enürezis ile başvuran erkek Çocukta kronik böbrek

347

Olgu Sunumu/Case Report

Turk Neph Dial Transpl 2017; 26 (3): 347-350

Chronic Kidney Disease in a Boy with Enuresis: The Diagnosis Behind the Smile

Enürezis ile Başvuran Erkek Çocukta Kronik Böbrek Hastalığı: Gülümsemenin Ardındaki Tanı

Belde KaSap Demir1

Robert Hall2

William G NeWmaN2

1 İzmirKatipÇelebiUniversity, FacultyofMedicine, DepartmentofPediatricNephrology, İzmir,Turkey2 UniversityofManchester,Manchester

CentreforGenomicMedicine,Manchester,England

doi: 10.5262/tndt.2017.1003.17

CorrespondenceAddress:Belde Kasap DemirİzmirKatipÇelebiÜniversitesi,TıpFakültesi,ÇocukNefrolojiBilimDalı,İzmir,TurkeyPhone :+905325034675E-mail :[email protected]

aBStRaCt

A 13-year-old boy was admitted with enuresis. He had no history of urinary tract infection,daytime incontinenceor fecal incontinence.Previously performedultrasoundhad revealedbilateralhydroureteronephrosis and trabeculated bladder. Voiding cystoureterography had detected multiplediverticuliwithout reflux.Renal scanhad revealed reduceduptakewithmultiple renal scarringanddiureticrenogramhadshownbilateralobstruction.Urodynamicevaluationhadrevealednon-complianthyperactivebladderandsignificantresidualvolume.Laboratorytestshadbeenconsistentwithchronickidneydiseaseandhehadbeenreferredtoourclinic.Onadmission,hewasdiagnosedwithurofacialsyndrome, due to the grimacing expressionwhile trying to smile onphysical examination, and thediagnosis was further confirmed by genetic analysis during follow-up. This case was reported toincreasetheawarenessofphysiciansaboutthisrarecauseofchronickidneydiseaseasearlydiagnosisismandatory.Askingthepatienttosmilewouldeasilyleadtothediagnosis.

Key WORdS: Urofacialsyndrome,Chronickidneydisease,Enuresis,Children

Öz

Onüçyaşındaerkekolgugeceleriidrarkaçırmaşikayetiilebaşvurdu.Geçirilmişidraryoluenfeksiyonu,gündüzidrarkaçırmayadadışkıkaçırmagibişikayetlerininolmadığınıbelirtti.Başvuruöncesiyapılanultrasonografisindebilateralhidroüreteronefrozununolduğuvemesanesinintrabeküleolduğugörüldü.İşemesistoüretrogramındareflüsününolmadığıancakçokludivertiküllerininolduğugözlendi.Diüretikrenogramında bilateral obstrüksiyonu izlendi. Ürodinamik değerlendirmede kompliyansı düşükhiperaktif mesanesinin olduğu ve anlamlı miktarda rezidüel idrarının kaldığı görüldü. Laboratuvartestlerinin kronik böbrek hastalığı ile uyumlu olması üzerine olgu kliniğimize yönlendirildi.Başvurusunda olgunun fizik bakısında gülmeye çalışırken yüzünde gelişen ağlama/buruşma ifadesinedeni ile ürofasyal sendrom tanısı aldı ve izleminde tanısı genetik olarak doğrulandı.Olgu, erkentanınınönemliolduğusondönemböbrekyetmezliğininnadirnedenlerindenolanürofasyalsendromkonusundahekimlerinfarkındalığınıarttırmakamacıilesunulmuştur.Hastadansadecegülümsemesiniistemekkolaylıklatanıyagötürmektedir.

aNaHtaR SÖzCüKleR: Ürofasyalsendrom,Böbrekyetmezliği,Enürezis,Çocuk

Received :11.12.2016Accepted :24.01.2017INtROduCtION

Urofacial syndrome (UFS), alsoknownas Ochoa syndrome, is a rare autosomalrecessive disorder characterized by non-neurogenic bladder dysfunction (BD)associatedwithaninvertedfacialexpression(1,2). Early recognition is mandatory toprevent further damage to the kidneys (1-3).WereportanadolescentboywithUFS,

whohadsevererenaldamageduetodelayeddiagnosis.

