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REZUMATUL TEZEI DE DOCTORAT

Model de screening i tratament modern


pentru malformaiile genito-urinare
la copii

Doctorand Vasile Dan Stanca

Conductor de doctorat prof. dr. Constantin Ciuce

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CUPRINS

INTRODUCERE 15

STADIUL ACTUAL AL CUNOATERII 17


Introducere 19
1. Embriologia normal i patologic a aparatului uro -genital 21
2. Fiziopatologia malformaiilor genito-urinare 27
3. Strategii de diagnostic al malformaiilor congenitale genito-urinare 33
4. Tratamentul malformaiilor congenitale genito-urinare 37
CONTRIBUIA PERSONAL 45
1. Obiective 47
2. Metodologie general 47
3. Studiul 1 - Evaluarea eficienei unui program de screening pentru
depistarea malformaiilor uro-genitale la copii aparent sntoi de 49
vrst precolar i colar
4. Studiul 2 - Evaluarea rezultatelor obinute prin tratamentul modern
57
al malformaiilor congenitale ale tractului genito-urinar la copii
5. Studiul 3 - Identificarea unor factori etiologici genetici implicai n
97
apariia anomaliilor congenitale urinare sporadice (non-sindromice)
6. Studiul 4 - Evaluarea implicrii unor factori de mediu n apariia
103
malformaiilor genitale i a leziunilor gonadale secundare acestora
7. Studiul 5 - Crearea unei baze de date informatic i a unor aplicaii
pentru gestionarea datelor pacienilor i studiul rolului etiologic al 115
factorilor de mediu prin metode de data mining
8. Concluzii generale (sintez) 121
9. Originalitatea i contribuiile inovative ale tezei 123

REFERINE 125

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CUVINTE-CHEIE
anomalii congenitale genito-urinare, screening, ecografie, obstrucie urinar congenital, reflux vezico -
ureteral, laparoscopie, endoscopie urinar, spermatogenez, data mining.

INTRODUCERE
Un procent important de copii se nasc cu anomalii congenitale genito-urinare, cu grade diferite de
severitate. Acestea pot evolua mult vreme cu simptome puin specifice astfel nct depistarea lor este tardiv,
uneori n faza de insuficien renal cronic. Anomaliile congenitale urinare reprezint la nivel naional i
internaional principala cauz a insuficienei renale cronice la copil. Prin aceasta ele genereaz costuri
financiare semnificative i drame familiale ce ar putea fi n bun msur evitate. Consider prin urmare c orice
efort menit s diminue efectele detrimentale ale acestora este binevenit.
n cadrul proiectului de cercetare doctoral am realizat primul program naional de diagnosticare a
malformaiilor genito-urinare la copii prin examinri de tip screening a copiilor aparent sntoi. De
asemenea, am realizat tratamentul acestor anomalii prin aplicarea protocoalelor de diagnostic i tratament
recomandate de asociaiile europene de specialitate, cu implementarea tehnicilor minim invazive de
diagnostic i tratament (endoscopie urinar joas pentru valve de uretr posterioar, terapie laparoscopic
pentru criptorhidie i anomalii ale tractului urinar superior). Am elucidat rolul etiopatogenetic al unor factori
de mediu (temperatur, ritm circaanual) n cazul anomaliilor genitale i al unor mutaii genetice n cazul celor
urinare. n fine, am creat o aplicaie care permite nregistrarea datelor pacienilor din screening i prelucrarea
lor prin tehnici de data mining pentru descoperirea unor factori de risc pentru afeciuni congenitale genito-
urinare.

I. STADIUL ACTUAL AL CUNOATERII


1. Embriologia normal i patologic a aparatului uro -genital
nelegerea evenimentelor semnificative din embriologia aparatului genito-urinar este esenial att
pentru diagnosticul anomaliilor congenitale ct i pentru interpretarea relaiilor dintre diversele afeciuni
prezente la un singur pacient.
Formarea diverselor organe ale aparatului uro-genital are loc n etape care se suprapun parial i care
au un determinism genetic bine stabilit. Aciunea unui factor teratogen sau expresia unei gene mutate poate
influena dezvoltarea unuia sau a mai multor organe n funcie de momentul n care a survenit.
2. Fiziopatologia malformaiilor genito -urinare
Anomaliile congenitale urinare reprezint principala cauz a insuficienei renale la copii; mecanismele
prin care acioneaz sunt multiple. Rinichii acestor copii sufer prima lovitur n perioada intrauterin prin
formarea imperfect a parenchimului renal i apariia displaziei renale. Prin urmare rinichii copilului cu
malformaii urinare sunt deja afectai la momentul naterii, prezentnd leziuni de gravitate mai mare sau mai
mic.
Deficienele de curgere i evacuare a urinii (reflux, staz, obstrucie) favorizeaz dup natere apariia
unor complicaii redutabile care decompenseaz parenchimul displazic i grbesc instalarea insuficienei
renale cronice: pielonefritele acute recidivante i modificri cronice de presiune la nivelul membranei filtrante
glomerulare. Aceste mecanisme produc n final atrofie parenchimatoas renal i fibroz. Dei n ultimii ani
progresele n terapia de substituie renal au fost deosebite, rata de supravieuire a copiilor cu boal renal
terminal este n continuare de circa 30 de ori mai redus comparativ cu cea a copiilor sntoi.
Primele teorii cu privire la modul de apariie a displaziei renale subliniau legtura dintre ectopia
mugurelui ureteral i inducerea ineficient a blastemului metanefrogen. n prezent a fost precizat substratul
molecular al apariiei displaziei, defecte de comunicare i mediere intercelular ce duc la difereniere
insuficient, apoptoz i proliferare necontrolate. Este foarte probabil c cercettorii urmresc acelai

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fenomen, ns cu lupe de putere diferit: unii examineaz nivelul histologic al problemei, ceilali nivelul
molecular.
Obstrucia urinar congenital este prezent n timpul formrii rinichilor i prin urmare are un rsunet
diferit fa de cea dobndit n timpul vieii de adult, pe un rinichi matur. Dezvolt area unui rinichi fetal n
condiii de obstrucie urinar duce la deficiene pe trei direcii: controlul creterii, diferenierea celular i
fibroz.
n cazul n care obstrucia urinar nu este nlturat dup natere evoluia spre insuficien renal este
accelerat de infeciile urinare ce apar pe acest teren i de creterea presiunii din cile urinare. O intervenie
chirurgical corectoare nu previne ns progresia n toate cazurile ntruct aceti rinichi nu au rezervele
funcionale normale. Formar ea lor n condiii anormale afecteaz nsi caracterele structurale i funcionale
de baz. n anii care urmeaz operaiei corectoare nefronii restani sunt supui unui proces de hiperfiltrare
compensatorie care duce treptat la pierderea lor.
3. Strategii de diagnostic al malformaiilor congenitale genito-urinare
Diagnosticarea ct mai precoce a malforma iilor congenitale genito-urinare permite iniierea rapid a
tratamentului. Prin aceasta se ncearc vindecarea copiilor afectai sau ncetinirea evoluiei spre boala renal
n stadiu terminal acolo unde leziunile renale congenitale sunt foarte severe nc de la natere.
Exist dou tipuri de strategii de diagnostic: examenul ecografic antenatal i examinarea nou-nscuilor
la ieirea din maternitate. Acestea permit identificarea majoritii anomaliilor. Un numr semnificativ de
pacieni pot ns s nu fie identificai n urma acestui bilan ntruct anumite anomalii devin manifeste la un
interval de timp dup natere (uneori la civa ani). Apare prin urmare necesitatea unui filtru diagnostic
aplicat mai trziu, n perioada de copil precolar sau colar.
Examinarea ecografic antenatal a aparatului urinar poate identifica aspectele structurale ale multor
anomalii de dezvoltare. Momentul optim pentru diagnostic este la 27-28 sptmni de gestaie. O anomalie
sever detectat n aceast perioad poate justifica o decizie obstetrical ce s modifice cursul sarcinii.
Dei ecografia prenatal poate defini anatomia tractului urinar fetal, ea nu d informaii legate de
funcia rinichilor. Evaluarea funcional renal rmne a fi efectuat postnatal, cu toate eforturile unor
cercettori de a gsi elemente predictive (imagistice i biochimice) ale funciei renale fetale.
Un aspect important trebuie avut n vedere atunci cnd se indic i efectueaz o ecografie fetal pentru
identificarea unor malforma ii: riscul de supradiagnostic. Beneficiile depistrii precoce a anomaliilor trebuie
comparate cu riscul ca o hidronefroz antenatal s dispar curnd dup natere i s nu mai fie gsit (cu
alte cuvinte s nu aib semnificaie patologic). Medicul examinator nu poare prevedea modul n care va
evolua afeciunea dup natere; comunicarea diagnosticului induce viitorilor prini un stress de intensitate
crescut. n acest mod perioada de graviditate se transform ntr-o lung a teptare ncrcat de anxietate.
Bilanul diagnostic prezentat mai sus are capacitatea de a depista majoritatea anomaliilor congenitale
genito-urinare prezente la natere. Exist ns o serie de afeciun i care trec neidentificate: fimoza este
diagnosticat (cu excepia formelor extreme) dup vrsta de 3 ani; testiculele pot s lipseasc din scrot la
natere (n special la prematuri), pentru a i ncheia coborrea n lunile urmtoare, iar hipospadiasul (f orma
cu prepuiu intact) devine evident dup vrsta de 3 ani. Nu trebuie neglijat faptul c nu toi copiii trec prin
ecografii antenatale sau la ieirea din maternitate, datorit unor motive ce in de nivelul cultural i de
nelegere al prinilor, precum i de dotarea material i disponibilitatea serviciilor medicale de specialitate.
Apare prin urmare nevoia unui nou filtru diagnostic prin care s fie depistai pacienii purttori ai
acestor anomalii. Un astfel de bilan poate fi efectuat de ctre medi cii de familie care au pregtirea i dotarea
necesar; o alt strategie poate fi un screening adresat tuturor copiilor aparent sntoi. Programe de
screening separate pentru anomaliile urinare respectiv genitale au existat n unele ri ale Uniunii Europene,
n Japonia i n Statele Unite ale Americii; nu am gsit ns prezentat nici o aciune pentru depistarea
simultan a anomaliilor urinare i congenitale.
4. Tratamentul malformaiilor congenitale genito -urinare

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Anomaliile congenitale genito-urinare au reprezentat o patologie de grani ntre chirurgia pediatric i
urologie. n trecut copiii mici cu diverse afeciuni erau identificai i diagnosticai de ctre medicii pediatri,
apoi adresai chirurgilor pediatri pentru gestul intervenional. n situaia n care malformaiile nu erau foarte
zgomotoase pacienii ajungeau s fie diagnosticai n perioada vieii de adult (de exemplu criptorhidia
identificat cu ocazia nrolrii pentru efectuarea stagiului militar sau hidronefroza gsit n cursul evalurii
unei hipertensiuni arteriale), iar bilanul diagnostic i terapia erau efectuate de ctre medicul urolog.
n ultimii 30 de ani situaia s-a schimbat substanial la nivel mondial. Capacitatea de a conduce i
integra bilanul diagnostic cu gestul terapeutic , precum i cunotinele avansate de anatomie funcional i
fiziologie a aparatului urinar i genital masculin i-au permis medicului urolog s preia i patologia pediatric.
n prezent urologia pediatric a devenit o specialitate de sine stttoare sau medicii urologi interesai pot
dobndi supraspecializarea n urologie pediatric.
Urologia pediatric a beneficiat de toate achiziiile urologiei de aduli n materie de diagnostic i
terapie. ntre acestea se numr i tehnicile minim invazive de explorare i tratament ale aparatului urinar:
endoscopia urologic, laparoscopia, chirurgia robotic, explorrile urodinamice. Viteza de penetrare a acestor
tehnici n practica zilnic a fost mai redus dect n cazul adulilor; motivul a fost tendina urologilor pe diatri
de a evalua mult mai critic avantajele i riscurile acestor metode noi pentru pacienii pediatrici, nscut i din
gradul lor de implicare emoional mai mare n tratarea copiilor. Acest tip de abordare a dus ns la o finee
mai mare a interveniilor i o siguran sporit a gesturilor terapeutice specific acestei specialiti.

II. CONTRIBUIA PERSONAL


Am fixat urmtoarele obiective de cercetare:
1. Evaluarea eficienei unui program de screening pentru depistarea anomaliilor uro-genitale la copiii
aparent sntoi de vrst precolar i colar.
2. Evaluarea rezultatelor obinute prin tratamentul cu mijloace terapeutice moderne al anomaliilor
congenitale ale tractului genito-urinar la copii.
3. Identificarea unor factori etiologici genetici implicai n apariia anomaliilor congenitale urinare
sporadice (non-sindromice).
4. Evaluarea rolului unor factori de mediu n apariia anomaliilor genitale i a leziunilor gonadale
secundare.
5. Crearea unei baze de date informatic i a unor aplicaii pentru gestionarea datelor pacienilor i
studiul rolului etiologic al factorilor de mediu prin metode de data mining.
Finanarea cercetrii a fost realizat prin grantul CEEX 154/2006: Screening, profilaxie i corecie a
malformaiilor congenitale genito-urinare la copil n epoca tehnicilor terapeutice minim invazive
(laparoscopie, endoscopie) SCANURGENT.
Pentru realizarea obiectivelor 3, 4 i 5 am colaborat cu alte instituii de cercetare n cadrul grantului
sus-menionat: Institutul Oncologic Cluj -Napoca, Universitatea de tiine Agricole i Medicin Veterinar Cluj-
Napoca i Universitatea Tehnic Cluj -Napoca.

1. Evaluarea eficienei unui program de screening pentru depistarea anomaliilor uro-genitale


la copiii aparent sntoi de vrst precolar i colar
n intervalul de timp 2005 2008 am realizat primul screening din Romnia pentru depistarea
malformaiilor congenitale uro-genitale la copii. Programul a constat din examinarea copiilor de vrst
precolar i colar de la 10 coli i grdinie din judeele Cluj, Sibiu i Mure (coala General nr. 18 Cluj -
Napoca, coala i Liceul pentru copii cu deficiene de vedere Cluj -Napoca, coala i Liceul pentru Surzi Cluj-
Napoca, coala General Chinteni jud. Cluj, coala General Deuu jud. Cluj, coala General Iclod jud. Cluj,
coala General Aluni jud. Cluj, coala General Apoldu de Sus jud. Sibiu, coala General eulia de Cmpie
jud. Mure).

