In 1964, Dent and Friedman were the first to describe two English males presenting with rickets, hypercalciuria and tubular proteinuria of unknown origin [6]. The term Dent disease (MIM #300009) was first introduced in 1993 to describe a form of X-linked incomplete renal Fanconi syndrome presenting with LMWP, hypercalciuria, nephrocalcinosis and nephrolithiasis and, less frequently, with aminoaciduria, phosphaturia, kaliuresis, glycosuria, uricosuria, and impaired urinary acidification [7]. In 1994, Fisher et al. cloned the CLCN5 gene, and proposed it as a culprit for Dent disease [8]. Ten years later Hoopes et al. identified the OCRL gene, as responsible for the Dent disease phenotype in five males without CLCN5 mutations and introduced the term DD2 (MIM#300555) to distinguish it from DD1 [2]. Mutations in the OCRL gene have been associated with both DD2 and Lowe (oculocerebrorenal) syndrome with the former being a milder form of the latter [9,10,11,12]. In 2009 one of the two original patients described by Dent and Friedman was found to carry a mutation in the OCRL gene [4] while the other had a CLCN5 mutation, supporting thus the phenotypic similarities between DD1 and DD2 patients. An excellent review comparing the various presentations of DD has recently been published by Gianesello et al. [13].
Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria or even CKD. In our female carries we noticed a reduced threshold for renal phosphate transport.
The males in the initial report of DD2 exhibited none of the classic extrarenal symptoms of Lowe syndrome [2], which is characterized by a) congenital cataracts, glaucoma, microphthalmia and keloids [14], b) hypotonia, delayed motor milestones, intellectual disability, and c) renal tubular involvement associated with bone disease and growth retardation [15]. Fanconi syndrome and tubular acidosis, both cardinal signs of Lowe syndrome, are rare in DD2 [9]. Hypercalciuria, nephrocalcinosis and nephrolithiasis are common in DD2 but rare in Lowe syndrome [3, 16]. The renal biopsy findings in DD2 include nephrocalcinosis, interstitial fibrosis and FSGS [17, 18].
A genotype–phenotype correlation has been suggested, because almost all severe mutations associated with Lowe syndrome are located among exons 8 and 24, while missense mutations in exons 4–15 are involved in DD2 [19].
The OCRL gene encodes the lipid phosphatase (OCRL1), a phosphatidylinositol 4,5-bisphosphate (PIP2) phosphatase, localized in the Golgi network, early endosomes, lysosomes and tight junctions [20]. It is involved in actin polymerization and lysosomal and endosomal membrane trafficking. In proximal tubular cells, defective recycling of the megalin receptor after endocytosis accounts for the characteristic loss of LMW proteins in Lowe syndrome and DD2 patients [21, 22].
In a mouse model of DD2 it was shown that inhibition of phosphoinositole kinase with the use of alpelisib can restore cytoskeleton and endocytosis abnormalities in tubular cells improving the renal tubular dysfunction [23].
No guidelines have been established for the treatment of Dent disease. There is a substantial risk for progressive kidney disease. The main treatment goals are to decrease hypercalciuria, prevent nephrocalcinosis and kidney stones, and delay the progression of CKD. It has been proposed that the use of thiazide may reduce hypercalciuria [24,25,26]. However, diuretics can deteriorate hypokalemia and volume depletion. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been used to prevent further loss of kidney function particularly in those with FSGS. In our case angiotensin blockade effectively reduced proteinuria and has probably delayed the progression of eGFR decline.
Citrate is commonly used in Lowe syndrome to treat the metabolic acidosis resulting from renal tubular acidosis. A high citrate diet has been shown to slow progression of CKD in CLCN5 knockout mice [27] and has been used in the treatment of Dent disease; however, no human trials have proven its effectiveness and acidosis is not always present.
Growth failure can be successfully treated with human growth hormone without adversely affecting kidney function [28]. Bone disease may respond to vitamin D supplementation and phosphorus repletion in those with elevated serum alkaline phosphatase levels [29]. Vitamin D supplementation was avoided in our patient, because calcitriol levels were higher than normal and were associated with the presence of hypercalcemia, hypercalciuria and nephrocalcinosis. Contrary to vitamin D, phosphate repletion proved very successful in our case, because it not only corrected bone disease but also improved muscle strength, musculoskeletal aches, body weight and abolished hypercalciuria. There is a clinical trial (NCT02016235) going on, examining whether phosphorus repletion can reduce hypercalciuria in patients with DD1 or DD2. The results of this trial may confirm our allegations about phosphorus treatment and are eagerly awaited.
When Dent disease progress to ESRD, renal replacement therapy or kidney transplantation becomes necessary. Because DD pathogenesis is inherent to kidney defects, the disease will not recur after transplantation.
The clinical characteristics of our patient are concordant with the diagnosis of DD2. The exclusion of mutations in other relevant genes and the meticulous investigation of the clinical phenotype render the Asp631Glu amino acid substitution as the only pathogenetic possibility. It is recognized that the presence of CLCN5 or OCRL mutations almost always leads to the diagnosis of Dent disease [13]. However, there is marked phenotypic heterogeneity that impedes correct diagnosis and treatment [13]. Indeed, in our proband, we noticed severe salt and potassium wasting associated with severe metabolic alkalosis, something unusual in patients with DD [13]. In a recent review of a large DD cohort (109 DD1 and 9 DD2 patients) it was noticed that a significant proportion of patients presented hypokalemia and metabolic acidosis [1]. In contrast, only six subjects (5.5%) displayed a Bartter-like syndrome with hypokalemia and metabolic alkalosis. However, in two series describing exclusively DD2 patients [2, 30] no one had metabolic acidosis, but there is no mention of metabolic alkalosis also. There are reports where both DD1 and Bartter phenotypes were seen in the same patient [31,32,33], but a whole genome screening was not undertaken.
It remains unclear if the Bartter-like phenotype in our proband can be solely attributed to Dent’s disease or there is a contribution by the Pro970Ser CaSR polymorphism [34,35,36]. In this respect, we have to notice that 1) all other Bartter related genes were excluded by the whole exome analysis, 2) hypocalcemia has never been recorded in carriers of Pro970Ser in our kindred, 3) phosphate repletion led to complete correction of hypercalciuria. These findings collectively preclude a pathogenetic role for the CaSR polymorphism or contribution of other Bartter related genes. They further support the hyper-absorptive nature of hypercalcemia and hypercalciuria which, in our case, was associated with increased calcitriol synthesis in response to primary phosphaturia and hypophosphatemia. The hyper-absorptive nature of hypercalcemia, is also supported by experimental data showing that OCRL deficiency results in an unrestricted expression of intestinal TRPV6, offering an alternative or complementary explanation for increased calcium absorption [37].
Beyond hypercalciuria, in the series of Charnas et al. the vast majority (21 out of 23) of patients with OCRL mutations presented dehydration with salt loss and decreased concentrating capacity [38]. Therefore, these Bartter-like features may not actually be so rare as previously thought and consist part of the DD phenotypic variability.
In conclusion we present a Family with DD2, due to a rare Asp631Glu OCRL mutation, with a Bartter-like phenotypic variation that could not be attributed to any Bartter associated mutations. Angiotensin blockade improved proteinuria and stabilized kidney function for several years. Finally, we showed that phosphate repletion can effectively alleviate several debilitating features of the disease and should be given early in childhood to prevent hypercalciuria and bone disease.
