Abstract
Dent’s disease is an X-linked proximal tubulopathy. It often manifests in childhood with symptoms of Fanconi syndrome and low-molecular-weight proteinuria. We describe four boys from three unrelated families whose only presenting symptoms of Dent’s disease were nephrotic-range proteinuria and histological findings of focal segmental and/or global glomerulosclerosis. In all families, a causal mutation in the CLCN5 gene, encoding a voltage-gated chloride transporter and chloride-proton exchanger, was identified. All three mutations are pathogenic: two are novel (p.Asp727fs and p.Trp122X), and one is a recurrent mutation, p.R648X. Given the atypical phenotype of these patients with Dent’s disease, it is possible that this clinical entity is markedly underdiagnosed and that our report represents only the tip of the iceberg. The diagnosis of Dent’s disease should be considered in all patients with nephrotic-range proteinuria without hypoalbuminemia or edema. Establishing the diagnosis of Dent’s disease will prevent the administration of unnecessary immunosuppressive medications with their undesirable side effects.
Similar content being viewed by others
References
Ludwig M, Utsch B, Monnens LAH (2006) Recent advances in understanding the clinical and genetic heterogeneity of Dent’s disease. Nephrol Dial Transplant 21:2708–2817
Pook MA, Wrong O, Wooding C, Norden AGW, Feest TG, Thakker RV (1993) Dent’s disease, a renal Fanconi syndrome with nephrocalcinosis and kidney stones, is associated with a microdeletion involving DXS255 and maps to Xp11.22. Hum Mol Genet 2:2129–2134
Lloyd SE, Pearce SHS, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Hrding B, Bolino A, Devoto M, Goodyer P, Rigden SPA, Wrong O, Jentsch TJ, Craig IW, Thakker RV (1996) A common molecular basis for three inherited kidney stone diseases. Nature 379:445–449
Dent CE, Friedman M (1964) Hypercalciuric rickets associated with renal tubular damage. Arch Dis Child 39:240–249
Muller-Suur R, Gutsche H-U (1995) Tubular reabsorption of Technetium-99 m-DMSA. J Nucl Med 36:1654–1658
Suzuki S, Suzuki J, Kume K, Yoshida K, Suyama H, Kawasaki Y, Nozawa R, Suzuki H, Fujiki T, Kamiyama S, Suzuki A (1999) Poor renal accumulation of 99mTc-DMSA in idiopathic tubular proteinuria. Nephron 81:49–54
Lloyd SE, Gunther W, Pearce SHS, Thomson A, Blanchi ML, Bosio M, Craig IW, Fisher SE, Scheinman SJ, Wrong O, Jentsch TJ, Thakker RV (1997) Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders. Hum Mol Genet 6:1233–1239
Igarashi T, Gunther W, Sekine T, Inatomi J, Shiraga H, Takahashi S, Suzuki J, Tsuru N, Yanagihara T, Shimazu M, Jentsch TJ, Thakker RV (1998) Functional characterization of renal chloride channel, CLCN5, mutations associated with Dent’s Japan disease. Kidney Int 54:1850–1856
Ludwig M, Doroszewicz J, Seyberth HW, Bokenkamp A, Balluch B, Nuutinen M, Utsch B, Waldegger S (2005) Functional evaluation of Dent’s disease-causing mutations: implications for ClC-5 channel trafficking and internalization. Hum Genet 117:228–237
Smith AJ, Reed AAC, Loh NY, Thakker RV, Lippiat JD (2009) Characterization of Dent’s disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure. Am J Physiol Renal Physiol 296:F390–F397
Hodgin JB, Corey HE, Kaplan BS, D’Agati VD (2008) Dent disease presenting as Fanconi syndrome and hypercalciuria. Kidney Int 73:1320–1323
Murakami T, Kawakami H (1990) The clinical significance of asymptomatic low molecular weight proteinuria detected on routine screening of children in Japan: a survey of 53 patients. Clin Nephrol 33:12–19
Copelovitch L, Nash MA, Kaplan BS (2007) Hypothesis: Dent disease is an underrecognized cause of focal glomerulosclerosis. Clin J Am Soc Nephrol 2:914–918
Pollak MR (2002) Inherited podocytopathies: FSGS and nephrotic syndrome from a genetic viewpoint. J Am Soc Nephrol 13:3016–3023
Devuyst O, Christie PT, Courtoy PJ, Beauwens R, Thakker RV (1999) Intra-renal and subcellular distribution of human chloride channel, CLC-5, reveals a pathophysiological basis of Dent’s disease. Hum Mol Genet 8:247–257
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary materials
Below is the link to the electronic supplementary material.
Supplementary Table
Quantitative measurement of the urinary amino acid profile indexed to creatinine excretion (DOC 61 kb)
Rights and permissions
About this article
Cite this article
Frishberg, Y., Dinour, D., Belostotsky, R. et al. Dent’s disease manifesting as focal glomerulosclerosis: Is it the tip of the iceberg?. Pediatr Nephrol 24, 2369–2373 (2009). https://doi.org/10.1007/s00467-009-1299-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-009-1299-2