Family history may be misleading in the diagnosis of Dent’s disease

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The rare Dent’s disease manifests with medullary nephrocalcinosis, nephrolithiasis, hypercalciuria, low molecular weight proteinuria and other tubular dysfunctions, rickets or osteomalacia, and renal failure, in various combinations. It is a

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  Case report 2 BA is a 15-year-old boy who has been followed upregularly for a year now due to a chance discovery of microhematuria and mild proteinuria (0.8–1.0 g/24 h) ata sports medical check-up. His BW is 65 kg and he is175 cm tall and otherwise normal; his personal history isirrelevant. His family history suggested a dominantautosomal transmission of stone-related conditions,since the grandfather and an uncle on the mother’s sidewere renal stone formers, and a great uncle has end-stage renal disease (ESRD) with a history of renal stonesand a nephrocalcinosis disorder labeled as medullarysponge kidney (Fig. 2).Serum creatinine is 45.1  l mol/l. Immunological ser-um indices (complement, immunoglobulins, immuno-complexes, rheumatoid factor, anti-nucleus, and DNAantibodies) are all normal, as are audiometric and renalUS test results. Given the finding of calcium oxalatecrystals in his urine, oxaluria and calciuria were testedand hypercalciuria (16.4 mmol/24 h) was detected. Aurine protein selectivity index of 0.64 prompted thesuspicion of a glomerular disease, however, so a renalbiopsy was performed.Optical microscopy disclosed numerous glomeruli, allnormal except two, which were hyaline. Patchy inter-stitial fibrosis was observed, associated with cellularinfiltrates in one area. Non-specific segmental or diffusemesangial deposition of IgM and C3 was seen in someglomeruli. Electron microscopy showed normal GBM.On the whole, the picture suggested a non-immunolog-ical interstitial disorder. The finding of concomitanthypercalciuria prompted von Kossa staining to rule outDD and a sample of the patient’s DNA was requestedfor the referring nephrologist.While the former ruled out any tissue calcifications,molecular analysis on the  CLCN5  gene identified anucleotide G to T substitution in exon 7 in position1,070 (1,070 C>T), leading to the non-conservativeglycine  fi  valine substitution (G260V). This is a CLCN5  gene mutation never hitherto described. It wasalso found in the mother and in the ESRD uncle. Themother had abnormal urinary levels of   b 2 -microglobu-lin. Discussion Dent’s disease (DD) is characterized by medullarynephrocalcinosis, nephrolithiasis, hypercalciuria, LMWproteinuria and other tubular dysfunctions, rickets orosteomalacia, and renal failure, in various combinations[3]. This rare disease presents in childhood or early adultlife. Females are only exceptionally affected [3] becauseit is a recessive X-linked condition caused by mutationsin the chloride channel  CLCN5  gene [4, 5], located on the short arm of the X chromosome (Xp11.22) [6]. Thisgene encodes a 746-amino acid protein expressed in therenal proximal tubules, the thick ascending loop of Henle, and  a -intercalated cells of the collecting ducts [7,8], which has a role in endosomal acidification processes.A defect in endosomal-dependent phenomena, i.e. inrenal proximal tubule LMW protein absorption andreceptor trafficking, appears to be the pathophysiologi-cal culprit for the disease [9].Clinicians quite often consider family history a rele-vant, possibly even fundamental pointer to the diagnosisof DD, but this is not invariably the case since puzzling Fig. 1  Case 1’s family pedigree.  SS   short stature,  S   renal stone,  NC  nephrocalcinosis,  arrow  proband,  full black symbol   mutatedindividual,  crossed symbol   dead individual. The clinical phenotypesSS or rickets affect both genders (apparently ruling out an X-linkeddisorder, and thus pointing to a autosomic condition; since thesephenotypes are not described in two generations, this suggests arecessive autosomic trait). Same conclusion if NC and S areconsidered as different expression of the same genetical disorder Fig. 2  Case 2’s family pedigree.  S   renal stone,  NC   nephrocalcino-sis,  HC   hypercalciuria,  arrow  proband,  full black symbol   mutatedindividuals,  crossed symbol   dead individual. By considering NC, Sand HC as different signs of the same genetical disorder, since allgenerations are affected, an autosomic dominant disorder (withincomplete penetrance in consideration that the proband’s motheris healthy) might be suggested62  inheritance patterns may certainly be the consequence of the DD composite phenotype, and the fact that someDD manifestations are widespread clinical problems.The two case reports depict misleading inheritance pat-terns.They are characterized by a family history apparentlywithout the X-linked inheritance typical of DD. Theinheritance pattern suggested a recessive autosomaltransmission of the short stature rickets in the first caseand