CaSe SummaRy

A 13-year-old boy was admittedto clinic with enuresis. He denied anyprevious urinary tract infection, daytimeincontinenceoranyhistoryofconstipation.His parents were third-degree cousins. Hehad been detected in another clinic and

348

türk Nefroloji diyaliz ve transplantasyon dergisiTurkish Nephrology, Dialysis and Transplantation Journal Kasap Demir B et al: Enuresis and Chronic Kidney Disease


the radiological tests were as follows: Renal ultrasonographyrevealedbilateral increasedkidney sizes, renal echogenicities,severe bilateral hydronephrosis and tortuous ureters. Renalparenchymal thicknesswas 6mm in the left kidney.Bladderwallwasseverelythickened,trabeculated,andtherewereseveraldiverticuli.Voidingcystoureterographyrevealednoreflux,butconfirmedthetrabeculatedbladderandmultiplediverticuliwithamaximumdiameterof4 cm (Figure1).Dimercaptosuccinicacid (DMSA) scan demonstrated bilateral multiple corticaldefectiveareaswithadifferentialcountof67%fortherightand33%fortheleftkidney(Figure2).Diureticrenogramshowedbilateral obstruction. Urodynamic evaluation revealed poorlycompliant hyperactive bladder with high voiding pressuresandsignificantresidualvolumewithdyssynergia.Hewasthenreferredwhen laboratory findings showed high levels of ureaand creatinine.

On admission, the heightwas 165 cm (75-90 centile) andweight 47kg (25-50 centile).Thebloodpressurewas100/70mmHg (95 centile: 129/83mmHg).The abdomenwas soft,therewasnohairtuftorbonydefectonthelowerback.Deeptendon reflexes and the rest of his physical examinationwerenormal.However,itwasnoticedthathewasgrimacingwhenheattemptedtosmile(Figure3).

Complete blood cell count on admission was normal.Urinalysis revealed pH 6, specific gravity 1010, protein (-)with few leukocytes on microscopic examination. Otherlaboratoryfindingswere as follows: blood pH7.29, pCO2 34 mmHg,HCO316mmol/L, urea95mg/dL, serumcreatinine3.34mg/dL,sodium134mmol/L,potassium4.9mmol/L,uricacid 6.9 mg/dL, calcium 7.5 mg/dL, phosphorus 5.4 mg/dL,alkalinephosphatase367U/L,parathyroidhormone139.3pg/mL (normal 12-65), 25 (OH) vitaminD 18.5 ng/mL (normal10-80). Fractional sodium excretion was 7.6% (normal<1%),fractional potassium excretion was 49.4% (normal<15%),tubular phosphorus reabsorption was 75% (normal>80%),calcium excretion was 1.92 mg/kg/d (normal<4), proteinexcretion was 9.6 mg/m2/h (normal<4). Glomerular filtrationrate (GFR) calculated according to theSchwartz formulawas34.6 ml/min/1.73 m2 and creatinine clearance calculated using 24 hour collected urine was 14 mL/min/1.73 m2. When theradiographic and laboratory findings were evaluated togetherwith the grimacing gesture, he was thought to have chronickidneydiseaseduetoUFS.

In this patient, we identified a homozygous nonsensemutation[c.429T>A,p.(Y143*)]inexon2oftheHPSE2 gene (2). Both parents were, as expected, heterozygous for themutation(Figure3).Hewasstartedonantibioticprophylaxis,anticholinergicsandcleanintermittentcatheterization.

Figure 1: Voiding cystoureterography revealing neurogenic bladder with trabeculation and multiple diverticuli.

Figure 2: Characteristic inversion of facial expression appearing when the patient was asked to smile.

