Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon

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Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon Lisa Gianesello1   · Dorella Del Prete1   · Franca Anglani1   · Lorenzo A. Calò1  Received: 24 June 2020 / Accepted: 20 August 2020 © The Author(s) 2020

Abstract Dent disease is a rare genetic proximal tubulopathy which is under-recognized. Its phenotypic heterogeneity has led to several different classifications of the same disorder, but it is now widely accepted that the triad of symptoms low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis/nephrolithiasis are pathognomonic of Dent disease. Although mutations on the CLCN5 and OCRL genes are known to cause Dent disease, no such mutations are found in about 25–35% of cases, making diagnosis more challenging. This review outlines current knowledge regarding Dent disease from another perspective. Starting from the history of Dent disease, and reviewing the clinical details of patients with and without a genetic characterization, we discuss the phenotypic and genetic heterogeneity that typifies this disease. We focus particularly on all those confounding clinical signs and symptoms that can lead to a misdiagnosis. We also try to shed light on a concealed aspect of Dent disease. Although it is a proximal tubulopathy, its misdiagnosis may lead to patients undergoing kidney biopsy. In fact, some individuals with Dent disease have high-grade proteinuria, with or without hematuria, as in the clinical setting of glomerulopathy, or chronic kidney disease of uncertain origin. Although glomerular damage is frequently documented in Dent disease patients’ biopsies, there is currently no reliable evidence of renal biopsy being of either diagnostic or prognostic value. We review published histopathology reports of tubular and glomerular damage in these patients, and discuss current knowledge regarding the role of CLCN5 and OCRL genes in glomerular function.

Introduction Dent disease is a group of X-linked recessive renal disorders characterized by an incomplete renal Fanconi syndrome. Dent disease may vary in clinical presentation with proteinuria alone or in combination with nephrocalcinosis/nephrolithiasis, with or without chronic kidney disease (CKD) (Dent and Friedman 1964; Lloyd et al. 1996; Thakker 2000). Like most genetic disorders, the onset is usually in childhood (Blanchard et al. 2016). Asymptomatic cases are sometimes diagnosed in adult age, however, usually due to the early

Electronic supplementary material  The online version of this article (https​://doi.org/10.1007/s0043​9-020-02219​-2) contains supplementary material, which is available to authorized users. * Franca Anglani [email protected] 1



Nephrology, Dialysis and Transplantation Unit, Kidney Histomorphology and Molecular Biology Laboratory, Department of Medicine‑DIMED, University of Padua, Via Giustiniani n° 2, 35128 Padua, Italy

development of an idiopathic CKD (at 30–50 years old) (Wrong et al. 1994; Lloyd et al. 1997; Zaniew et al. 2018). The gene most often involved is CLCN5 (responsibl

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