AE Shrimpton

Andrea Pasini

Chiara De Mutiis

Claudio La Scola

D Böckenhauer

F Claverie-Martín

Fabrizio Pugliese

G Gambaro

Giovanni Montini

H Hichri

L Copelovitch

M Ludwig

MT Cramer

O Devuyst

RR Hoopes Jr

T Sekine

Y Frishberg

The Italian Journal of Pediatrics

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CASE REPORT Open AccessNephrotic-range Albuminuria as thepresenting symptom of Dent-2 diseaseChiara De Mutiis, Andrea Pasini, Claudio La Scola, Fabrizio Pugliese and Giovanni Montini*AbstractDent disease is a rare X-linked tubulopathy with low molecular weight proteinuria, hypercalciuria, nephrolithiasis,nephrocalcinosis and progressive renal failure. We describe the case of a 9-year-old boy who presented withnephrotic-range albuminuria at the age of 3 years. In the absence of a clear diagnosis, a renal biopsy was performed at4 years, which revealed minimal change disease. Due to the presence of low molecular weight proteinuria, even in theabsence of hypercalciuria, a diagnosis of Dent disease was considered. While there were no mutations in the CLCN5 gene,the diagnosis was confirmed by the presence of a missense mutation (p.Arg318Cys) in the OCRL gene. Conclusion: Giventhe large phenotypic variability of the disease and based on our experience, we believe that children with low molecularweight proteinuria, even without hypercalciuria, should be investigated for Dent disease.Keywords: Dent disease, Low molecular weight proteinuria (LMWP), Hypercalciuria, OCRL, CLCN5, p.Arg318CysBackgroundDent disease is a rare, X-linked disorder characterizedby low molecular weight proteinuria (LMWP), hypercal-ciuria, and at least one of the following criteria: nephro-lithiasis, nephrocalcinosis, hematuria, hypophosphatemiaor progressive renal failure [1]. Other features of proximaltubulopathy can be present, such as glycosuria, amino-aciduria and acidification defects [1, 2]. It is caused bymutations in the CLCN5 gene (Dent-1 disease, OMIM#300009) in ~ 60 % of cases, in the OCRL gene (Dent-2disease, OMIM#300555) in ~15 % of cases,, while inthe remaining 25 % of cases [3, 4] other unidentifiedgenes are responsible for the disease. The incidenceand prevalence of Dent-1 and 2 disease are unknown.Several recent papers have reported an atypical pheno-type of Dent-1 disease, presenting with high range pro-teinuria and LMWP as a unique clinical feature [5–8].We describe a boy who presented with asymptomatichigh range proteinuria, LMWP and normocalciuria atthe age of 3 years, and who was subsequently diagnosedwith Dent-2 disease with an OCRL mutation.Case reportAt the age of 10 months, the child presented with pro-teinuria and hematuria (urine dipstick: pH 6, S.G. 1020,Hb 1+, Albumin 3+) following a febrile viral infection.Renal function, C3 and C4 serum levels were all normal;extractible nuclear antigen, antinuclear antibodies and antiDNA antibodies were negative. Proteinuria (600–800 mg/day) was confirmed in subsequent evaluations withouthypoalbuminemia, edema or hyperlipidemia. Kidneyultrasound was normal. There was no family history ofkidney disease.At the age of 4, he was referred to our hospital withnephrotic range proteinuria (uPr/uCr mg/mg between1.4 and 4.4), albuminuria 100–300 mg/dl and a high com-ponent of LMWP, but without hypercalciuria (uCa/uCrmg/mg: 0.38 normal < 0.4 for children from 3 to 5 years),nephrocalcinosis or signs of tubular damage (tubular re-absorption of phosphate > 82 %, absence of glycosuria andaminoaciduria). A technetium-99 m-dimercaptosuccinate(DMSA) scan revealed: “poor renal accumulation of radio-nuclide 3 h after injection”. A renal biopsy was then per-formed which showed “minor glomerular abnormalities”typical of minimal change disease.The child underwent regular six-monthly check-upsduring which time no clinical, laboratory or renal USchanges were observed. Albuminuria, LMWP were* Correspondence: giovanni.montini@aosp.bo.itNephrology and Dialysis Unit, Department of Pediatrics, AziendaOspedaliero-Universitaria Sant’Orsola-Malpighi Bologna, Via Massarenti 11,40138 Bologna, ItalyITALIAN JOURNALOF PEDIATRICS© 2015 De Mutiis et al. This is an Open Access article distributed under