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Programarea vizitelor a fost fcut prin intermediul medicilor colari i a conducerilor unitilor de
nvmnt. Cu ajutorul lor au fost create condiiile necesare pentru desfurarea consultaiilor: ne-a fost pus
la dispoziie cabinetul medical colar sau o sal de clas amenajat (figurile 1 i 2) i am programat copiii
pentru consultaie. Prinii copiilor au primi t un chestionar care urmrea strngerea unor date referitoare la
expunerea lor profesional la diverse categorii de substane toxice i la evoluia sarcinilor.
Am utilizat un ecograf portabil Medison SA 600 cu transductor de 3,5 MHz.
Protocolul de investigare a cuprins:
- anamneza pentru depistarea simptomelor evocatoare (accese de febr neexplicate, infecii urinare
recidivante n antecedente, controlul sfincterian etc);
- examenul clinic al organelor genitale externe pentru evidenierea anomaliilor genitale (fimoz,
hipospadias, criptorhidie);
- examenul ecografic al aparatului urinar pentru vizualizarea anomaliilor de numr i poziie a organelor
urinare sau a dilataiei diverselor segmente ale tractului urinar.
Am examinat 1006 copii cu vrste ntre 5 i 18 ani i am constatat existena unor afeciuni uro-genitale
la un numr de 93 pacieni (9,3%). n urma examenului clinic a celor 497 biei din lotul studiat am identificat
anomaliile congenitale ale aparatului genital prezentate n tabelul I.

Tabelul I: Anomaliile congenitale ale aparatului genital masculin identificate prin programul de screening
Tipul anomaliei Numr de Procent din totalul Imagini cu cazuri
cazuri bieilor examinai selecionate
(N=497)
criptorhidie unilateral 8 1,6% figura 3
testicule flotante 8 1,6% figura 4
criptorhidie bilateral 3 0,6% figura 5
fimoz sau hipertrofie a 31 6,2% figura 6
frenului prepuial
hipospadias 8 1,6% figura 7
hidrocel 5 1%
varicocel 1 0,2% figura 8
micropenis 1 0,2%
chist de cordon spermatic 1 0,2%
Total 66 13,3%
Procedeul de screening iniiat n cadrul proiectului de cercetare a fost primul program de acest tip din
Romnia i a constat n evaluarea unor parametrii clinici i ecografici. Examenul clinic ne-a adus cele mai
multe informaii referitoare la prezena anomaliilor uro-genitale. Au fost depistate n cazul bieilor
malformaii de tip criptorhidie uni sau bilateral, testicule flotante, hidrocel, varicocel, fimoz, hipertrofie de
fren prepuial, hipospadias. Examenul ecografic a evideniat proporional mai puine malformaii.
Necesitatea unui astfel de program de diagnostic este subliniat de numrul mare de copii aparent
sntoi identificai ca fiind purttori ai unor anomalii ur o-genitale; surprinde n special prevalena
afeciunilor genitale masculine: 13,3% dintre bieii examinai.
Acestea sunt afeciuni fr simptomatologie evident care s determine copilul sau prinii acestuia s
solicite consultaie medical. De asemenea, sunt situaii patologice care se valideaz dup un interval variabil
de timp de la natere, trecnd astfel neobservate de medicul obstetrician sau neonatolog. Privind problema
din aceast perspectiv devine evident rolul pe care trebuie s l aib medicul de familie i medicul pediatru
atunci cnd consult un copil indiferent pentru ce motiv se prezint acesta la medic. Examenul clinic general i
evaluarea organelor genitale externe efectuate indiferent de motivul solicitrii consultaiei ar extrapola
rezultatele acestui program de cercetare la nivelul ntregii populaii pediatrice. i prinii copiilor trebuie
sensibilizai cu privire la explorarea conformaiei organelor genitale externe a copiilor n ideea de a remarca
eventualele anomalii.

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Ideea screening-ului combinat pentru cele dou tipuri de anomalii congenitale a fost ntmpinat cu
interes de urologi att n Romnia ct i n strintate; n anul 2008 am prezentat rezultatele acestui program
att pe plan naional, cu ocazia Congresului Asociaiei Romne de Urologie ct i internaional, la Congresul
Societii Internaionale de Urologie de la Santiago de Chile i la Consftuirea Central European organizat la
Varovia de ctre Asociaia European de Urologie.

2. Evaluarea rezultatelor obinute prin tratamentul cu mijloace terapeutice moderne al


anomaliilor congenitale ale tractului genito-urinar la copii.
n cadrul proiectului de cercetare doctoral mi-am fixat ca obiectiv evaluarea rezultatelor obinute prin
tratamentul modern al anomaliilor congenitale ale tractului genito-urinar la copii. De asemenea. am evaluat
modul n care tehnicile diagnostice i terapeutice minim invazive din urologia standard pot fi adaptate
patologiei pediatrice.
Tratamentul copiilor cu anomalii congenitale genito-urinare a fost realizat n Secia de Urologie a
Spitalului Clinic Municipal Cluj-Napoca, serviciu coordonat de prof. dr. Ioan Coman. Am evaluat datele
medicale ale copiilor operai n n intervalul ianuarie 2005-decembrie 2010.
Prin intermediul grantului CEEX 154/2006 Screening, profilaxie i corecie a malformaiilor
congenitale genito-urinare la copil n epoca tehnicilor terapeutice minim invazive (laparoscopie, endoscopie)
SCANURGENT am achiziionat instrumentar medical pentru intervenii chirurgicale clasice i minim invazive
i am amenajat spaiul pentru funcionarea nou-nfiinatului Departament de Urologie Pediatric.
Am nregistrat tipurile de proceduri diagnostice i chirurgicale efectuate, numrul de pacieni care au
beneficiat de serviciile instituiei noastre, protocoalele de lucru utilizate i rezultatele obinute. De asemenea
am cuantificat complicaiile i dificultile ntlnite n procesul de ngrijire a acestor copii.
n intervalul ianuarie 2005-decembrie 2010 n Departamentul de Urologie Pediatric de la Spitalul
Clinic Municipal Cluj-Napoca au fost operai un numr de 262 de pacieni, dintre care 202 de copii cu anomalii
congenitale genito-urinare.
Au fost realizate urmtoarele tipuri de intervenii chirurgicale:

Tabelul II: tipul de intervenii chirurgicale realizate n Departamentul de Urologie pediatric a Spitalului Clinic
Municipal Cluj-Napoca n intervalul ianuarie 2005-decembrie 2010.
Tipul interveniei Numr de cazuri Total
clasic laparoscopic endoscopic
Pieloplastie pentru 44 2 46
hidronefroz prin sindrom de
jonciune pielo -ureteral
Nefrectomie pentru 17 17
hidronefroz decompensat
Nefrectomie pentru displazie 12 2 14
renal
Reimplantare uretero-vezical 12 12
pentru reflux vezico-ureteral
Nefrectomie parial pentru 4 4
duplicaie pielo-ureteral
Cura megaureterului 14 14
obstructiv primar
Cistoscopie pentru patologie 8 8
de tract urinar inferior

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Valv de uretr posterioar 2 1 3
Orhidopexie pentru 27 2 29
criptorhidie
Orhiectomie n caz de 3 4 7
criptorhidie
Uretroplastie pentru 25 25
hipospadias
Circumcizie pentru fimoz 21 21
Inseria endoscopic a 2 2
stentului ureteral
Total 179 10 11 200
Tratarea copiilor cu malformaii congenitale genito -urinare presupune constituirea unei echipe de
lucru din care fac parte obligatoriu medici de mai multe specialiti: urologie pediatric, pediatrie, anestezie-
terapie intensiv, radiologie i medicin nuclear. n urma unor eforturi organizatorice susinute din pa rtea
echipei de urologi de la Spitalul Clinic Municipal Cluj-Napoca condus de prof. dr. Ioan Coman a luat natere
un astfel de colectiv care la ora actual include medici din toate clinicile de pediatrie din Cluj-Napoca i de la
Clinica de Medicin Nuclear a Spitalului Judeean Cluj. Din anul 2009 tratamentul chirurgical al copiilor cu
malformaii se desfoar n cadrul Departamentului de Urologie Pediatric a Seciei clinice de Urologie din
Spitalul Municipal Cluj-Napoca, nfiinat prin Ordinul Ministrului Sntii.
Departamentul a fost creat prin separarea de secia de urologie aduli a dou saloane cu 5 paturi.
Acestea au fost amenajate corespunztor; n Secia de Terapie Intensiv a fost rezervat un pat pentru pacienii
pediatrici. Personalul medical a fost instruit n ceea ce privete particularitile afeciunilor pediatrice i
manevrele particulare de ngrijire (recoltare probe biologice, cateterizare venoas, cateterism uretro-vezical).
Modul n care am procedat pentru a realiza acest departament a fost considerat interesant i de actualitate de
ctre colegii urologi din strintate, o lucrare tiinific ce prezint aceste etape fiind prezentat la al 31-lea
Congres al Socit Internationale dUrologie de la Berlin, 2011.
Hidronefroza prin obstrucia jonciunii pielo-ureterale a fost principala afeciune congenital urologic
tratat n serviciul nostru.
Am preferat drenajul urinar prin nefrostomie n detrimentul cateterului ureteral autostatic JJ ntruct
am avut controlul mult mai bun asupra produciei de urin din rinichiul operat. n plus, suprimarea tubului de
nefrostomie se face fr anestezie, n condiii de ambulator, pe cnd extragerea stentului ureteral necesit
condiii de sal de operaie i anestezie general. Am nregistrat un singur incident legat de tubul de
nefrostomie: ruperea accidental a cateterului la momentul suprimrii cu retenia captului distal la nivel
renal, situaie care a impus reintervenie pentru ndeprtarea lui.
Pieloplastia laparoscopic poate fi o alternativ minim invaziv de tratament. Exist ns cteva
limitaii ale indicaiei ce deriv din particularitatea pacienilor pediatrici: nu poate fi aplicat n siguran la
vrste mici (sub 7 ani) datorit spaiului insuficient de lucru i gradul de dificultate presup us de suturile
extensive intracorporeale. n cazuistica proprie avem 2 pacieni operai laparoscopic retroperitoneal; unul
dintre ei a prezentat fistul lombar urinar ce s-a nchis spontan dup 14 zile. Rezultatele funcionale la
distan sunt foarte bune n ambele cazuri. Chirurgia laparoscopic asistat robotic ofer condiii mai bune
pentru realizarea suturilor intracorporeale.
Am nregistrat un numr relativ mare de nefrectomii pentru hidronefroz decompensat: 17 cazuri din
63 (27%), din care 6 cazuri erau n stadiul de pionefroz. Proporia mare se datoreaz probabil unor
deficiene n programul de diagnostic precoce (antenatal sau perinatal) i semnaleaz necesitatea unei
examinri ecografice de rutin fie antenatal, fie nainte de externarea din maternitate.
n serviciul nostru au fost tratai un numr de 14 copii cu displazie renal. Diagnosticul pozitiv a fost
susinut de evidenierea ecografic a unui rinichi cu diferenierea cortico -medular sczut i parenchim

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hiperecogen, cu chiste multiple, cu dimensiuni variabile. Scintigrafia renal (sau urografia) certific funcia
redus sau absent a acestui rinichi.
nainte de luarea deciziei terapeutice trebuie evaluate riscurile pe care maladia le creeaz pentru
purttorul ei. Complicaiile cele mai importante citate n literatur sunt apariia unor tumori Wilms (risc de 4x
mai mare dect n populaia general), hipertensiunea arterial, ruptura chistelor de mari dimensiuni n caz
de traumatism abdominal i compresiunea pe organele din jur. Rata mic de complicaii importante, mpreun
cu faptul c majoritatea rinichilor multichistici i reduc dimensiunile n timp sau chiar dispar ar sugera o
atitudine conservativ, cu monitorizare ecografic pe termen lung. Exist ns i puncte de vedere conform
crora o intervenie chirurgical care n general este bine tolerat de copii (nefrectomia simpl) i care poate
fi fcut i pe cale laparoscopic ar fi opiunea principal, pentru a evita riscurile citate i programul de
supraveghere, care poate ajunge la fel de costisitor ca i intervenia n sine.
n serviciul nostru au fost tratai un numr de 14 copii cu megaureter obstructiv primar. Indicaia
terapeutic a fost de rezecie a segmentului ureteral distal obstructiv urmat de ureteroplastie reducional i
reimplantare uretero-vezical n manier antireflux. Toate interveniile au fost efectuate pe cale
extraperitoneal, prin abord combinat lateroperitoneal i transvezical.
Diagnosticul pozitiv a fost evocat de evidenierea ecografic a unei hidronefroze n soite de dilataia
ureterului, evideniat n segmentul juxtavezical i susinut de scintigrafia renal (sau urografia) care
evideniau uretero-hidronefroz cu caracter obstructiv. Diagnosticul diferenial cu etiologia refluant a
megaureterului se face prin cistografie retrograd. Am practicat abord chirurgical lateroperitoneal prin incizie
Gibson cu rezecia segmentului ureteral distal stenotic, ureteroplastie pe stent n manier Kalicinski i
reimplantare uretero-vezical n manier Paquin. Nu au existat incidente sau complicaii intraoperatorii; nu a
fost necesar transfuzie de snge la nici un pacient. Am nregistrat o singur complicaie postoperatorie,
stenoza anastomozei uretero-vezicale care a impus reintervenie corectoare la un an postoperator.
Atitudinea chirurgical intervenional nu este ntotdeauna necesar ntruct pn la 85% dintre
cazurile de megaureter primar cunosc rezoluie spontan. Operaia de prim intenie ar fi rezervat cazurilor
cu obstrucie sever, infecii urinare i deteriorare a funciei renale. Rezecia excesului de ureter n
completarea exciziei segmentului stenotic este esenial pentru succesul interveniei. n lipsa acestui lucru
peristaltica ureteral este deficitar (lipsa de coaptare a pereilor ureterali duce la o obstrucie urinar
funcional).
n Departamentul de urologie pediatric din clinica noastr au fost operai 12 copii cu reflux vezico-
ureteral. Diagnosticul pozitiv s-a bazat pe cistografia retrograd (figurile 48, 49), examinare care a permis i
gradarea refluxului. Am realizat reimplantarea uretero-vezical prin abord transvezical. Am preferat tehnica
de reimplantare Cohen datorit facilitii de execuie i a rezultatelor bune raportate n literatur. Nu am
nregistrat complicaii intra sau postoperatorii care s impun reintervenie chirurgical.
Modul n care este privit refluxul vezico-ureteral difer substanial fa de situaia de acum 20 de ani. n
prezent se disting dou situaii ce reclam sanciune terapeutic diferit. Refluxul vezico-ureteral boal este
cauzat de incompetena anatomic a jonciunii uretero -vezicale (traiect intramural insuficient al ureterului
terminal). Se ntlnete mai ales la biei, la vrste mai mici (0 -3 ani) i are grad mai mare. ansa de renisie
spontan a sa este important. Refluxul simptom este ntlnit de regul la fete, este diagnosticat la vrste
mai mari (dup ctigarea controlului sfincterian) i are grad mai mic. Acesta este secundar unei disfuncii
micionale, definit ca i contracii ale sfincterului uri nar striat aprute n timpul miciunii. Presiunea
intrevezical ridicat duce la forarea jonciunii uretero-vezicale. Acest tip de reflux are anse mici de
rezoluie spontan n lipsa corectrii disfunciei de tract urinar inferior.
Refluxul nu mai este privit ca i cauz principal a infeciei urinare; relaia nu este unidirecional
reflux-infecie, ci mai complex (figurile 101 -102). Consecina acestei schimbri de optic este faptul c
tratamentul chirurgical nu este recomandat fr intervenii terapeutice de reeducare micional acolo unde
sunt prezente simptome de tract urinar inferior.