a dominant one of the stone disease in the second.The clinical diagnosis of DD can prove difficult becausethe clinical picture may be very vague or non-specific,possibly flawed by recall bias (e.g. the short stature incase 1’s family), or purely biochemical (hypercalciuria,LMW proteinuria, i.e. two findings demanding non-routine analyses even in the nephrological setting). Casesmay even present with hypercalciuria alone, with noneof the other features of the disease [10], or with ESRDwithout nephrocalcinosis [3], or with seemingly idio-pathic calcium nephrolithiasis. That is why some casescan go unrecognized, preventing the recognition of aninherited pattern and particularly of a clear X-linkedtransmission. This is even more likely in the small familyunits now typical of western countries.On the other hand, one of the main signs of DD, i.e.,calcium renal stones, is very common in the generalpopulation (the prevalence of idiopathic calcium neph-rolithiasis is as high as 10%), so it may be that calciumnephrolithiasis, in its idiopathic form, is a chanceoccurrence in DD families (as in one member of each of the two families), giving rise to atypical, confoundinginheritance patterns.The message in this paper is that a diagnosis of DD issuggested primarily by a patient’s clinical signs, whilethe familial transmission pattern is not necessarily afeature. While the presence of an X-linked inheritancepattern supports the diagnosis of DD, its absence by nomeans suffices to rule out the disorder. The finding thatprobands’ mothers have LMW proteinuria is a stronghint to the diagnosis of DD. Actually both probands’mothers had abnormal urinary excretion of   b 2 -micro-globulin. Thus, in accordance with the literature [11], webelieve that assaying LMW proteinuria (or  b 2 -micro-globulin,  a 1 -microglobulin, or retinol-binding protein) infirst-degree female relatives of suspected cases is avaluable diagnostic tool before searching for  CLCN5 gene mutations or mutations of the OCRL1 gene whichhas been recently reported as causing an X-linked dis-order similar to DD [12]. On the contrary, LMW pro-teinuria is not found in first-degree female carriers of conditions mimicking DD, such as autosomal recessiveproximal tubulopathy with hypercalciuria [13]. References 1. Godefroid N, Proesmans W (2003) A girl with rickets andnephrocalcinosis. Pediatr Nephrol 18:5732. Tosetto E, Graziotto R, Artifoni L, Nachtigal J, Cascone C,Conz P, Piva M, Dell’Aquila R, De Paoli Vitali E, Citron L,Nalesso F, Antonello A, Vertolli U, Zagatti R, Lupo A,D’Angelo A, Anglani F, Gambaro G (2005) Dent’s disease andprevalence of renal stones in dialysis patients in north-easternitaly. J Human Genet (in press)3. Wrong OM, Norden AGW, Feest TG (1994) Dent’s disease; afamilial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolicbone disease, progressive renal failure and a marked malepredominance. Q J Med 84:4734. Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B,Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P,Rigden SP, Wrong O, Jentsch TJ, Craig IW, Thakker RV(1996) A common molecular basis for three inherited kidneystone diseases. Nature 379:4455. Thakker RV (2000) Pathogenesis of Dent’s disease and relatedsyndromes of X-linked nephrolithiasis. Kidney Int 57:7876. Scheinman SJ, Pook MA, Wooding C, Pang JT, Frymoyer PA,Thakker RV (1993) Mapping the gene causing X-linkedrecessive nephrolithiasis to Xp11.22 by linkage studies. J ClinInvest 91:23517. Gunther W, Luchow A, Cluzeaud F, Vandewalle A, Jentsch TJ(1998) ClC-5, the chloride channel mutated in Dent’s disease,colocalizes with the proton pump in endocytically active kidneycells. Proc Natl Acad Sci USA 95:80758. Devuyst O, Christie PT, Courtoy PJ, Beauwens R, Thakker RV(1999) Intra-renal and subcellular distribution of the humanchloride channel, ClC-5, reveals a pathophysiological basis forDent’s disease. Hum Mol Genet 8:2479. Piwon N, Gunther W, Schwake M, Bosl MR, Jentsch TJ (2000)ClC-5 Cl  -channel disruption impairs endocytosis in a mousemodel for Dent’s disease. Nature 408:36910. Scheinman SJ, Cox JP, Lloyd SE, Pearce SH, Salenger PV,Hoopes RR, Bushinsky DA, Wrong O, Asplin JR, LangmanCB, Norden AG, Thakker RV (2000) Isolated hypercalciuriawith mutation in CLCN5: relevance to idiopathic hypercalci-uria. Kidney Int 57:23211. Reinhart SC, Norden AG, Lapsley M, Thakker RV, Pang J,Moses AM, Frymoyer PA, Favus MJ, Hoepner JA, ScheinmanSJ (1995) Characterization of carrier females and affected maleswith X-linked recessive nephrolithiasis. J Am Soc Nephrol5:145112. Hoopes RR Jr, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B,Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nuss-baum RL, Scheinman SJ (2005) Dent Disease with mutations inOCRL1. Am J Hum Genet 76:26013. Magen D, Adler L, Mandel H, Efrati E, Zelikovic I (2004)Autosomal recessive renal proximal tubulopathy and hyper-calciuria: a new syndrome. Am J Kidney Dis 43:60063
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