the terms of the Creative Commons AttributionLicense (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.De Mutiis et al. Italian Journal of Pediatrics  (2015) 41:46 DOI 10.1186/s13052-015-0152-4persistently elevated while values of urinary calciumwere within the normal range for age.On the basis of some reports of patients with Dent-1disease, whose initial clinical presentation was proteinuriawith LMWP but without hypercalciuria [5, 6], we decidedto screen our patient for CLCN5 and OCRL1 mutations.A missense mutation (p.Arg318Cys) was identified in exon11 of the OCRL gene. Carrier status was confirmed in themother.At present, the child is nine years old and has normalrenal function (eGFR: 130 ml/min/1.73 m2), proteinuria(uPr/uCr: 2.2) with albuminuria 201 mg/L, alpha-1 mi-croglobulin 329 mg/L (normal 0–12 mg/L), and beta-2microglobulin 128 mg/L (normal < 10.0 mg/L), withouthypercalciuria (uCa/uCr: 0.24 normal < 0.25) [9, 10],nephrolithiasis or nephrocalcinosis. Mild elevations ofmuscle enzymes (CPK 332 U/L, LDH 375 U/L) have beendocumented, without clinical evidence of muscle weakness.Growth, intellectual development and ophthalmic exami-nations have all been normal up to now.DiscussionWe report a child with atypical Dent-2 disease, documentedby an OCRL mutation, who presented with isolated protein-uria in the absence of any of the other classic criteria, par-ticularly hypercalciuria. To date, approximately 250 familieswith Dent disease have been reported [1], of whom around40 patients had Dent-2 disease, with various OCRL muta-tions described [1, 4].Some studies have shown a large variability in the clin-ical phenotype of Dent disease, so much so that we canconsider this disease to be a heterogeneous group ofproximal tubular defects called “The Dent disease complex”[11]. A proportion of them have glomerular involvement,as was demonstrated in six of the nine children withDent-1 disease presenting with asymptomatic high rangeproteinuria associated with LMWP, without hypercalciuria,and showing a focal segmental glomerulosclerosis and/orfocal global glomerulosclerosis on biopsy [5–7]. Ludwig etal described two patients with LMWP as the only symptomof Dent-1 disease [8]. Cramer MT et al recently re-ported seven males with nephrotic-range proteinuria andCLCN5 mutations, two of which showed no hypercalciuria(Table 1). Our patient had a very similar clinical presenta-tion to these patients, with the exception of minimalchange disease on biopsy, which, however, was performedearly in the course of the disease, perhaps before the de-velopment of sclerotic lesions.In this respect, it is possible that these children couldbenefit from ACE inhibition, which may help protect thekidneys from the appearance of sclerotic lesions secondaryto proteinuria. Copelovitch et al. [6] documented moder-ate improvement in proteinuria in a Dent patient afterstarting enalapril therapy, However, only a small numberof the reported patients have been treated with these drugs[5, 7]. More studies are needed in order to draw more solidconclusions.Our patient has a missense mutation (p.Arg318Cys) inexon 11 of the OCRL gene. To our knowledge, only 6patients with the same mutation and Dent disease havebeen described: two brothers by Hoopes et al. [3], onemale by Sekine T. et al [9], two brothers by BöckenhauerTable 1 Patients with Dent-1 disease in the absence of hypercalciuria reported in the literatureParameters Patient1 [5]Patient2 [5]Patient3 [5]Patient4 [5]Patient5 [6]Patient6 [7]Patient7 [7]Patient8 [8]Patient9 [8]Age (years) 9 11 14 9 9 6 6 36 15CrCl (cc/min/1.73 m2) >90 97 105 95.5 126 79 98 135 >80 >80S-Alb (gr/dl) 3.5-5.3 4.5 4.9 4.1 4.4 4.6 4.5 4.9 - -U-prot (mg/day) <200 800–1000 600–1400 750–1100 1240 1321 – - - -U-prot/U-Cr (mg/mg) <0.2 - - - - - 3.4 2.6 - -U-β2MG (mg/l) < 10 91.2 103 120 74.4 52.7 - - >10 >10U-β2MG (mcg/g cr) < 132 166.1 >132 >132U-Ca/U-Cr (mg/mg) < 0.5 for 1-3y 0.15 0.14 0.13 0.12 0.07 0.18 0.10 < 0.25 < 0.25<0.4 for 3-5 y<0.3 for 5-7 y< 0.25 for >7yU-gluc absent neg neg neg neg - - - - -TRP (%) 82-95 87.4 91.8 86.2 95.8 85 - - -Nephrocalcinosisby Renal USYes Yes No No No No Yes No NoCrCl creatinine clearance, S-Alb