9
n Departamentul de urologie pediatric din clinica noastr au fost operai 4 copii cu duplicaie pielo-
ureteral. Diagnosticul pozitiv s-a bazat pe ecografie, urografie i scintigrafie renal. n toate cele 4 cazuri am
realizat nefrectomie parial a hemirinichiului superior cu ureterectomie. Interveniile au decurs fr
incidente sau complicaii. Nu au fost necesare transfuzii sanguine.
De obicei duplicaia pielo-ureteral nu este o anomalie cu consecine grave asupra rinichiului. n cadrul
campaniei de depistare a malformaiilor genito-urinare pe care am realizat-o am diagnosticat 14 copii cu acest
tip de afeciune (1,4% dintre copiii examinai), nici unul dintre acetia neavnd nevoie de intervenie
terapeutic. Singurele cazuri n care se pune n discu ie o corecie chirurgical sunt cele n care anomalia este
complicat de asocierea unor mecanisme fiziopatologice distincte: reflux urinar (de regul n ureterul
pielonului inferior) i obstrucie urinar (la nivelul jonciunii uretero -vezicale a ureterului superior).
n perioada ianuarie 2005 decembrie 2010 au fost tratai n Secia Clinic de Urologie a Spitalului
Clinic Municipal Cluj-Napoca un numr de 36 pacieni pediatrici cu criptorhidie uni sau bilateral (n total 45
testicule necoborte). Opt pacieni au prezentat un total de 11 testicule nepalpabile. n cazul copiilor cu
testicule nepalpabile primul timp operator a fost laparoscopia exploratorie efectuat transperitoneal.
Diagnosticul intraoperator de atrofie testicular a dus la finalizarea interveniei. La cazurile la care am
identificat testicule intraabdominale laparoscopia exploratorie a fost imediat urmat de gestul corector
(orhidopexie sau orhiectomie) realizate tot pe cale laparoscopic. n cazul pacienilor cu testicule palpabile la
nivelul canalului inghinal am realizat abordul chirurgical clasic.
n luarea deciziei terapeutice trebuie avute n vedere pe de o parte recomandrile formulate n
ghidurile de practic medical elaborate de Asociaia European de Urologie i pe de alt parte preferina
pacientului i a prinilor lui. Laparoscopia a adus beneficii certe n managementul pacienilor cu testicule
nepalpabile; rolul su este att diagnostic ct i terapeutic, putnd fi iniiat terapia cu ocazia aceleiai edine
operatorii.
Abordul laparoscopic i utilizarea tehnicii Fowler-Stephens permite obinerea unei poziii scrotale
satisfctoare pentru testiculul afectat. Tehnica a fost descris pentru prima dat n 1959 i presupune
ligatura i secionarea pediculului vascular testicular, gonada urmnd a fi vascularizat arterial prin artera
deferenial i artera cremasteric. Se pare c anastomozele ntre aceste vase exist n toate cazurile i se
gsesc subperitoneal, n regiunea imediat cranial de orificiul inghinal intern (existena lor a fost dovedit
recent n cadrul unor studii anatomice prin injectare de cear). Ele pot fi prezervate n cursul interveniilor
chirurgicale laparoscopice sau clasice prin pstrarea unui segment peritoneal triunghiular cu vrful la nivelul
orificiului inghinal intern i mrginit de ductul deferent i vasele testiculare i pot asigura supravieuirea
testiculului dup orhidopexie. Folosind aceast abordare terapeutic se obine o poziie scrotal a unui
testicul viabil n circa 80% din cazuri, neobservndu-se diferene ntre tehnica clasic i cea laparoscopic din
acest punct de vedere. Eecurile se datoreaz probabil obstruciei vaselor anastomotice arteriale prin
tensionarea lor n momentul pexiei sau calibrului insuficient al acestora.
Autotransplantul testicular se constituie ntr-o alternativ terapeutic promitoare pentru testiculele
situate intraabdominal. Intervenia presupune disecia pediculului vascular testicular cu prezervarea
peritoneului suprajacent vaselor, urmat de secionarea lor. Ulterior se disec pediculul vascular epigastric
inferior pe o lungime de 8-9 cm i se secioneaz. Anastomozarea vaselor testicular e cu cele epigastrice
inferioare se realizeaz sub microscop operator, cu fire 10/0.
n Romnia prima intervenie de acest tip a fost realizat de ctre Proca n 1987, cu anastomoza doar a
vaselor arteriale. n acel caz vena spermatic a fost ligaturat, n sperana unui drenaj venos eficient prin vena
cremasteric i cea deferenial. Pe plan naional primul autotransplant testicular cu anastomoza ambelor
vase (artera i vena) a fost realizat la Cluj-Napoca de ctre o echip de chirurgi i urologi sub coordonarea
prof. Ciuce.
n caz de hipospadias proximal am utilizat uretroplastie n manier Tiersch-Duplay sau Duckett, iar
pentru hipospadiasul distal am preferat maniera Snodgrass. Rezultatele au fost bune din punct de vedere
cosmetic i funcional dup prima intervenie chirurgical la 90% dintre pacienii cu hipospadias distal i la

10
45% dintre cei cu meat la nivelul corpului penian sau perineal. La pacienii cu hipospadias proximal am
nregistrat o rat de eec a uretroplastiei de 55%: 2 cazuri de dehis cen total i 6 cazuri de fistul uretro -
cutanat. Factorii care au favorizat obinerea unor rezultate bune au fost lipsa interveniilor chirurgicale
peniene n antecedente (prin urmare esuturi mai bine vascularizate), drenajul urinar prin cateter vezic al
suprapubian i interpoziia unui lambou vascularizat de dartos ntre neouretr i trana de sutur
tegumentar. Pentru copiii cu hipospadias distal procentul de complicaii postoperatorii a fost de doar 10%
(un caz de stenoz uretral). Nu am nregistrat incidente sau complicaii legate de montarea trocarului
suprapubian.
Calitatea esuturilor peniene influeneaz decisiv rezultatul uretroplastiei. Un penis cicatriceal oblig la
adaptarea tehnicii (tubularizarea lamboului prepuial cu risc crescut de fis tul sau gref de mucoas bucal cu
risc de strictur uretral) n condiiile unor esuturi de vecintate slab vascularizate sau a absenei
prepuiului. Rata global a complicaiilor constatat n cadrul lotului luat n studiu a fost de 36% i se
ncadreaz ntre procentele citate n literatur.

3. Identificarea unor factori etiologici genetici implicai n apariia anomaliilor congenitale


urinare sporadice (non-sindromice).
Dezvoltarea i diferenierea rinichiului presupune interaciuni secveniale ntre celulele epiteliale i
mezenchimale, guvernate de produii de expresie ai unor gene. Interaciunea duce la proliferare celular,
apoptoz i difereniere. Unele dintre aceste mecanisme de control au fost elucidate, altele sunt nc sub
semnul ntrebrii. Lipsa de expresie a acestor gene sau generarea unor produi nefuncionali ca urmare a unor
mutaii duce la alterarea ontogenezei renale cu grade variate de gravitate (de la displazia parenchimului renal
pn la agenezia renal).
Exist anomalii congenitale urinare care apar cu caracter sindromic; studiul pacienilor afectai a
permis identificarea genelor responsabile. Majoritatea cazurilor sunt ns sporadice, lucru ce a ngreunat
evaluarea substratului genetic i a lsat un cmp de lucru deschis pentru vii toare studii. Unul dintre
obiectivele acestei cercetri a fost fixat pornind de la aceast premis.
Am avut ca obiectiv de cercetare evaluarea existenei unor mutaii genetice specifice ( PAX2, KAL, EYA1
i HNF-1beta) la nivelul celulelor aparatului urinar al copiilor cu anomalii urinare non-sindromice. Am inclus
n studiu pacieni cu anomalii congenitale ale tractului urinar (hidronefroz congenital, megaureter
congenital). De la aceti pacieni am recoltat cte o prob de esut (perete de cale urinar) ce a fost introdus
imediat dup recoltare n azot lichid (-196oC). Materialul biologic a fost utilizat pentru investigaii genetice.
Am inclus n studiu 8 pacieni cu anomalii obstructive urinare (sindrom de jonciune pielo-ureteral i
megaureter). Identificarea unei gene cu expresie alterat care s fie specific anomaliilor urinare ar permite
formularea acordarea unui sfat genetic i luarea unei decizii terapeutice bazat pe argumente tiinifice n
cazul diagnosticului antenatal al unei anomalii urinare. n cadrul dozrilor efectuate la pacienii inclui n
studiu am constatat c gena TCF2 este supraexprimat n 4 din 6 cazuri de anomalii obstructive genito-
urinare. Numrul de cazuri este insuficient pentru a permite formularea unor recomandri, dar permite
orientarea unor proiecte de cercetare ulterioare n aceast direcie. Pentru celelalte gene studiate nu am
constatat modificri semnificative n lotul de pacieni studiat.
Datele obinute n studiul nostru (supraexpresia genei TCF2) difer de cel e publicate n literatur, unde
este citat deleia sau lipsa de expresie a acesteia. Cercetri ulterioare vor stabili dac acest tip de exprimare a
genei poate fi folosit n cadrul diagnosticului antenatal al anomaliilor urinare.
4. Evaluarea rolului unor factori de mediu n apariia anomaliilor genitale i a leziunilor
gonadale secundare
Creterea incidenei anomaliilor congenitale genitale la biei n ultimii 50 ani a adus n discuie rolul
unor factori de mediu care deregleaz embriogeneza normal. n Marea Britanie incidena criptorhidiei a
crescut de la 2,7% la 4,1% ntre anii 1950 i 1980; n acelai interval n Danemarca incidena a crescut de la
1,8% la 8,4%. Expunerea prinilor la substane chimice cu proprieti estrogenice sau antiandrogenice n

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perioada de concepie i pe parcursul sarcinii ar duce la creterea riscului de apariie a criptorhidiei i
hipospadiasului. Profesiile citate ca fiind la risc sunt cele de cur tori, tehnicieni de laborator, coafezi,
agricultori i muncitori din industria metalelor grele. Ipoteza c substanele xenobiotice pot altera semnalele
hormonale normale a fost intens studiat, dar nc insuficient dovedit.
Un alt factor de mediu ce ar putea cauza criptorhidie este ritmul circa-anual, mai precis perioada din an
n care se nate biatul. Copiii nscui iarna ar avea un risc crescut de anomalii genitale comparativ cu ceilali
copii, mecanismul fiziopatologic implicat fiind endocrin, legat de influena cantitii de lumin din mediul
nconjurtor asupra producerii unor hormoni hipofizari.
Pornind de la premisele sus-menionate mi-am fixat ca obiectiv evaluarea implicrii unor factori de
mediu (expunerea profesional a prinilor la substane cu efecte endocrine, ritmul circaanual, temperatura
scrotal ridicat) n apariia malformaiilor genitale i a disfunciilor testiculare secundare acestora folosind
cazurile identificate prin screening. Am studiat sensibilitatea la temperatur mai mare dect cea fiziologic a
fiecrui tip de celule din ciclul de spermatogenez pentru a evalua rolul temperaturii n etiologia infertilitii
la pacienii cu criptorhidie . Am realizat expunerea experimental a testiculelor unor oareci de experien la
temperatur crescut i am studiat repercursiunile acestui lucru asupra spermatogenezei.
Expunerea testiculelor animalelor de experien la temperatur crescut efect detrimental asupra
funciei lor exocrine. Acest lucru este evident urmrind modul n care evolueaz parametrii spermatici pe
durata unui ciclu de spermatogenez ce dureaz la oarece 40 de zile. Efectul cldurii asupra spermatozoizilor
aflai n epididim este evideniat prin recoltrile realizate la 6 ore dup expunere la temperatur. Pentru cei
aflai n plin proces de formare n testicul modificrile sunt evideniate n zilele 7, 14, 21, 28 i 40 de zile dup
expunere, zile ce corespund cu principalele etape din spermatogenez
Dei toate stadiile spermatogenezei sunt afectate, sensibilitatea maxim pare s fie caracteristic
primelor etape (evideniate experimental prin recoltrile de la 21 i 28 de zile).
Informaia este util n ncercarea de a extrapola rezultatele acestei cercetri n patologia uman.
Neajunsul principal al acestui experiment const n faptul c am realizat o expunere acut pe durat limitat a
testiculelor la cldur, n timp ce testiculul criptorhid este expus n mod cronic (permanent). Cu toate acestea,
experimentul a demonstrat sensibilitatea anumitor celule precursoare din ciclul de spermatogenez la
cldur.
Rezultatele acestui studiu au fost prezentate n 2009 la Congresul Societii Internaionale de Urologie
de la Shanghai, China.
n urma evalurii datelor programului de screening pentru malforma ii uro-genitale am constatat
diferene de inciden a anomaliilor genitale n funcie de perioada din an n care s-a nscut copilul. Anomaliile
de migraie testicular sunt mai frecvente la bieii nscui n sezonul rece (octombrie -aprilie) comparativ cu
cei nscui n sezonul cald (aprilie-octombrie), iar diferena este semnificativ statistic.
Aceast observaie confirm date din literatur; primii care au suspectat existena unei legturi ntre
ritmul circaanual i anomaliile de migraie testicular au fost cercettori din Scandinavia, unde diferenele
var-iarn sunt semnificative. Cauza acestei distribuii pare s fie un factor de mediu, cantitatea de lumin
natural din mediul nconjurtor care variaz n funcie de sezon i care ar influena secreia unor hormoni
hipofizari.
5. Crearea unei baze de date informatic i a unor aplicaii pentru gestionarea datelor
pacienilor i studiul rolului etiologic al factorilor de mediu prin metode de data mining
Produsele Data mining aparin familiei Business Intelligence (BI) mpreun cu uneltele OLAP
(Online Analytical Processing), enterprise reporting i ETL (Extragere, Transformare, ncarcare(Load)).
Data mining ajut organizaiile care posed o cantitate mare de informaii, procesnd aceste informaii,
gsind i extrgnd reguli greu vizibile, pentru a crea cunotine noi despre domeniu. Avantajele oferite de
aceast tehnologie sunt capabilitatea de a lucra cu cantitai mari de informaii, de a gsi grupri de date
semnificative, i abilitatea de a utiliza atribute continue sau discrete. Utilizri comune ale Data mining sunt
pentru strategii de marketing, sau pentru prezicerea unor date.

