CLCN5 mutation (R347X) associated with hypokalaemic metabolic alkalosis in a Turkish child: an unusual presentation of Dent's disease

Abstract

Dent’s disease, an X-linked recessive tubular disorder, is characterized by low molecular weight proteinuria (LMWP) and nephrolithiasis associated with nephrocalcinosis and hypercalciuria. It is due to mutations that inactivate the renal voltage-gated chloride channel ClC-5 [1,2], which is encoded by a gene (CLCN5) located on chromosome Xp11.22. It is possible, however, that causative mutations were not identified in some patients with Dent’s disease [3–6]. Renal acidification abnormalities have not been a consistent feature of the phenotype, probably being secondary to long-standing hypercalciuria and nephrocalcinosis. Hypokalaemic metabolic alkalosis, however, has not been reported previously in Dent’s disease. Inherited disorders that manifest hypokalaemic metabolic alkalosis, such as the Bartter–Gitelman syndrome or the hyperprostaglandin E syndrome (also referred to as antenatal Bartter’s syndrome), are caused by the malfunction of renal tubular electrolyte transporters or ion channels. The hyperprostaglandin E syndrome is linked to the dysfunction of the sodium– potassium–chloride co-transporter (NKCC2) [7] or the renal outer medullary potassium channel (ROMK) [8]. The cardinal features of the syndrome are its antenatal onset—with polyhydramnios due to fetal polyuria, isothenuria and medullary nephrocalcinosis. When associated with sensorineural deafness or autosomal dominant hypocalcaemia, the hyperprostaglandin E syndrome is due to mutations in barttin, a b subunit of voltage-gated chloride channels [9], and the calcium-sensing receptor CaSR [10]. Bartter–Gitelman syndrome is linked to mutations in the basolateral chloride channel (ClC-Kb) [11] or in the sodium– chloride co-transporter (NCCT) [12]. The course of this disease is usually milder, mimicking chronic use of thiazides. ROMK, NKCC2 and NCCT mutations usually have uniform clinical presentations, whereas mutations in CLCNKB, encoding ClC-Kb, occasionally lead to phenotypic overlaps with the ROMK/ NKCC2 cohort. This study describes the first case of Dent’s disease due to a loss-of-function mutation in the CLCN5 gene, R347X, associated with a Bartter-like syndrome that is characterized by hypokalaemic metabolic alkalosis and secondary hyper-reninaemic hyperaldosteronism.