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dISCuSSION

Urofacial syndrome is theassociationofanon-neurogenicBDwith a typical facial expression,whichmay lead to renaldamageifleftuntreated(4).Facialexpressionisnormalatrest,thepatienthasgrimacingwhenattemptedtosmileandhasnosufferingexpressionbutnormalfacialexpressionwhilecrying(5).Ithasbeenhypothesizedthatthisgeneticdisordercausesasimultaneouseffectbothin“laughingandcryingcenters”andthe“micturitioncenter”,whichhavecloseproximityinupperpons(5). Some others proposed that two separate lesions affectingfacialnervenucleusandsacralcordmotornucleiinnervatingtheexternalsphincterwereresponsible(6).Themostrecentstudiesin animalmodels indicate a peripheral autonomic neuropathyforBDinUFS(7,8).

It is reported that UFS is an autosomal recessive diseaseand patients with Ochoa Syndrome usually have a genetic

background (5). Thus, a positive family history should alsoalertthephysicians.Ourpatienthadnorelativewithasimilarproblembuthisparentswerethird-degreecousins.

MutationshavebeendetectedinseveralfamilieswithUFS.Initially,twodifferentgroupsdefinedthesamebiallelicmutationin HPSE2 (chromosome 10q24.2) gene and published theirstudiesonthesamejournalatthesametime(1,3).Afterwards,biallelicLRIG2 (chromosome 1p13.2)mutationswereidentifiedinUFSpatients(2).However,therearestillsomeUFSfamiliesthemembersofwhichhadnoneofthesemutations.Inaddition,some family members with the same mutation may have nogrimacing butBD ormay have noBD but just characteristicgrimacing while their siblings have full-blown UFS in someseries(3,9).

Patients with HPSE2 mutations have been classified as“UFS1”andthosewithLRIG2mutationshasbeenclassifiedas“UFS2”(10).BothHPSE2 and LRIG2 transcriptsweredetectedinnervetrunksinvadingthefirsttrimesterbladder(2,3,11).Theexact biological function of HPSE2 and LRIG2 is not clear,butitwashypothesizedthatbothproteinsplayakeyroleintheregulatorynetworkofbladderfunction(11).

The nonsense mutation in HPSE2 gene of our patient hasbeen formerlydefined in twoTurkishbrothers (8).TheybothhadlargetrabeculatedbladderwithoutVURandonealsohadhighScr as inourpatient.Aydogduet al. reported16and19yearoldbrotherswithUFS,presentingwithelevatedsCrlevelsin their series (9).Fiveofninecases reportedbyVarlamandDippellhadCRFandonehadend-stagekidneydisease(12).Itwasnotedthatpatientsdiagnosedatschoolageorlatergenerallyexhibitagreaterdegreeofkidneydamage(5).

CaseswithUFS usually have urgency, urge incontinence,enuresis,recurrenturinarytractinfectionsduetodysfunctionalbladderandresidualurineinadditiontodysfunctionaleliminationfindings including constipation and encopresis (4,5,13). Theinterestingpointinourpatientwasthatalthoughhehadseverepathological urinary tract features leading to chronic renalfailure,hehadnocomplaintsotherthanenuresis.Thus,althoughrare, it is reasonable to consider UFS in patients presentingwithenuresisandseekforthecharacteristicinversionoffacialexpressionwith smiling. In addition,our case emphasizes theimportanceofurinarysystemultrasonographyintheevaluationofpatientswithenuresis(14).

In conclusion, UFS should be considered in patientswith dysfunctional voiding, even in thosewith only enuresis,particularly in countries where consanguineous marriagesarecustomary.Asking thepatient to smilecan facilitateearlydiagnosis, prevent unnecessary interventions and upper tractdamageandthediagnosismaybeconfirmedbygenetictesting.

Figure 3: Sequence traces shows homozygous c.429T>A (p.Tyr143*) in exon 2 of HPSE2. Sequencing of exon 2 in both parents was carried out to confirm they were both heterozygotes.