12
n cadrul proiectului de cercetare au fost dezvoltate trei tipuri de aplicaii: aplicaii de achiziie (mobile)
de date, aplicaii de centralizare de date i aplicaii de analiz de date. Acestea sunt utile pentru colectarea
datelor pacienilor n cadrul unei campanii de consultaii screening, transmiterea lor ctre o baz de date i
analiza legturii dintre diverii parametri nregistrai i afeciunile descoperite cu ocazia consultaiilor.
Scopul cercetrii a fost crearea unor aplicaii care s permit gestionarea corect a informaiilor
colectate cu ocazia campaniei de consultaii pentru depistarea anomaliilor congenitale genito-urinare
Aplicaiile au fost dezvoltate folosind t ehnologii variate de ultima ora, incluznd tehnologii de aplicaii
mobile (Java Mobile, Microsoft .NET Compact Framework), tehnologii desktop (Microsoft .NET Framework),
tehnologii server (Microsoft ASP.NET, Apache Tomcat, Microsoft IIS 6.0, Google Web Toolkit) i tehnologii de
baze de date clasice pentru managementul datelor (Microsoft SQL Server) i pentru analiza datelor (Microsoft
Analysis Server). Aplicaia ScanUrgent Mobile .NET poate fi folosit instalat pe sisteme de operare Windows
Mobile PoketPC cu versiuni ncepnd de la 5.0. Pentru rularea aplicaiei este necesar ca Microsoft .NET
Framework 2.0 s fie instalat pe dispozitivul mobil. Acest framework se poate downloada de pe situl
Microsoft. Pentru a instala aplicaia pe dispozitivul mobil aceasta se poate copia direct pe card-ul folosit de
dispozitiv sau folosind aplicaia Active Sync pus la dispoziie de ctre Microsoft.
Pentru a colecta date aplicaia ScanUrgent Mobile .NET pune la dispoziia utilizatorului un formular
pentru salvarea datelor descriptive ale pacientului (2 taburi numite E1 i E2) i un formular pentru
introducerea datelor din chestionar (3 taburi numite C1, C2, C3).
Pentru a mbunti experiena utilizatorului numele sesiunilor anterioare i datele folosite anterior se
salveaz i se pot selecta din list, nefiind necesar reintroducerea lor. Sesiunea se refer la numele unei
grupri de nregistrri, grupare care poate fi a elevilor unei anumite coli, testai la o anumit dat. Experiena
utilizatorului e mbuntit att prin optimizarea colectrii i analizei datelor, precum i prin reducerea
posibilitilor de apariie a erorilor n date.
Aplicaiile pot fi utilizate la colectarea datelor despre malformaiile genitale i urinare ale copiilor, la
descoperirea de pattern-uri legate de problema studiat. Analiza datelor se bazeaz pe un model de arbori de
decizie creat pe datele medicale inserate n baza de date cu ajutorul aplicaiilor de captur. Modelul reflect
clustere de variabile de intrare i impactul lor n diagnosticul pacientului

6. Concluzii
i. Avnd n vedere numrul mare de copii aparent snto i depistai ca fiind purttori ai unor afeciuni
congenitale (9,3% dintre copiii examinai) programul de screening pentru anomalii congenitale genito-
urinare este eficient i necesar. Incidena mare a afeciunilor genitale rmase nediagnosticate dup bilanul
standard antenatal i perinatal trebuie s atrag atenia medicilor de familie i pediatrilor asupra acestor
organe n cursul examinrilor de rutin pe care le efectueaz.
ii. Costurile financiare i dotarea material necesare pentru realizarea unui astfel de program sunt reduse,
fiind suficient un ecograf portabil i un cabinet pentru consultaii.
iii. Tratamentul copiilor cu malformaii congenitale genito-urinare poate fi fcut n condiii optime n
cadrul unei uniti medicale de sine stttoare, un Departament de urologie pediatric. Acesta poate fi
constituit n cadrul unei Clinici de urologie prin conjugarea eforturilor unei echipe ce include specialiti din
mai multe domenii medicale i factori de decizie administrativi.
iv. Pacienii pediatrici pot beneficia de metodele diagnostice i terapeutice minim invazive caracteristice
urologiei pentru aduli. n cazuistica noastr aplicarea tratamentelor laparoscopice i endoscopice la copii a
dus la rezultate comparabile cu cele ale tehnicilor clasice fr a nregistra creterea ratei complicaiilor.
Afeciunile pentru care am reuit s aplicm tehnici de diagnostic i tratament minim invazive sunt rinichiul
displazic multichistic, sindromul de jonciune pielo -ureteral, valvele de uretr posterioar, refluxul vezico-
ureteral i criptorhidia. Au fost realizate nefrectomie laparoscopic, pieloplastie laparoscopic, cistoscopie,
orhidopexie i orhiectomie laparoscopic, laparoscopie diagnostic transperitoneal.

13
v. Hidronefroza congenital prin sindrom de jonciune pielo-ureteral este afeciunea cu incidena cea
mai mare n cazuistica clinicii, o treime dintre copiii operai avnd aceast afeciune.
vi. Copiii cu valv de uretr posterioar au avut prognosticul cel mai nefavorabil, 66% fiind deja n faza de
insuficien renal cronic.
vii. Am nregistrat o rat foarte sczut de eec al interveniilor chirurgicale: doar 3 copii din 177 au avut
nevoie de reintervenii chirurgicale (1,6%). Excepie fac pacienii cu hipospadias proximal, la care rata de
reintervenie a fost de 50%.
viii. Gena TCF2 este supraexprimat n majoritatea cazurilor de anomalii obstructive urinare analizate
indiferent de normalizarea fa de cele dou gene house keeping RPLPO i HPRT1. Prin urmare nivelul crescut
al genei TCF2 poate deveni un marker important n evaluarea ontogenezei imperfecte a aparatului urinar la
copil.
ix. Expunerea testiculelor la temperatur mai mare dect cea fiziologic afecteaz toate tipurile de celule
precursoare ale spermatozoizilor. Sensibilitatea maxim pare s fie caracteristic primelor etape din
spermatogenez. Spermatozoizii rezultai din spermatogenez la temperatur crescut au caracteristici
modificate fa de cei formai n condiii normale (concentraie, viabilitate, motilitate progresiv); rata de
fertilitate in vivo a oarecilor cu testicule expuse la cldur este diminuat comparativ cu cea a martorilor.
Temperatura crescut la nivelul testiculelor este una dintre cauzele care duc la scderea fertilitii pacienilor
cu criptorhidie bilateral.
x. Bieii nscui iarna au un risc mai mare de a avea anomalii de migrare testicular comparativ cu cei
nscui vara, diferena fiind semnificativ statistic.
xi. Nu am reuit s evideniez o legtur ntre expunerea profesional a mamei pe perioada sarcinii i
apariia malformaiilor genitale.
xii. n contextul unui program de consultaii pentru depistarea malformaiilor congenitale nregistrare a
mai multor parametri cu privire la subiecii examinai va permite folosind infrastructura creat pentru
colectarea datelor i prelucrarea lor prin data mining stabilirea rolului cauzal al unor factori de mediu. De
asemenea, aceast platform integrat de lucru va oferi o vizualizare grafic a regulilor i concluziilor
descoperite, facilitnd o perspectiv de ansamblu, valoroas asupra datelor colectate.

14
PhD THESIS ABSTRACT

Screening and modern treatment model for


genito-urinary malformations on children

PhD Vasile Dan Stanca

PhD coordinatorProfConstantinCiuce PhD


Contents

INTRODUCTION 15

Current state of knowledge 17

Background 19

1. Normal and pathologic embryology of uro-genital tract 21

2. Physiopathology of genito-urinary malformations 27

3. Congenital genito-urinary malformations diagnosis strategies 33

4. Treatment of congenital genito-urinary malformations 37

PERSONAL CONTRIBUTION 45

1. Objectives 47

2. General methodology 47

3. 1st study - Evaluating the efficiency of a screening program to discover


uro-genital anomalies on apparently healthy children of preschool and 49
school age

4. 2nd study - Evaluating the obtained results through modern treatment


57
of congenital genito-urinary tract anomalies on children

5. 3rd study - Identifying new ethiologicalgenetical factors involved in


97
apparel of congenital urinary sporadical anomalies (non-syndrome)

6. 4th study - Evaluating the environmental factors in apparel of genital


103
anomalies and secondary gonadal lesions

7. 5th study - Creating a date base of applications for management of


patient data and study of ethiologic role of environmental factors by 115
using data mining

8. General conclusions (synthesis) 121

9. originality and inovativity of thesis 123

REFERENCES 125
KEY WORDS

Congenital genito-urinary anomalies, screening, ultrasonography, congenital urinary obstruction, bladder-


ureter reflux, laparoscopy, urinary endoscopy, spermatogenesis, data mining.

BACKGROUND

A large percentage of children are born with different severity grades of congenital genito-urinary
anomalies. These can evolve for a long period of time without specific symptoms allowing a late diagnostic,
most of the times in the faze of chronic renal failure. Nationally and internationally congenital urinary
anomalies represent the main cause of chronic renal failure on children. These generate major financial costs
and family dramas that could be avoided. I therefore believe that any effort to diminish the detrimental effect
of these is well justified.
Through my PhD research project I established the first national genito-urinary malformations diagnostic
program on children by screening examination of apparently healthy children. I also established treatment of
these anomalies by applying the diagnostic and treatment protocols recommended by the European
associations, implementing minimal invasive techniques of diagnostic and treatment (low urinary endoscopy
for posterior urethral valve, laparoscopic treatment for cryptorchidism, upper urinary tract anomalies). We
elucidated the etiopathogenetic role of various environmental factors (temperature, circa-annual rhythm)in
cases of genital anomalies and genetic mutations in case of urinary anomalies. Finally we created an
application which allows recording of patient screening data and processing them using data mining for
uncovering environmental risk factors for congenital genito-urinary conditions.
I. Current state of knowledge
1. Normal and pathologic embryology of uro-genital tract
Understanding significant events in the embryology of the genito-urinary tract is essential for diagnosis
of congenital anomalies and understanding and interpretation of correlations between different conditions
encountered in one patient.
Development of organs belonging to the uro-genital tract takes place in stages which partially overlap and
have a well-established genetic determinism. Action of a teratogenic factor or expression of a mutant gene
may influence the development of one or multiple organs, depending of the moment it occurred.
2. Physiopathology of genito-urinary malformations
Congenital urinary anomalies are the main cause of renal failure on children; the mechanisms of action are
multiple. The Kidneys of these children suffer the first blow in the intrauterine period by forming an imperfect
renal parenchyma and appearance of renal dysplasia. Therefore the kydneys of the child with urinary
malformations are already affected at the moment of birth, presenting injuries of greater or lower gravity.
Urinary drainage deficiencies (reflux, obstruction, stasis) favor apparition of complications that decompensate the
dysplasic parenchyma and hurry the onset of relapsing chronic renal failure and chronic pressure changes on the
glomerulus filtering membrane. These mechanisms finally lead to renal parenchyma atrophy and fibrosis. Although
in he last years there have been significant progresses in renal substitution therapy, the survival rate of children
with renal terminal disease continues to be 30 times lower that that of healthy children.
First theories regarding the apparelof renal dysplasia underline the connection between ectopic ureteric bud and
inefficient induction of metanefrogen blast. At present time the molecular substrate of dysplasia apparel, of
intercellular communication and mediation defects that lead to insufficient differentiation, apoptosis and
uncontrolled proliferation. It is highly possible that researchers watch for the same phenomena but with different
lenses: some examine the histological level of the subject while others examine the molecular level.
Congenital urinary obstruction is present during kidney development and has a different impact over the one
acquired during adulthood on a mature kidney. Development of a fetal kidney in conditions of urinary obstruction
leads to deficiencies on three levels: growth control, cellular differentiation and fibrosis.
In case that the urinary obstruction is not removed after birth evolution towards renal failure is accelerated by
urinary infections and growth of pressure in the urinary paths. A correcting surgical intervention does not prevent
progression in all cases because these kidneys do not have normal functional reserves. Their development in
abnormal circumstances affect the basic structural and functional character. In the years following the correcting
intervention the remaining nephrons are subjected to a compensatory hyperfiltration process that leads to their
loss.
3. Congenital genito-urinary malformations diagnosis strategies
Early diagnosis of congenital genito-urinary malformations allows early onset of treatment. This helps healing
affected children or slowing down the evolution towards terminal renal disease in cases where congenital renal
injuries are severe since birth.
There are two diagnosis strategies: prenatal ultrasound exam and examining the new-borne. They allow for most of
the anomalies to be identified. A significant number of patients may pass undiagnosed because some anomalies
manifest after a certain period after birth (years). Applying a diagnosis filter becomes necessary in preschool and
school children.
Ultrasound prenatal exam of the urinary tract may identify structural aspects of many development anomalies.
th th
Optimum moment for diagnosis is the 27 -28 gestation week. A severe anomaly detected at this age may justify
an obstetrical decision that could influence the pregnancy.
Even though prenatal ultrasound may define the anatomy of the fetal urinary tract it does not give information
about the function of kidneys. Renal functional evaluation is to be conducted after birth with all efforts to find
predictive elements (imagistic and biochemical) of fetal kidney function.
A major aspect must be held into consideration when a fetal ultrasound is being indicated and performed:
overdiagnosis risk. The benefits of early diagnosis must be compared with the risk of a fetal hydronephrosis to
disappear soon after birth (no pathological significance). The examining physician cannot foresee the evolution
after birth; communicating the diagnosis may induce in the future parents a high intensity stress and the gestation
period could be transformed in a waiting period full of anxiety.
The presented diagnosis protocol allows for the majority of congenital genito-urinary anomalies to be discovered at
birth. There are a series of conditions that pass unidentified: phimosis is diagnosed (except for severe forms) after
the age of 3; the testis could be missing from the scrotum at birth (especially in prematures), and hypospadias (with
intact foreskin) become obvious after the age of 3. We must not neglect the fact that not all children go through
prenatal ultrasounds or after birth, due to cultural level and parentsunderstanding level or due to lack of material
or medical personnel.
The need of a new diagnosis filter is needed so that carriers of these conditions could be identified. Such a protocol
may be applies by family doctors with special equipment and knowledge; a different strategy may be a screening
program designed for apparently healthy children. Separate screening programs for urinary and genital anomalies
are implemented in some countries of The European Union, in Japan and USA. We did not find any action for
simultaneous discovery of urinary and genital anomalies.
4. Treatment of congenital genito-urinary malformations
Congenital genito-urinary anomalies represent a borderline pathology between pediatric surgery and urology.
Small children with various conditions used to be identified and diagnosed by pediatricians and then referred to
pediatric surgeons for the interventional gesture. If the anomalies were not extremely obvious, patients used to be
diagnosed in adulthood (cryptorchidism was identified when joining the army, or hydronephrosis found during high
blood pressure evaluation), and the diagnosis protocol and therapy were conducted by the urologist.
In the last 30 years situation has changed on an international level. The capacity to lead and integrate a diagnosis
protocol with the therapeutic gesture and advance knowledge in functional anatomy and physiology of urinary
tract and male genitalia allowed the urologist to take over the pediatric pathology. In present pediatric urology
became a sole specialty or interested urologist may acquire competence in pediatric urology.
Pediatric urology has received all acquisitions of adult urology in matter of diagnosis and therapy. These include
minimal invasive exploring and treatment techniques; urologic endoscopy, laparoscopy, robotic surgery,
urodynamic explorations. The penetration speed of these techniques was lower than in adultscase; the reason was
the tendency of pediatric urologists to overevaluate the advantages and risks of these new methods on pediatric
patients, originated in a higher emotional implication in treating children. These types of approach lead to a greater
delicacy of interventions and a greater safety of therapeutic gestures.