serum albumin, U-prot urinary protein, U-β2MG urinary beta2microglobuline, U-Ca/U-Cr urinary calcium/urinary creatinine, U-prot/U-Crurinary protein/urinary creatinine, U-gluc urinary glucose, TRP tubular reabsorption of phosphate, Renal US renal ultrasoundDe Mutiis et al. Italian Journal of Pediatrics  (2015) 41:46 Page 2 of 4et al. [4] and one male by Hichri et al [12] (Table 2).Interestingly, the same mutation was identified by Hichriet al in another patient diagnosed with Lowe syndrome.The patients described by Hoopes and Böckenhauer hadcarrier females, as did our child, while the boy describedby Sekine likely had a de novo mutation.At diagnosis, the six patients had a mean age of16.6 years and showed the classic hallmarks of Dentdisease with LMWP and hypercalciuria, except forthe patient described by Sekine, who lacked hypercal-ciuria and the patient reported by Hichri, whose datais not available. Two patients (3 and 5 in Table 2) de-veloped a reduction in GFR during adolescence, whilea renal biopsy performed only in patient 3, demon-strated minimal change disease, as was found in our pa-tient. This histologic finding could lead to misdiagnosisand inappropriate and ineffective therapies such as theuse of corticosteroids or immunosuppressive agents.Furthermore, patients with Dent- 2 disease may sharesome extra-renal symptoms with the more severe Lowe’ssyndrome, such as peripheral cataracts, mental impairment,growth retardation and elevated creatinine kinase and lac-tate dehydrogenase, without evidence of muscle weakness[4, 10]. Regarding the p.Arg318Cys mutation, the patientwith Lowe syndrome reported by Hichri et al [12] pre-sented with severe myopia, while patients with Dent diseaselack cataracts or other forms of ocular damage. An increaseof CPK and LDH enzymes was present in our patient andin the two brothers described by Böckenhauer (patients 4and 5 in Table 2). Some degree of mental impairment wasdetected in patients 1 and 2 and short stature was noted inpatient 5. These figures confirm that, even within the samegenotype, there is a certain variability in the expression ofthe severity of the disease.The absence of hypercalciuria in our patient may bedue to his younger age and it is possible that he couldexpress all the hallmarks of Dent disease in the future,but there is also the possibility that other mechanismscould regulate and compensate for the tendency to in-crease calcium excretion, reducing the degree of calciuria.Therefore, the presence of hypercalciuria, typically con-sidered pathognomonic of Dent disease, could be absentand this should be considered as part of the variability inthe phenotype of this disease.ConclusionDent-2 disease may have a variable phenotype, lackingall the classic hallmarks, as described for some patientswith CLCN5 mutations [5–8], such that it could remainunderdiagnosed.Based on our experience and data from the literature,the diagnosis of Dent disease should be considered in allpatients with high range proteinuria and LMWP, even inthe absence of hypercalciuria. The CLCN5 gene, and ifnegative, the OCRL1 gene should be analyzed before con-sidering a renal biopsy in males with nephrotic rangeproteinuria and no clinical signs of nephrotic syndrome.Extra-renal symptoms (ocular involvement, mental impair-ment, growth retardation and elevated creatinine kinaseTable 2 Patients with Dent-2 disease with the same missense mutation in exon 11 (p.Arg318Cys) as our patientPatient 1 [3]a Patient 2 [3]a Patient 3 [9] Patient 4 [4]b Patient 5 [4]b Patient 6 [12] Our patientAge at presentation - - 7 - - - 2Age at diagnosis (years) 22 27 15 12 17 7 6CrCl (cc/min/1.73 m2) - - 90 107 77 - 140Hypercalciuria (>0.24) yes yes no yes yes - noLMWP yes yes yes yes yes yes yesLow TRP (%) - - - no no - noRenal biopsy - - minor glomerularabnormalities- - - minimal changediseaseElevated CPK/LDH no/no no/no yes/no yes/yes yes/yes - yes/yesglycosuria no no no no no - noaminoaciduria - - no no no - noRenal tubular acidosis - - no no no - noNephrocalcinosis/stones no/no no/no no/no yes/no yes/no - no/noOcular involvement no no no no no - noCognitive function mild mentalretardationmild mentalretardationnormal