm of X chromosome. Laboratory examinations showed that the patient had LMWP, hypercalciuria, hypophosphatemia, delayed bone age, and genital dysplasia. CONCLUSION:The combination of i(X)(q10) and CLCN5 mutation causes the deletion of the wild-type CLCN5 allele that results in Dent-1 and TS. To the best of our knowledge, this is the first case that a female CLCN5 mutation hemizygote is diagnosed with Dent-1 and Turner syndrome due to isochromosome X. Also, our case has indicated that the prevalence of the situation may be largely underestimated because of the mild signs of females with Dent-1.

SUBMITTER: Ye Y

PROVIDER: S-EPMC7216489 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Case report: a Chinese girl with dent disease 1 and turner syndrome due to a hemizygous CLCN5 gene mutation and Isochromosome (Xq).

Ye Yuhong Y Wang Jingjing J Quan Xiaofang X Xu Ke K Fu Haidong H Gu Weiyue W Mao Jianhua J

BMC nephrology 20200511 1

<h4>Background</h4>Female Dent disease 1 patients with low-molecular-weight proteinuria (LMWP) due to CLCN5 gene mutation were rarely reported, and these cases that the people were also with Turner syndrome (TS) were even hardly documented before.<h4>Case presentation</h4>Here we report a 3-year and 11-month old Chinese girl with short stature who had a karyotype of 46,X,i(X)(q10) and a de novo pathogenic variant in the CLCN5 gene on the short arm of X chromosome. Laboratory examinations showed ...[more]

PMID: 32393202

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Project description:BackgroundDent disease-1 is a rare X-linked recessive renal tubular disorder caused by pathogenic variants in the chloride voltage-gated channel 5 (CLCN5) gene. It is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive renal failure. This is the first report of a CLCN5 pathogenic variant in a Dent disease-1 family of Sri Lankan origin, and it highlights the value of genetic evaluation in children with refractory proteinuria.Case presentationA 2-year-old boy with non-nephrotic range proteinuria was referred for evaluation. His maternally related 24-year-old uncle had been investigated for similar features at the age of 14 years and his renal histology had shown few sclerosed glomeruli. He remained asymptomatic apart from proteinuria. Biochemical investigation of the child showed β-2 microglobulinuria and hypercalciuria. After providing pre-test counseling and obtaining written informed consent, the child, his mother and maternal uncle underwent genetic testing for confirmation of the clinically suspected diagnosis of Dent disease-1. Both the child and his maternal uncle were found to be hemizygous for a nonsense pathogenic variant in exon 9 of the CLCN5 gene [NM_000084.4; c.1399C>T; rs797044811] which results in a stop codon at residue 467, leading to a truncated non-functional protein [NP_000075.1; p.R467X]. His mother was confirmed to be an unaffected heterozygous carrier for the same variant. Following confirmation of the diagnosis our patient was started on thiazide diuretics and potassium citrate.ConclusionsEven though the typical phenotype of Dent disease-1 often enables a clinical diagnosis to be made, less severe sub-clinical cases may go undiagnosed. The underlying diagnosis may be missed especially in children who are treated for non-minimal change nephrotic syndrome with steroids. This case highlights the need for tubular proteinuria to be considered in the differential diagnosis of children with refractory proteinuria and for appropriate genetic evaluation to be done to confirm the precise underlying diagnosis in such cases.

Project description:Dent disease (DD) is a rare X-linked recessive renal tubulopathy characterised by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis and/or nephrolithiasis. DD is caused by mutations in both the CLCN5 and OCRL genes. CLCN5 encodes the electrogenic chloride/proton exchanger ClC-5 which is involved in the tubular reabsorption of albumin and LMW proteins, OCRL encodes the inositol polyphosphate 5-phosphatase, and was initially associated with Lowe syndrome. In approximately 25 % of patients, no CLCN5 and OCRL mutations were detected. The aim of our study was to evaluate whether calcium phosphate metabolism disorders and their clinical complications are differently distributed among DD patients with and without CLCN5 mutations. Sixty-four male subjects were studied and classified into three groups: Group I (with CLCN5 mutations), Group II (without CLCN5 mutations) and Group III (family members with the same CLCN5 mutation). LMWP, hypercalciuria and phosphaturic tubulopathy and the consequent clinical complications nephrocalcinosis, nephrolithiasis, bone disorders, and chronic kidney disease (CKD) were considered present or absent in each patient. We found that the distribution of nephrolithiasis, bone disorders and CKD differs among patients with and without CLCN5 mutations. Only in patients harbouring CLCN5 mutations was age-independent nephrolithiasis associated with hypercalciuria, suggesting that nephrolithiasis is linked to altered proximal tubular function caused by a loss of ClC-5 function, in agreement with ClC-5 KO animal models. Similarly, only in patients harbouring CLCN5 mutations was age-independent kidney failure associated with nephrocalcinosis, suggesting that kidney failure is the consequence of a ClC-5 dysfunction, as in ClC-5 KO animal models. Bone disorders are a relevant feature of DD phenotype, as patients were mainly young males and this complication occurred independently of age. The triad of symptoms, LMWP, hypercalciuria, and nephrocalcinosis, was present in almost all patients with CLCN5 mutations but not in those without CLCN5 mutations. This lack of homogeneity of clinical manifestations suggests that the difference in phenotypes between the two groups might reflect different pathophysiological mechanisms, probably depending on the diverse genes involved. Overall, our results might suggest that in patients without CLCN5 mutations several genes instead of the prospected third DD underpin patients' phenotypes.

Dataset Information

Case report: a Chinese girl with dent disease 1 and turner syndrome due to a hemizygous CLCN5 gene mutation and Isochromosome (Xq).

Publications

Case report: a Chinese girl with dent disease 1 and turner syndrome due to a hemizygous CLCN5 gene mutation and Isochromosome (Xq).

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