II. Personal contribution


We established the following research objectives:
1. Evaluating the efficiency of a screening program to discover uro-genital anomalies on apparently
healthy children of preschool and school age
2. Evaluating the obtained results through modern treatment of congenital genito-urinary tract
anomalies on children
3. Identifying new ethiological genetical factors involved in apparel of congenital urinary sporadical
anomalies (non-syndrome)
4. Evaluating the environmental factors in apparel of genital anomalies and secondary gonadal lesions
5. Creating a date base of applications for management of patient data and study of ethiologic role of
environmental factors by using data mining
Research founding was realized through CEEX 154/2006grant: Screening, prophylaxis and correction of
congenital genito-urinary malformations on child in the era of minimal invasive therapeutic techniques
(laparoscopy, endoscopy)- SCANURGENT.
For realizing objectives 3,4 and 5 we collaborated with other institutions of research in the mentioned
grant: The oncologic Institute Cluj-Napoca, University of Agricol Science and Veterinary Medicine Cluj-
Napoca and Technical University Cluj-Napoca.

1. Evaluating the efficiency of a screening program to discover uro-genital anomalies on apparently


healthy children of preschool and school age
Between 2005-2008 we realized the first screening in Romania for discovering congenital uro-genital
malformations on children. The program consisted of examining children of preschool and school from 10
schools and kindergartens in Cluj, Sibiu, Mures (18 th General School ClujNapoca, School and High-School for
blind children Cluj-Napoca, School and High-School for deaf Cluj-Napoca, General School Chinteni, General
School Deusu, General School Iclod, General ScholAlunis, General School Apoldu de Sus, General School Seulia
de Campie)
Programing was made through school physicians. With their help we created the necessary conditions
to consult: the school medical cabinet and a school room (figures 1 and 2) and we scheduled children for
consult. The parents received a questionnaire aimed to gather data regarding professional exposure to
different toxic substances and pregnancy evolution.
We used a portable Medison SA600 Ultrasound with 3,5 MHz transductor.
The investigation protocol included:
History for evoking symptoms (unexplained fever episodes, recurent urinary infections, sphincter
control, etc)
Clinical exam of external genital organs for genital anomalies (fimosis, hypospadias, cryptochidia)
Ultrasound exam of urinary tract for visualizing anomalies of number and position of urinary organs
or dilatation of various segments of urinary tract.
We examined 1006 children with ages between 5 and 18 and acknowledged the existence of uro-genital
conditions on 93 patients (9,3%). Following the clinical exam of 497 boys in the studied lot we identified
congenital anomalies of the genital tract (table 1).

Table I: Congenital anomalies of male genital tract identified through the screening programe
Type of anomaly Number Percent of total of Images with
of examined boys selected cases
cases (N=497)
unilateral cryptorchidia 8 1,6% figure 3
testiculeflotanting testis 8 1,6% figure 4
bilateral cryptorchidia 3 0,6% figure 5
fimosis or hypertrophy of 31 6,2% figure 6
prepuialfren
hypospadias 8 1,6% figure 7
hydrocel 5 1%
varycocel 1 0,2% figure 8
micropenis 1 0,2%
spermatic cord cist 1 0,2%
Total 66 13,3%
The screening procedure initiated in our research project was the first program of this type in Romania
and implied evaluation of clinical and ultrasonographic parameters. The clinical exam brought the most
information about uro-genital anomalies. In case of boys we discovered malformations such as uni or bilateral
chryptochia, floating testis, hydrocel, varycocel, fimosis, preputialfren hypertrophy, hypospadias. Ultrasound
exam showed proportionally less malformations.
The necessity of such a diagnosis program is underlined by the great number of children apparently
healthy identified as carriers of uro-genital anomalies; it especially catches the prevalence of masculine
genital conditions: 13,3% of examined boys.
These are conditions without significant symptomatology that determines the child or parents to see a
medical doctor. There are also pathological situations that become valid after a certain amount of time from
birth passing unobserved by the obstetrician or neonathologist. From this point of wiew the role of the family
doctor and the pediatrician becomes obvious when consulting a child regardless of the motif of presentation.
General clinical exam and evaluation of external genital organs done regardless of the motif of presentation in
the medical office would extrapolate the rsults of this research program to the level of the general pediatric
population. The parents must also be sensitized regarding the exploration of external genital organs of
children.
The idea of combined screening for those two types of congenital anomalies was greated with interest
by urologists in Romania and abroad; in the year 2008 we presented the results of this program nationally
with the occasion of The Romanian Association of Urology Congress and internationally at the International
Urology Society Congress in Santiago Chile and at The Central European Gatheraround in Warsaw.

2. Evaluating the obtained results through modern treatment of congenital genito-urinary


tract anomalies on children
For my PhD research I aimed to evaluate the results obtained by modern treatment of congenital
genito-urinary tract anomalies in children. I also evaluated the way diagnosis techniques and minima invasive
treatment techniques in standard urology may be adapted for pediatric pathology.
Treatment of Children with congenital genito-urinary anomalies was realized in The Urology
department of The Clinical Municipal Hospital Cluj-Napoca, coordinated by Prof. IoanComan PhD. I evaluated
the medical data of children operated between January 2005 and December 2010.
Through CEEX 154/2006 grant Screening, prophylaxis and correction of congenital genito-urinary on
children in the era of minimal invasive therapeutical techniques (laparoscopy, endoscopy)-SCANURGENT we
acquired medical instrument for classical and minimal invasive interventions and we organized a space for
our new-founded Department of Pediatric Urology.
We recorded the types of diagnostic and surgical procedures done, the number of patients that
benefitted from the services of our institution, the working protocols and the obtained results. We also
quantified the complications and difficulties encountered in the process of care of these children.
Between January 2005 and December 2010 262 patients were operated in The Department of Pediatric
Urology from Clinical Municipal Hospital Cluj-Napoca. 202 children had congenital genito-urinary anomalies.
The following types of interventions were made:

Table II: type of surgical interventions realised in The Departmet of Pediatric Urology of Clinical Municipal Hospital
Cluj-Napoca Between January 2005 and december 20101.
Type of intervention Number of cases Total

classic laparoscopic endoscopic

Pieloplasty for hydronefrosis 44 2 46


from pielo-ureteral junction
syndrome

Nephrectomy for 17 17
decompensated
hydronephrosis

Nephrectomy pentru renal 12 2 14

dysplasia

Uretero-vezical 12 12

Reimplantation for Bladder-


ureteral reflux

Partial Nephrectomy for 4 4

pielo-ureteral duplication

Obstructive primary 14 14

Megaureterul Cure

Cistoscopy for patology of 8 8


lower urinary tract

Posterior uretral valve 2 1 3

Orhidopexy for 27 2 29

cyiptorhidy
Orhiectomyn case of 3 4 7
cryptorchidy

Uretroplasty for 25 25

hypospadias

Circumcision for fimosis 21 21

Endoscopic insertion of 2 2

Ureteral stent

Total 179 10 11 200

Treating children with congenital genito-urinary anomalies requires establishing a multidisciplinary


working team: pediatric urology, pediatry, anesthesiology and intensive care, radiology and nuclear medicine.
Following sustained organizing efforts on behalf of the urology team from Clinical Municipal Hospital Cluj-
Napoca lead by Prof IoanComan such a team was organized and at present time includes doctors from all the
pediatric clinics in Cluj-Napoca and from the Nuclear Medicine Clinic of The Local Hospital Cluj-Napoca. From
the year 2009 surgical treatment of childrenwith malformations is being done in the Department of Pediatric
Urology of the Clinical Municipal Hospital Cluj-Napoca by The Order of the Ministry of Health.
The department was created by separating 2 rooms with 5 beds from the adult urology department.
These were properly managed; in the ICU a bed was reserved for pediatric patients. Medical personnel was
instructed in dealing with the particularities of pediatric conditions and caring maneuvers
(biologicalsampling, venous catheterization, bladder catheterization). The process of creating this department
was considered to be interesting by urologists from abroad; a scientific paper that presents the stages of this
process will be presented on the 31st Congress of SocieteInternationaledUrologie in Berlin 2011.
Hydronephrosis through pielo-ureteral obstruction was the main congenital urological condition
treated in our department.
We preferred to use nephrostomy for urinary drainage in the detriment of the JJ autostatic catheter for
better control of the urine production in the operated kidney. Also, the nephrostomy tube extraction is done
without anesthesia contrary to extraction of the ureteral stent which needs operating room conditions and
general anesthesia. We recorded one single incident regarding the nephrostomy tube; accidental breakage of
the catheter in the moment of extraction with retention of the distant ending in the renal parenchyma; this
implied a reintervention for extracting the tube.
Laparoscopic pieloplasty may be a minimal invasive treatment manner. There are some limitations that
derive from the particularities of the pediatric patients: it cannot be safely applied at young ages (under 7
years old) due to insufficient working space the difficulty level of extensive intracorporeal sutures. In our own
casuistic we have 2 patients laparoscopic operated by retroperitoneal approach; one of them presented a
urinary lumbar fistula that spontaneously occluded after 14 days. The distant functional results were very
good in both cases. Robotic assisted laparoscopic surgery creates better conditions for intracorporeal sutures.
We recorded a relatively big number of nephrectomies for decompensated hydronephrosis: 17 cases of
63 (27%), out of which 6 were pionephrosis. The great proportion is due to deficiencies in the early screening
program (prenatal and perinatal) and signals the necessity of a routine prenatal ultrasonographic exam or
before leaving the maternity
.