normal normal normal normalGrowth - - normal normal short stature - normalCrCl creatinine clearance, LMWP low molecular weight proteinuria, TRP tubular reabsorption of phosphate, CPK creatine phosphate kinase, LDH lactate dehydrogenasea,bbrothersDe Mutiis et al. Italian Journal of Pediatrics  (2015) 41:46 Page 3 of 4and lactate dehydrogenase) should be looked for and couldlead to a diagnosis of Dent-2 disease.ConsentWritten informed consent was obtained from the patientfor publication of this Case report and any accompanyingimages. A copy of the written consent is available forreview by the Editor-in-Chief of this journal.AbbreviationsCrCl: Creatinine clearance; LMWP: Low molecular weight proteinuria;TRP: Tubular reabsorption of phosphate; CPK: Creatine phosphate kinase;LDH: Lactate dehydrogenase; S-Alb: Serum albumin; U-prot: Urinary protein;U-β2MG: Urinary beta2microglobuline; U-Ca/U-Cr: Urinary calcium/urinarycreatinine; U-prot/U-Cr: Urinary protein/urinary creatinine; U-gluc: Urinaryglucose; Renal US: Renal ultrasound; ACE: Angiotensinconverting enzyme.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsCD: Study conception and design of the manuscript. AP: was involved inclinical care of the patient and writing up of first draft of the paper. CL andFP: were involved in clinical care and helped draft the manuscript. GM:Critical revision of the article and approved final manuscript. All authors readand approved the final manuscript.AcknowledgementsThe authors are grateful to Dr. Ian Hewitt who contributed towards thestudy by revising it critically and to Ms. Alexandra Rachel Teff for editing themanuscript.Received: 19 April 2015 Accepted: 16 June 2015References1. Devuyst O, Thakker RV. Dent’s disease. Orphanet J Rare Dis. 2010;5:28.2. Claverie-Martín F, Ramos-Trujillo E, García-Nieto V. Dent’s disease: clinicalfeatures and molecular basis. Pediatr Nephrol. 2011;26:693–704.3. Hoopes Jr RR, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, et al.Dent disease with mutation in OCRL1. Am J Hum Genet. 2005;76:260–7.4. Böckenhauer D, Bökenkamp A, Nuutinenc M, Unwind R, Van’t Hoffa W,Sirimanna T, et al. Novel OCRL mutations in patients with Dent-2 disease.J Pediatr Genet. 2012;1:15–23.5. Frishberg Y, Dinour D, Belostotsky R, Becker-Cohen R, Rinat C, Feinstein S,et al. Dent’s disease manifesting as focal glomerulosclerosis: Is it the tip ofthe iceberg? Pediatr Nephrol. 2009;24:2369–73.6. Copelovitch L, Nash MA, Kaplan BS. Hypothesis: Dent disease is anunderrecognized cause of focal glomerulosclerosis. Clin J Am Soc Nephrol.2007;2:914–8.7. Cramer MT, Charlton JR, Fogo AB, Fathallah-Shaykh SA, Askenazi DJ,Guay-Woodford LM. Expanding the phenotype of Proteinuria in Dentdisease: a case series. Pediatr Nephrol. 2014;29:2051–4.8. Ludwig M, Utsch B, Balluch B, Fründ S, Kuwertz-Bröking E, Bökenkamp A.Hypercalciuria in patients with CLCN5 mutations. Pediatr Nephrol.2006;21:1241–50.9. Sekine T, Nozu K, Iyengar R, Fu XJ, Matsuo M, Tanaka R, et al. OCRL1 mutations inpatients with Dent disease phenotype in Japan. Pediatr Nephrol. 2007;22:975–80.10. Shrimpton AE, Hoopes Jr RR, Knohl SJ, Hueber P, Reed AAC, Christie PT, et al.OCRL1 mutations in dent 2 patients suggest a mechanism for phenotypicvariability. Nephron Physiol. 2009;112:27–36.11. Gambaro G, Vezzoli G, Casari G, Rampoldi L, D’Angelo A, Borghi L. Geneticsof hypercalciuria and calcium nephrolithiasis: from the rare monogenic tothe common polygenic forms. Am J Kidney Dis. 2004;44:963–86.12. Hichri H, Rendu J, Monnier N, Coutton C, Dorseuil O, Poussou RV, et al. FromLowe syndrome to Dent disease: correlations between mutations of the OCRL1gene and clinical and biochemical phenotypes. Hum Mutat. 2011;32:379–88.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color ﬁgure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitDe Mutiis et al. Italian Journal of Pediatrics  (2015) 41:46 Page 4 of 4

Italian Journal of Pediatrics

Nephrotic-range Albuminuria as the presenting symptom of Dent-2 disease

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Nephrotic-range Albuminuria as the presenting symptom of Dent-2 disease

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