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RefeReNCeS1. PangJ,ZhangS,YangP,Hawkins-LeeB,ZhongJ,ZhangY,Ochoa

B,AgundezJA,VoelckelMA,FisherRB,GuW,XiongWC,MeiL,SheJX,WangCY:Loss-of-functionmutationsinHPSE2causethe autosomal recessive urofacial syndrome. Am J Hum Genet2010;86:957-962

2. StuartHM,RobertsNA,BurguB,DalySB,UrquhartJE,BhaskarS,DickersonJE,MermerkayaM,SilayMS,LewisMA,OlondrizMB,GenerB,BeetzC,VargaRE,GülpınarO,SüerE,SoygürT,OzçakarZB,YalçınkayaF,KavazA,BulumB,GücükA,YueWW,ErdoganF,BerryA,HanleyNA,McKenzieEA,HiltonEN,WoolfAS,NewmanWG:LRIG2mutationscauseurofacialsyndrome.AmJHumGenet2013;92:259-264

3. Daly SB,Urquhart JE,Hilton E,McKenzie EA,KammererRA,LewisM,KerrB,StuartH,DonnaiD,LongDA,BurguB,AydogduO,DerbentM,Garcia-MinaurS,ReardonW,GenerB,ShalevS,SmithR,WoolfAS,BlackGC,NewmanWG:MutationsinHPSE2causeurofacialsyndrome.AmJHumGenet2010;86:963-969

4. Stamatiou K, Tyritzis S, Karakos C, Skolarikos A: Urofacialsyndrome:Asubsetofneurogenicbladderdysfunctionsyndromes?Urology2011;78:911-913

5. Ochoa B: Can a congenital dysfunctional bladder be diagnosedfromasmile?TheOchoasyndromeupdated.PediatrNephrol2004;19:6-12

6. Ganesan I,ThomasT:More thanmeets the smile:FacialmuscleexpressioninchildrenwithOchoasyndrome.MedJMalaysia2011;66:507-509

7. Roberts NA, Woolf AS, Stuart HM, Thuret R, McKenzie EA,Newman WG, Hilton EN: Heparanase 2, mutated in urofacialsyndrome, mediates peripheral neural development in Xenopus.HumMolGenet2014;23:4302-4314

8. Stuart HM, Roberts NA, Hilton EN, McKenzie EA, Daly SB,HadfieldKD,RahalJS,GardinerNJ,TanleySW,LewisMA,SitesE,AngleB,AlvesC,LourençoT,RodriguesM,CaladoA,AmadoM,GuerreiroN,Serras I,BeetzC,VargaRE,SilayMS,DarlowJM, DobsonMG, Barton DE, HunzikerM, Puri P, Feather SA,Goodship JA,GoodshipTH,LambertHJ,CordellHJ;UKVURStudy Group, Saggar A, Kinali M; 4C Study Group, Lorenz C,MoellerK,SchaeferF,BayazitAK,WeberS,NewmanWG,WoolfAS:UrinarytracteffectsofHPSE2mutations.JAmSocNephrol2015;26:797-804

9. AydogduO,BurguB,DemirelF,SoygurT,OzcakarZB,YalcinkayaF,TekgulS:Ochoasyndrome:Aspectrumofurofacialsyndrome.EurJPediatr2010;169:431-435

10.Woolf AS, Stuart HM, Roberts NA,McKenzie EA, Hilton EN,Newman WG: Urofacial Syndrome: A genetic and congenitaldisease of aberrant urinary bladder innervations. PediatrNephrol2014;29:513-518

11.RobertsNA,HiltonEN,WoolfAS:Fromgenediscovery tonewbiologicalmechanisms:Heparanasesandcongenitalurinarybladderdisease.NephrolDialTransplant2016;31:534-540

12.VarlamDE,DippellJ:Non-neurogenicbladderandchronicrenalinsufficiencyinchildhood.PediatrNephrol1995;9:1-5

13.Derbent M, Melek E, Arman A, Uçkan S, Baskin E: Urofacial(ochoa) syndrome: Can a facial gestalt represent severe voidingdysfunction?RenFail2009;31:589-592

14.Alpay H, Karaaslan-Bıyıklı N. İşeme bozuklukları. TNDT2003;12:122-126

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