In our department 14 children with renal dysplasia were treated. Positive diagnosis was sustained by
ultrasonographic highlight of a kidney with low cortico-medulardifferentiationanhyperechogenparenchyma,
with multiple cists of various sizes. Renal scintigraphy (or urography)certifies the diminished or absent
function of kidney.
Before deciding on a therapeuticalapproach we must evaluate the risks created by the condition. The
most important complications cited in specialty literature isWilms tumor (4 times more at risk than the
general population), high blood pressure, breakage of big cysts in case of abdominal trauma. The low rate of
important complications along with the knowledge that the majority of renal cysts decrease in size with time
or even disappear sustain a conservative attitude with long term ultrasonographic monitoring. There are
point of views that sustain that a surgical procedure which is generally well tolerated by children (simple
nephrectomy)and can be done laparoscopically should be the main option. This avoids the cited risks and the
screening program which could turn out to be as expensive as the surgical procedure.
In our department 14 children with obstructive primary megaureterus were treated. The terapeutical
indication was to excision of the obstructive distal ureteral segment followed by reductionalureteroplastyand
uretero-bladder reinplantation in antyreflux manner. All interventions were done laparoscopically in extra
peritoneal approach through combined lateroperitoneal and trans bladder manner.
Positive diagnosis was sustained by ultrasonographic showing of hydronephrosis accompanied by
dilatation of the ureter in the juxtabladder segment and by renal scintigraphy (or urography) that shows
obstructive uretero hydronephrosis. Differential diagnosi with the refluantethiology of the megaureterus is
done by retrogradcistography. We adopted lateroperitoneal surgical approach through Gibson incision with
resection of the distal stenotic ureteral segment, Kalicinski stent ureteroplasty and Paquinuretero-bladder
reimplantation. There were no incidents or intraoperatory complications; blood transfusion was not
necessary. We recorded only one post operatory complication, stenosis of the uretero-bladder anastomosis
that required correcting reintervention one year post operatory.
Interventional surgical attitude is not always necessary because 85% of primary megaureterus cases
resolve spontaneously. First intention operation is reserved for cases with severe obstruction, urinary
infections and deterioration of renal function. Resection ef excess ureter to complete excision of the stenotic
segment is essential for achieving interventional success. If this aspect is missing, ureteral perstaltic is
deficitary (lack of coaptation of ureteral walls leads to functional urinary obstruction).
In the Pediatric urology department in our clinic 12 children with bladder ureteral reflux were
operated. Positive diagnosis was based on retrogradcistography (figures 48, 49), examination that allowed
grading of reflux. We realised ureteral-bladder reinplantationthroughtransbladderapproach. Wepreferred
Cohen reinplantation technique due to the facility of execution and good results reported in literature. We did
not record intra or postoperatory complications that would require surgical reintervention.
The way in which bladder-ureteral reflux is seen significantly differs from 20 years ago. At present two
situations that require different terapeutical approach are distinguished. Bladder-ureteral reflux the disease
is caused by anatomic incompetence of ureteral-bladder junction (insufficient intramural trajectory of the
terminal ureter). It is more common in boys of young ages (0-3 years) and has a high grade. Spontaneous
remission is important in these cases. Reflux (the symptom) is more commonly found in girls and is diagnosed
at bigger ages (after gaining sphincter control) and has a low grade. This is secondary to a
mictionaldysfunction defined as contractions of the striate urinary sphincter during mictiun. High
intrabladder pressure leads to forcing the ureteral-bladder junction. This type of reflux has small chances to
resolve spontaneously in lack of correcting the low urinary tract dysfunction.
Reflux is no longer considered the main cause of urinary infection; reflux-infection relationship is not
unilateral but more complex (figures 101-102). The consequence of this change in vision is the fact that
surgical treatment is not recommended without mictional reeducation therapeutical interventions where low
urinary tract symptoms are present.
In the Department of Pediatric Urology in our clinic 4 children with pielo-ureteral duplication were
operated. Positive diagnosis was established based on ultrasound exam and renal scintigraphy. In all 4 cases
we did partial nephrectomy of the superior hemi kidney with ureterectomy. The intervention did not record
incidents or complications. No blood transfusions were needed.
Usually pielo-ureteral duplication is not a condition with severe consequences over the kidney. During
the campaign we did aimed to find genito-urinary malformations we diagnosed 14 children with this
pathology (1.4% of examined children), none of those requiring therapeutical intervention. The only cases
that needed a correcting surgical intervention were those in which the anomaly was complicated by
distinctfiziopathological mechanisms: urinary reflux (in the inferior pielon of the ureter) and urinary
obstruction (at the level of uretero-bladder junctionof the superior ureter)
From January 2005 to December 2010 a number of 36 pediatric patients with uni or bilateral
cryptorchidia (45 undescended testis) were operated in the Urology department of the Clinical Municipal
Hosptal Cluj-Napoca. Eight patient presented a total number of 11 unpalpable testis. In case of children with
unpalpable testis, first operative time was trans peritoneal exploratory laparoscopy. Intraoperatorydiagnosis
of testicular atrophy lead to finalizing the intervention. On cases in with identified intraabdominal testis,
exploratory laparoscopy was followed by the correcting gesture (orhidopexy or orhiectomy) done
laparoscopically. In case of patients with palpable testis in the inguinal channel we opted for classic surgical
approach.
Therapeuticaldecision making must take into consideration the recommendations from the medical
practical guides elaborated by The European Urology Association and the patients desire. Laparoscopy
brought certified benefits in managing patients with unpalpable testis; the diagnostic and terapeutical role can
be done in the same operating session.
Laparoscopic approach and Fowler-Stephens technique allowssatisfying scrotal positioning for the
affected testicle. The technique was firstly described in 1959 and assumes ligature and section of vascular
testicular pedicle, the gonade remaining vascularized with blood from the differential artery and cremasteric
artery. It seems that anastomosis between these vessels exist in all cases and are found under peritoneal,
cranial of the internal inguinal hole (their existence was recently proven by anatomical studies with wax
injections). They can be reserved in laparoscopic or classical procedures by keeping a triunghiular peritoneal
segment with the top in in internal inguinal hole and margined by the deferent duct and the testicular vessels
and can assure survival of the testis post orchidopexy. Using this therapeutical approach we obtain a scrotal
positioning of viable testis in 80% of cases, with no differences between classic and laparoscopic techniques.
The failures are probably attributed to obstruction of anastomotic arterial vessels by tensioning them in the
moment of the pexy of insufficientcaliber.
Testicular auto transplant is done in a promisingtherapeutical manner for intraabdominal testis. The
intervention requires dissection of testicular vascular pedicle with preservation on peritoneum situated above
the vessels, followed by heir dissection. Then the epigastric vascular pedicle is dissected for 8-9 cm and
sectioned. Anastomosis between the testicular vessels and the inferior peritoneal vessels is done under
operating microscope, with 10/0 thread.
In Romania, the first intervention of this sort was done by Proca in 1987 with anastomosis of arterial
vessels. In this case the spermatic vein was ligatured hoping for an efficient venous drainage through the
cremasteric and differentiated vein. Nationally, the first testicular auto transplant with anastomosis of both
vessels (artery and vein) was done in Cluj-Napoca by a team of surgeons and urologists coordinated by Prof
Ciuce.
In case of proximal hypospadias we used Tiersch-Duplay or Duckett techniques and for distal
hypospadias we preferred the Snodgrass repair. Cosmetical and functional results were good after the first
surgical intervention on 90% of patients with distal hypospadias and 45% of patients with penian or perineal
meatus. On patients with proximal hypospadias we recorded a failure rate of 55%: 2 cases with complete
dehiscence and 6 cases with uretero-cutaneous fistula. The factors that favored obtaining good results were
lack of previous interventions (well vascularized tissues), urinal drainage through suprapubic bladder
catheter and use of a vascularized dartos flap between the neourethra and the suture plane. For children with
distal hypospadias the complication percentage was 10% (one case of ureteral stenosis). We did not record
incidents or complications regarding insertion of the suprapubic trocar.
The quality of penian tissues decisively influence the result of the uretroplasty. A scar penis obliges to
adapt the technique (tabularizing the preputial flap with risk of fistula of mouth mucosa graft with risk of
uretral stricture) with low vascularized proximity tissues or absence of foreschin. The global complication
rate was 36% and is framed in the percentages quoted in literature.

3. Identifying geneticaletiological factors with implication in apparition of non-syndrome


congenital urinary anomalies
Developing and differentiation of kidney allowssequential interactions between epithelial and
mesenchyme cells, governed by gene expression products. Interaction leads to cell proliferation, apoptosis
and differentiation. Some of these control mechanisms were elucidated, some are still under research. Lack of
gene expression or generation of unfunctional products following some mutations leads to alteration of renal
ontogenesis with serious grades of gravity (from renal parenchyma dysplasia to renal agenesis)
There are congenial urinary anomalies that have syndromatic character; study of affected patients
allowed identifying responsible genes. The majority of cases are sporadic, fact that hardened evaluation of the
genetic substrate and left an open field for future studies. One of the objectives of this research started from
this premises.
Our research aim was to evaluate the existence of specific gene mutation (PAX2, KAL,EYA1 and HNF-
1beta) in urinary tract cells in children with non-syndrome urinary anomalies. We included children with
congenital urinary tract anomalies (congenital hydronephrosis, congenital megaureterus). From these
patients we obtained a tissue sample (urinary tract wall) that was immediatelyimmersed in liquid Nitrogen (-
196C). The biological material was used for genetical studies.
We inclouded 8 patients with obstructive urinary anomalies (pielo-ureteral junction syndrome and
megaureterus). Identifying gene expression specific for urinary anomalies would allow genetical advice and
making a therapeutical decision based on scientific arguments in case of prenatal diagnosis of urinary
anomaly. We observed that TCF2 gene was overexprimated in 4 out of 6 cases of obstructive anomaly. The
number of cases is insufficient for forming recommendation but allows orientation of ulterior research in this
direction. For other studied genes we did not observe meaningful modifications.
Data obtained in our study (overexpression of TCF2 gene) differs from those published in literature where
deletion or lack of gene expression is cited. Following research will establish if this type of gene expression
may be used for prenatal diagnosis of urinary anomalies.

4. Evaluation of environmental factors role in appearance of genital anomalies and secondary


gonadal lesions
Growth of congenital genital anomalies frequency in the last 50 years brought into the physicians
attention the role of environmental factors that interferes with normal embryogenesis. In Great Britain
cryptorchidism incidence grew from 2.7% to 4.1% between 1950 and 1980; between those same years in
Denmark incidence grew from 1.8% to 8.4%. Exposure of parents to chemical substances with estrogenic and
antiandrogenic properties in the period of conception and during pregnancy might enhance the risk of
apparition of cryptorchidism and hypospadias. Risk professions include cleaners, laboratory technicians, hair
dressers, agricultures, heavy-metal industrial workers. The hypothesis that xenobiotic substances may alter
the normal hormonal signals was intensely studied but insufficient proven.
Another environmental factor that might cause cryptorchidism is the circa-annual rhythm more
precisely the time of birth. Children born in winter have a higher risk to develop genital anomalies compared
with other children; the physiopathogenetic mechanism is connected to the influence of the amount of light in
the environment on the production of hipofisary hormones.
Starting from the upper-mentioned premises we aimed to evaluate the involvement of environmental
factors (professional exposure of parents to substances with endocrinal effect, the circa-annual rhythm, high
scrotal temperature) in apparition of genital malformations and secondary testicular dysfunctions in cases
found through our screening program. We realized experimental exposure of the testicles of experimental
mice to high temperature and studied the effects of it on spermatogenesis.
Exposure of testicles of experimental animals to high temperature causes detrimental effect on the
exocrine function. This is obvious if following the evolution of sperm parameters in one cycle of
spermatogenesis that lasts 40 days in mice. The effect of heat on sperm cells in the epididymis is revealed by
samples harvested 6 hour post exposure. For those in full process of development in the testis, the altering is
revealed in day 7, 14,21,28 and 40 after exposure, days that correspond to the main stages of
spermatogenesis.
Even though all stages of spermatogenesis are affected, maximum sensitivity may be characteristic for
the first stages (experimentally objectified by harvestings from days 21 and 28).
This information is useful in the attempt to extrapolate the results of this research in human pathology.
The main shortcoming of this experiment consists in the fact that we realized an acute, limited exposure of the
testis to heat and the cryptorchidic testicle is chronically exposed (permanently). The experiment
demonstrated the sensitivity to heat of certain cells in the spermatogenesis cycle.
The results of this study were presented in 2009 to the International Urology Society Congress in
Shanghai, China.
Following the evaluation of data from the screening program for uro-genital malformations we
discovered a difference in the incidence of genital anomalies according to the time of the year in which the
child is born. Testicular migration anomalies are more frequent in boys born in the cold season (October-
April) as opposed to boys born in the warm season (April-October), but the difference has no statistical value.
This observation confirms the opinions cited in the literature; first to suspect the connection between
circa-annual rhythm and testicular migration anomalies were the researchers from Scandinavia, where
winter-summer differences are significant. Cause of this distribution seems to be an environmental factor, the
quantity of natural light in the environment that varies according to the season and which influences the
secretion of hipofisary hormones.
5. Creation of data base and of applications to manage the patient data and the study of
ethiogenetic role of environmental factors through screening methods.
Data mining products belong to the Business Intelligence family (BI) together with OLAP tools
(Online Analytical Processing), enterprise reporting and ETL (Extraction, Transformation, Load). Data
mining helps organizations that poses a large amount of information by processing this information
identifying and extracting hardly visible to create new information in the field. The advantages offered by this
technology are represented by the capability to work with large amount of information, to find significant data
groups, and the ability to use continue and discrete attributes. Common uses of Data miningare used for
marketing strategies and date predictions.
In the research study three types of application were developed: acquisition (mobile) data applications,
data centralization applications and data analysis applications. These are useful for collecting data patient
according to the screening consultations, sending them to a data base and analyzing the connection between
various parameters and the discovered affections.
The aim of the research was creating applications that would allow correct management of information
collected during the campaign initiated for screening of congenital genito-urinary anomalies.
The applications were developed using last hour technologies including mobile applications (Java
Mobile, Microsoft .NET Compact Framework), desktop technologies (Microsoft .NET Framework), server
technologies (Microsoft ASP.NET, Apache Tomcat, Microsoft IIS 6.0, Google Web Toolkit) and classic data base
for data management (Microsoft SQL Server) and for data analysis (Microsoft Analysis Server). Scan Urgent
Mobile .NET application can be installed on Windows Mobile PoketPC operating systems starting with version
5.0. For running this application Microsoft .NET Framework 2.0 is necessary to be installed on the mobile
device. This framework may be downloaded from the Microsoft official site. To install this application on the
mobile device it can be just copied on the devices card or application Active Sync may be used. This is also
available on the Microsoft site.
To collect data the Scan Urgent Mobile .NET application allows the user to use a questionnaire for
saving descriptive patient data (2 tabs named E1 and E2) and a form for introduction of the questioned data
(3 tabs named C1, C2, C3).
To improve the experience of the user names of anterior sessions and anterior used data are saved and
can be selected from the list reintroducing them not being necessary. The session refers to the name of a
group of recordings, group that can represent pupils of a certain school, tested on a certain date. User
experience is improved by optimizing data collection and analysis and by reducing error occurrence.
The applications can be used to collect data about congenital genital and urinary malformations of
children and discovering study related patterns. Data analysis is based on a model of decision algorithm
created on medical data inserted in the data base by using capture applications. The model reflects clusters of
variables and their impact on diagnosis.

6. Conclusions
i. Regarding the large number of apparent healthy children diagnosed as carriers of a congenital
malformation (9.3% of examined children) the congenital genito-urinary anomalies screening program is
efficient and necessary. High incidence of genital anomalies left undiagnosed after standard prenatal and
perinatal screening must draw attention of family doctors and pediatricians on these organsduring routine
examination.
ii. Financial costs and endowment with equipment necessary to develop such a program are low; a
portable ultra-sonographer and a consultation room are required.
iii. Treatment of children with congenital genito-urinary malformations may be done in optimum
conditions is a medical unit designed for this, a Pediatric Urology Department. This can be formed in the
Urology Department by gathering a team of specialists from different medical fields.
iv. Pediatric patients may benefit from diagnostic methods and minimal invasive therapeutic methods
characteristic for adult Urology. In our casuistic applying laparoscopic and endoscopic treatment on children
lead to comparable results to those of classical without recording a growth of complication rate. We managed
to use minimal invasive diagnostic and treatment techniques for dysplastic multicystic kidney, pielo-ureteral
junction syndrome, posterior urethral valves, bladder-ureteral reflux and cryptorchidism. We realized
laparoscopic nephrectomy, laparoscopic pieloplasty, cystoscopy, orchidopexy and laparoscopic orchiectomy,
trans peritoneal diagnostic laparoscopy.
v. Congenital hydronefrosis by pielo-ureteral junction syndrome is the anomaly with the highest
incidence in our clinics casuistic, one third of children being diagnosed with this disease.
vi. Children with posterior urethral valve had the most unfavorable prognostic, 66% of them being
diagnosed when chronic renal failure is installed.
vii. We recorded a very low failure rate of surgical interventions: only 3 children out of 177 needed
reintervention (1,6%). Exceptions are the cases with proximal hypospadias on which the reintervention rate
was 50%.
viii. TCF2 gene is overexpressed in the majority of cases with obstructive urinary anomalies regardless of
the normalization contrary to the two housekeeping genes RPLPO and HPRT1. The elevated level of TCF2
gene may become an important marker in evaluating imperfect ontogenesis of the urinary tract in children.
ix. Exposure of testicles to heat higher that the physiologic one affects all types of cells precursors of the
sperm. Maximum sensitivity seems to be characteristic to the first stages of spermatogenesis. Sperm resulted
in High temperature spermatogenesis has modified characteristics over the sperm formed in normal
conditions (concentration, viability, progressive mobility); in vivo fertility rate of mice with testicles exposed
to heat is lower than in the control group. High temperature in the testicle area leads to a decrease in fertility
of patients with bilateral cryptorchidism.
x. Boys born in winter have a higher risk to have testicular migration anomalies comparative to those
borne in summer, with a statistically significant difference.
xi. We did not manage to highlight a connection between professional exposure of the mother during
pregnancy and apparition of genital anomalies.
xii. In context of a consultation program for detection of congenital malformation recording parameters
regarding examined subjects will allow the use of the created infrastructure to collect data and processing
them through data mining setting the causal role of various environmental factors. This integrated working
platform will provide a graphic visualization of rules and conclusions discovered, facilitating a general view,
valuable over collected data.
RESUME DE LA THESE

Model de screening et traitement modern


pour les malformations genito-urinaires
chez lenfant

Doctorand Vasile Dan Stanca

Coordonateur prof. dr. Constantin Ciuce


TABLE DES MATIRES

INTRODUCTION 15

ETAT DES CONNAISSANCES 17


Introduction 19
1. Lembriologie normale et patologique de lappareil uro-gnital 21
2. La phisiopatologie des malformations congnitales gnito-urinaires 27
3. Des strategies de diagnostique des malformations congnitales
33
gnito-urinaires
4. Le traitement des malformations congnitales gnito-urinaires 37
CONTRIBUTION PERSONALE 45
1. Objectifs 47
2. Methodologie gnrale 47
3. Etude 1 valuation de l'efficacit d'un programme de dpistage
pour la dtection des anomalies uro-gnital chez les enfants 49
apparemment en bonne sant d'ge prscolaire et scolaire
4. Etude 2 - Le traitement moderne des anomalies congnitales de l'appareil
57
gnito-urinaire chez les enfants
5. Etude 3 - Identification des facteurs gntiques tiologiques impliqus
97
dans les anomalies congnitales urinaires sporadiques (non syndromiques)
6. Etude 4 - L'valuation du rle des facteurs environnementaux dans des
103
anomalies gnitales et des lsions secondaires des gonades
7. Etude 5 - Cration d'une base de donnes et des applications
informatiques pour la gestion des donnes patients et tude tiologique rle 115
des facteurs environnementaux au moyen d'exploration de donnes
8. Conclusions 121
9. Originalit de la these 123

REFERENCES 125
MOTS CLS

anomalies gnito-urinaires, chographie, obstruction urinaire, reflux vsico-urtral, la laparoscopie,


endoscopie, spermatogense urinaire, data mining.

INTRODUCTION

Un pourcentage important d'enfants sont ns avec des anomalies congnitales gnito-urinaires, avec divers
degrs de gravit. Ils peuvent avoir des symptmes moins spcifiques de sorte que leur dtection est retard,
parfois dans la phase dinsuffisance rnale chronique terminale. Les anomalies urinaires congnitales sont la
principale cause d'insuffisance rnale chronique chez les enfants. En cela, ils gnrent d'importants couts
financier et des drames familliels qui pourrait tre largement vit. Par consquence je crois que tout effort
visant diminuer leurs effets nfastes sont les bienvenus.

Dans le projet de recherche doctorale j'ai effectu le premier programme national de dpistage des anomalies
congenitales gnito-urinaires chez les enfants apparemment en bonne sant. J'ai aussi fait le traitement de ces
anomalies en appliquant des protocoles de diagnostic et de traitement spcialiss recommands par les
associations europennes, la mise en uvre des techniques mini-invasives pour le diagnostic et le traitement.
Nous avons lucid le rle tiopathognique des facteurs environnementaux pour des anomalies gnitales et
les mutations gntiques. Enfin, j'ai imagin une application qui permet la projection de donnes sur les
patients d'enregistrement et de techniques de transformation du "data mining" pour dcouvrir les facteurs de
risque pour les troubles congnitaux gnito-urinaires.

I. DES CONNAISSANCES

1. L'embryologie normale et pathologique de l'appareil uro-gnital

Comprendre les vnements importants de l'embryologie gnitales et urinaires est essentiel pour le
diagnostic des anomalies congnitales et d'interprter la relation entre diffrentes conditions prsentes chez
un patient.

La formation de divers organes des appareils urognital se droule en plusieurs tapes qui se chevauchent et
ont un dterminisme gntique bien tablie. Laction tratogne d'un facteur ou une expression du gne peut
influencer le dveloppement dun ou plusieurs organes en fonction du temps elle s'est produite.

2. Physiopathologie des malformations gnito-urinaires

Lobstruction urinaire congnitale est prsente lors de la formation du rein et a donc un effet diffrente de
celle acquise au cours de la vie adulte, qui agit sur un rein mature. Dveloppement d'un rein dans les
conditions foetales dobstruction urinaire conduit des carences dans trois domaines: le contrle de la
croissance, la diffrenciation cellulaire et la fibrose.

Si l'obstruction urinaire n'est pas enlev aprs la naissance la progrssion vers l'insuffisance rnale est
acclr par des infections des voies urinaire. Une chirurgie correctrice empche la progression dans les cas
des reins qui ont une rserve fonctionnelle. Leur formation dans des conditions anormales affectant les
caractristiques de base structurelles et fonctionnelles. Dans les annes qui suivent la chirurgie de correction
les nphrons restants vont subir hyperfiltration compensatrice d'un processus qui peut conduire
progressivement leur perte.

3. Les stratgies visant diagnostiquer des malformations gnito-urinaires


Le diagnostique prcoce des malformations gnito-urinaires permet l'initiation rapide du traitement. Par la
tentative de gurison des enfants touchs on previent le progrs des lesions et la maladie rnale au stade
terminal, o des lsions rnales sont des dfauts trs graves.

Il existe deux types de stratgies de diagnostique: l'chographie antnatale et l' chographie nonatale. Ils
permettent l'identification de la plupart des anomalies. Un nombre significatif de patients ne peut cependant
tre identifi utilisant ce bilan parce que certaines anomalies se manifestent un moment aprs la naissance
(parfois aprs plusieurs annes). C'est pourquoi cest necessaire d'apliquer un "filtre" diagnostic plus tard au
cours de l'ge prscolaire ou scolaire.

L'echographie prnatale de l'appareil urinaire peut identifier de nombreux aspects structurels et d'anomalies
du dveloppement. Le moment optimal pour le diagnostic est 27-28 semaines de gestation. Une grave
anomalie dtecte au cours de cette priode peut justifier une dcision obsttrique.

L'chographie prnatale ne donne pas que des donnes sur l'anatomie ftale de l'appareil urinaire; elle ne
peut donner des informations sur la fonction rnale. L'valuation de la fonction rnale ne peut pas tre
realise q'aprs la naissance, malgr les efforts des chercheurs pour trouver des prdicteurs (d'imagerie et
biochimiques) de la fonction rnale ftale.

Un aspect important doit tre considr lorsque on indique une chographie pour identifier les anomalies
foetales: le risque de surdiagnostique. Les avantages du dpistage prcoce des anomalies doivent tre
compars avec le risque de dcouvrir une hydronphrose prnatale qui disparat peu aprs la naissance et
n'est plus retrouve (celle ci n'a pas de signification pathologique). Le medecin ne peut pas prvoir comment
la maladie va voluer aprs l'accouchement. Par la communication d'un diagnostique prenatal on peut induire
un stress parental de haute intensit. La consquence est que la grossesse se transforme en longue priode
d'attente et de l'anxit.

Le protocol diagnostic prsont ci-dessus est en mesure de dtecter la plupart des anomalies congnitales
gnito-urinaires prsentes la naissance mais il y a un certain nombre de maladies qui passent inaperus: le
phimosis est diagnostiqu par l'ge de 3 ans (sauf les formes extrmes), les testicules peuvent manquer du
scrotum la naissance (en particulier chez les garcons prmaturs) ou peuvent terminer leur descente dans
les prochains mois et l'hypospadias (forme avec le prepuce intacte) devient vident aprs 3 ans. Nous ne
devons pas oublier que la posibilit de faire une chographie antnatale ou nonatale depend de la
comprhension, du niveau culturel des parents et de la disponibilit, de l'quipement des services mdicaux
spcialiss.

Nous avons bsoin donc d'un nouvel "filtre" diagnostique qui puisse prciser si les patients sont porteurs
d'une anomalie congenitale de l'appareil uro-gnital. Un dpistage peut tre effectue par les mdecins de
famille qui ont une formation et l'quipement ncessaire; ils doivent crer une stratgie de dpistage pour les
enfants apparemment en bonne sant.

4. Traitement des malformations gnito-urinaires

Le traitement des maladies gnito-urinaires congnitales se trouve a la frontire entre la chirurgie


pdiatrique et l'urologie. Plusieurs maladies urologiques ont t identifies et diagnostiques par les
pdiatres qui ont addrss les enfants au chirurgiens pdiatriques pour le geste interventionnel. Si les
malformations ne sont pas trs "bruyant" et sont diagnostiques chez l'adulte (par exemple la cryptorchidie
identifie lors de l'inscription pour le service militaire ou l'hydronphrose dcouverte pendant l'valuation
de l'hypertension), le diagnostic et la thrapie sont effectues par l'urologue.
L'Urologie pediatrique bneficie de tous les acquisitions de l'urologie adulte dans le diagnostique et la
thrapie. Cela comprend l'exploration et les techniques mini-invasives de traitement des voies urinaires:
urologique endoscopique, la laparoscopie, la chirurgie robotique, l'exploration urodynamique. La vithesse
d'acquisition de ces techniques dans la pratique quotidienne est infrieure celle des adultes, parce que
l'urologie pdiatrique value de faon plus critique les avantages, les risques et les implications
motionnelles de ces nouvelles mthodes pour les patients pdiatriques.

II. CONTRIBUTION PERSONNELLE

Nous avons tabli les objectifs de recherche suivants:

1. valuer l'efficacit d'un programme de dpistage des anomalies uro-gnitales chez les enfants
apparemment en bonne sant, d'ge prscolaire et scolaire.

2. L'valuation des mthodes de traitement moderne des anomalies congnitales de l'appareil gnito-urinaire
chez les enfants.

3. Identification des facteurs gntiques tiologiques impliqus dans les anomalies congnitales urinaires
sporadiques (non syndromiques).

4. L'valuation du rle des facteurs environnementaux dans des anomalies gnitales et des lsions
secondaires des gonades.

5. Cration d'une base de donnes et des applications informatiques pour la gestion des donnes patients et
tude tiologique rle des facteurs environnementaux au moyen d'exploration de donnes.

Le financement de la recherche a t ralis par le Grant CEEX 154/2006: Le dpistage, la prvention et la


correction des malformations gnito-urinaires chez les enfants utilisant des techniques thrapeutiques mini-
invasives (laparoscopie, endoscopie)" - SCANURGENT.

Pour raliser les objctifs 3, 4 et 5 nous avons collabor avec d'autres institutions de recherche: L'Institut
d'Oncologie Cluj-Napoca, l'Universit des Sciences Agricoles et de Mdecine Vtrinaire Cluj-Napoca et
l'Univrsit Tchnique Cluj-Napoca.

1. valuation de l'efficacit d'un programme de dpistage pour la dtection des anomalies uro-gnital
chez les enfants apparemment en bonne sant d'ge prscolaire et scolaire

Entre 2005 - 2008 j'ai fait le premier projet pour le dpistage des malformations urognitales chez les enfants
en Roumanie. Le groupe d'enfants xamins a t d'ge prscolaire et scolaire de 10 coles et cole
maternelle Cluj, Sibiu et Mures.

Calendrier des visites a t faite par les mdecins scolaires et les instituteurs. Les parents ont reu un
questionnaire pour obtenir des donnes concernant leurs expositions professionnelles aux differents
substances toxiques pendant le dveloppement.

Nous avons utilis un chographe portable Medison SA 600 avec transducteur de 3,5 MHz.

Le protocole d'investigation contient:

- L'histoire vocatrice de symptmes inexpliqus (pisodes de fivre, une histoire de infections urinaires
rcidivantes, le contrle du sphincter, etc);
- L'examen clinique des organes gnitaux externes (phimose, hypospadias, cryptorchidie);

- L'chographie pour visualiser les anomalies du nombre des voies urinaires, la position des organes de
l'appareil urinaire et la dilatation des voies urinaires.

Nous avons examin 1006 enfants gs de 5 18 ans et constat l'existence de troubles gnito-urinaires dans
un total de 93 patients (9,3%). Suite l'examen clinique de 497 garons nous avons identifi des anomalies
congnitales des organes gnitaux qui sont ilustres dans le tableau I.

Tableau I: Les anomalies congenitales identifiees par le projet de screening


Les anomalies Nr. des cas % des garcons
congenitales examines
(N=497)
cryptorchidie unilaterale 8 1,6%
Des testicules flotants 8 1,6%
Cryptorchidie bilaterale 3 0,6%
phymose ou hypertrophie 31 6,2%
du fren preputial
hypospadias 8 1,6%
hydrocel 5 1%
varicocel 1 0,2%
micropenis 1 0,2%
kyste du cordon 1 0,2%
spermatique
Total 66 13,3%
L'examen clinique nous a donn plusieurs informations sur les anomalies gnito-urinaires. Chez les garons
nous avons trouv des malformations comme la cryptorchidie unilatrale ou bilatrale, testicule flottant,
hydrocle, varicocle, phimosis, hypertrophie du fren prepuciel, hypospadias.

La ncessit d'un tel programme de diagnostique est mis en vidence par le grand nombre d'enfants
apparemment en bonne sant, identifis comme porteurs d'anomalies gnito-urinaires. La prvalence des
maladies gnitales chez les enfants de sexe masculin est particulirement surprenante: 13,3% des garons
examins.

Ces sont des maladies sans symptmes vidents pour dterminer l'enfant ou ses parents se prsenter a la
consultation mdicale. Il ya aussi des situations pathologiques qui sont valides aprs un temps variable
aprs la naissance, passant ainsi inaperues par l'obsttricien ou nonatologue. L'xamen clinique gnral et
l'valuation des organes gnitaux externes sont obligatoires, quelle que soit la raison de la consultation. Les
rsultats de ce programme de recherche sont xtrapols dans la population pdiatrique. Les parents doivent
tre conscients de l'importance de l'xploration de l'appareil gnital externe des enfants pour dtecter des
anomalies.

L'ide du dpistage combin des deux types de malformations congnitales a t reue avec intrt par les
urologues tant en Roumanie qu' l'tranger. En 2008 nous avons prsent les rsultats de ce programme
l'assemble nationale de l'Association Roumaine d'Urologie, au congrs internationale de la Socit
Internationale d'Urologie Santiago du Chili et la Rencontre en Europe Centrale de l'Association
Europenne d'Urologie, Varsovie.

2. Le traitement moderne des anomalies congnitales de l'appareil gnito-urinaire chez les enfants.
Le projet de ma recherche doctorale est de dfinir une valuation de la cible du traitement moderne des
anomalies congnitales de l'appareil gnito-urinaire chez les enfants. En outre. J'ai valu la modalit dont les
techniques diagnostiques et thrapeutiques minimalement invasives en urologie peuvent tre adaptes aux
normes de la pathologie pdiatrique.

Le traitement des enfants avec des anomalies congnitales gnito-urinaires a t realis dans le Dpartement
d'Urologie de l'Hpital Municipal Cluj-Napoca, coordonn par le professeur Ioan Coman. Nous avons valu
les dossiers mdicaux des enfants oprs entre Janvier 2005-Dcembre 2010.

Grce la subvention CEEX 154/2006 Le dpistage, la prvention et la correction des malformations gnito-
urinaires chez les enfants dans l'ge des techniques thrapeutiques mini-invasives (laparoscopie,
endoscopie)" - SCANURGENT J'ai achet des instruments mdicaux pour la chirurgie mini-invasive et
traditionnelle et nous avons organis l'espace pour le fonctionnement du dpartement nouvellement cr
d'urologie pdiatrique.

Nous avons enregistr les types de procdures diagnostiques et chirurgicales effectues, le nombre de
patients qui ont bnfici d'eux dans notre institution, les protocoles de travail et les lettres de sortie. Nous
avons aussi quantifi les complications et les difficults rencontres pendant la prise en charge de ces enfants.

Entre Janvier 2005 - Dcembre 2010, dans le Dpartement d'Urologie Pdiatrique l'Hpital Municipal Cluj-
Napoca ont t oprs un total de 262 patients pediatriques, dont 202 enfants avec anomalies congnitales
gnito-urinaires.

Les interventions suivantes ont t ralises :

Intervention Nr. des cas Total

A ciel Par voie Par voie


ouvert laparoscopique endoscopique

Pyeloplastie 44 2 46

Nefrectomie pour 17 17
hydronephrose

Nefrectomie pour dysplasie 12 2 14


renale

Reimplantation uretero- 12 12
vesicale

Nefrectomie partielle pour 4 4


duplication pyelo-ureterale

Cure du megaureter 14 14
obstructif

Cystoscopie 8 8

Valve de luretre 2 1 3
posterieure

Orchydopexie 27 2 29

Orchydectomie 3 4 7

Urethroplastie pour 25 25
hypospadias

Circumcision 21 21

Insertion endoscopique du 2 2
stent ureteral

Total 179 10 11 200

Le traitement des enfants necessite la mise en place d'une quipe qui comprend plusieurs spcialits
mdicales obligatoires: urologie pdiatrique, pdiatrie, anesthsie et ranimation, radiologie et mdecine
nuclaire. la suite des efforts d'organisation de l'quipe soutenue par des urologues de l'Hpital Municipal
dirig par le Professeur Dr Ioan Coman une telle quipe est form, qui comprend actuellement des mdecins
de toutes les cliniques pdiatriques et de la Mdecine Nuclaire de Cluj-Napoca. Depuis 2009, le traitement
chirurgical des enfants depuis la naissance a lieu dans le Dpartement d'Urologie Pdiatrique de l'Hpital
Municipal Cluj-Napoca, tabli par le Ministre de la Sant.

Le dpartement est bien organis, avec des lits de thrapie intensive rservs pour les patients pdiatriques.
Le personnel mdical a t instruit selon les particularits des patients pdiatriques et des manuvres de
soins particuliers (collecte d'chantillons biologiques, cathtrisme veineux, cathtrisme urethro-vesical). La
faon d'organiser ce dpartement a t consider intressant par les collgues urologues de l'tranger, un
document scientifique prsentant ces tapes tant prsent au 31e Congrs de la Socit Internationale
d'Urologie de Berlin, 2011 .

L'hydronphrose avec obstruction de la jonction pylo-urtrale a t la principale maladie congnitale


urologique traite dans notre service.

Aprs la pyloplastie j'ai prfr le drainage urinaire par nphrostomie que par sonde urtrale autostatique
J-J parce que j'ai eu un meilleur contrle sur la production de l'urine aprs la chirurgie rnale. En outre, le
retrait du tube de nphrostomie est fait sans anesthsie, dans le cabinet. L'xtraction du stent urtrale est
ffectue dans la salle d'opration, en anesthsie gnrale. Nous avons enregistr un seul incident avec le
tube de nphrostomie bris accidentlement lors de la suppression, avec l'extrmit au niveau du rein, une
situation qui exigeait une rintervention pour son retrait.

La pyloplastie laparoscopique peut tre une alternative de traitement minimalement invasive. Il ya quelques
limites de l'indication concernant les patients pdiatriques: on ne peut pas l'appliquer en toute scurit chez
les patients moins de 7 ans en raison de l'space de travail insuffisant et la difficult des sutures
intracorporels importantes. Nous avons opr 2 enfants par laparoscopie rtropritonale; un d'entre eux a
prsent une fistule urinaire lombaire qui s'est ferm spontanment aprs 14 jours. Les rsultats fonctionnels
en temps sont bons dans les deux cas. La chirurgie laparoscopique assiste par le robot offre des meilleures
conditions pour raliser les sutures intracorporels.
Nous avons enregistr un nombre relativement important des nphrectomies pour l'hydronphrose
dcompense: 17 cas sur 63 (27%), 6 cas taient au stade de pyonphrose. Forte proportion est
probablement d des lacunes dans le programme de diagnostic prcoce (prnatal ou prinatal) et signale la
ncessit pour les deux chographie prnatale de routine, ou avant la sortie de l'hpital.

Nous avons reu dans notre srvice 14 enfants atteints de dysplasie rnale. Le diagnostique positif a t mis
par l'chographie qui montre un parenchyme hyperecogen avec une faible diffrenciation cortico-mdullaire
et des kystes multiples de taille variable. La scintigraphie rnale (ou urographie) certifie une fonction rduite
ou absente du rein.

Avant de dcider le traitement on doit valuer les risques que la maladie pose son porteur. Les
complications les plus importantes cits dans la litrature sont l'apparition de la tumeur Wilms (4x risque
plus lev que la population gnrale), l'hypertension, rupture des grands kystes par des traumatismes et la
compression abdominale sur les organes environnants. Le taux bais de complications majeures, ainsi que le
fait que la plupart des reins multikystiques rduisent leur taille ou mme disparaissent au fil du temps
suggrent une approche conservatrice avec surveillance chographique long terme.

Nous avons reu un total de 14 enfants atteints de mga-uretre obstructif primaire. L'indication
thrapeutique est la rsection du segment urtral obstructif distal, urtroplastie et rimplantation urtro-
vsicale en manire anti-reflux. Toutes les interventions ont t effectues par voie extrapritonal ou par
approche combine latropritonal transvezical.

Le diagnostique positif a t suggr par l'aspect chographique d'hydronphrose accompagne par une
dilatation de l'uretre. La scintigraphie rnale (ou urographie), a montr aussi une urtro-hydronphrose.
Le diagnostic differentiel se fait avec le reflux vesico-urtral, par la cystographie rtrograde. J'ai pratiqu
l'approche chirurgical latroperitoneal par l'incision Gibson avec la rsection urtrale distale du segment
stnos, urtroplastie en manire Kalicinski et rimplantation urtro-vsicale en manire Paquin. Ils n'ont
pas xist d'incidents ou de complications per-opratoires, aucune transfusion sanguine n'a t ncessaire.
Nous avons enregistr une complication post-opratoire, une stnose de l'anastomose urtro-vsicale qui a
ncessit une rintervention corrective a moins q' un an aprs l'opration.

L'intervention chirurgicale n'est pas toujours ncessaire puisque jusqu' 85% des cas de mga-uretre
primitif prsentent une rsolution spontane. L'opration comme premier choix est rserve aux cas
d'obstruction svre, des infections urinaires rcidivantes et de l'aggravation de la fonction rnale. La
rsection du segment stnotique en excs et l'excision de l'uretre sont essentiellles pendant l'opration. Le
pristaltisme urtral (absence de coaptation de la paroi urtrale) conduit une obstruction urinaire
fonctionnelle.

Dans le dpartement d'urologie pdiatrique de notre hpital 12 enfants ont t oprs pour reflux vsico-
urtral. Le diagnostic positif a t mis sur la cystographie rtrograde (figures 48, 49), ce qui a permis le
classement du reflux. On a fait la rimplantation urtro-vsicale par approche transvsical. Je prfre la
technique de rimplantation Cohen en raison des bons rsultats rapports dans la littrature. Il n'y avait pas
de complications intra- ou postopratoire ncessitant une reintervention chirurgicale.

Le reflux vsico-urtral est considre significativement diffrente de la situation il ya 20 ans. En prsent il


ya deux situations qui ncessitent diffrents attitudes thrapeutiques. Le reflux vsico-urtral maladie est
cause par l'incomptence anatomique de la jonction urtro-vsicale (le trajet intramural insuffisant). Cette
situation est plus frquente chez les garons d'ge 0-3 ans. Les chances de remission spontane sont
importantes. Le reflux symptme est present en gneral chez les filles, est diagnostique un ge avanc
(aprs avoir obtenu le contrle des sphincters) et le degr du reflux est moins. C'est secondaire aux troubles
mictionelles de type dyssinrgie vsico-sphinctrienne, dfinie comme des contractions du sphincter urinaire
lors de la miction. La haute prssion intrevsicale fore la jonction urtro-vsicale produisant le reflux. Ce
type de reflux a peu de chances de rsolution spontane sans correction de la dysfonction du bas appareil
urinaire.

Le reflux n'est plus considr comme la cause de l'infection urinaire, la relation n'est pas unidirectionnelle
reflux-infection, mais plus complexe (figures 101-102). La consquence de ce changement de perspective est
que la chirurgie n'est plus recommande sans avoir trait les symptmes du bas appareil urinaire.

Dans le service d'urologie pdiatrique de notre hpital ont t oprs quatre enfants avec duplication pylo-
urtrale. Le diagnostic positif a t tabli utilisant l'chographie, l'urographie et la scintigraphie rnale. Dans
tous les cas nous avons ralis 4 nphrectomies partielles excisant la demie suprieure du rein. Les
interventions se sont droulles sans incidents ou complications. Des transfusions sanguines n'ont pas t
ncessaires.

D'habitude la duplication pylo-urtral n'est pas une anomalie avec des consquences graves pour le rein.
Suite a la campagne de dpistage des malformations gnito-urinaires nous avons diagnostiqu 14 enfants
avec ce type de trouble (1,4% des enfants examins), aucun d'entre eux n'ayant pas besoin d'une
intervention. Les seuls cas qui ncessitent une correction chirurgicale sont ceux dans lesquels l'anomalie est
complique par l'association des diffrents mcanismes physiopathologiques: reflux urinaire (habituellement
dans l'uretre du pylon infrieur) et obstruction des voies urinaires (obstruction de l'uretre suprieur la
jonction avec l'uretre infrieur).

Dans la priode Janvier 2005 - Dcembre 2010 nous avons trait 36 patients pdiatriques avec cryptorchidie
unilatrale ou bilatrale (testicule non descendu). Huit patients ont eu un total de 11 testicules impalpables.
Tout d'abord une chirurgie exploratoire par laparoscopie transpritonale a t ralise chez les enfants avec
des testicules impalpables. Le diagnostique peropratoire d'atrophie tsticulaire a dcid le fin de
l'intervention. Dans les cas o nous avons identifis par la clioscopie xploratoire des testicules intra-
abdominaux, le geste suivant a t la correction (orhidopxie ou orchictomie) ralise par laparoscopie.
Chez les patients avec des testicules palpables dans le canal inguinal on a fait l'approche chirurgical classique.

La laparoscopie a apport des avantages clairs dans la gestion des patients avec des testicules impalpable.

L'autotransplant tsticulaire est une alternative thrapeutique prometteuse pour les testicules situs intra-
abdominal. L'intrvention implique la dissection du tsticule du pritoin avec la prservation du pdicule
vasculaire sus-jacent suivie de son dtachement. On fait la dissection de l'artre pigastrique infrieure
longueur de 8-9 cm et la coupe. L'anastomose de l'artre pigastrique infrieure avec l'artre tsticulaire se
fait sous microscope opratoir.

En Roumanie, la premire intrvention de ce genre a t faite par Proca en 1987, avec anastomose des
vaisseaux sanguins seulement. Dans ce cas, la veine spermatique a t ligatur, esperant que le drainage
veineux sera efficace par la veine defrentielle et crmasterique. La premire autogreffe nationale des
testicules avec anastomose des deux vaisseaux (artre et veine) a t ralise Cluj-Napoca par une quipe
de chirurgiens urologues coordonns par le professeur Ciuce.

En cas d'hypospadias proximal nous avons utilis la tchnique d'uretroplastie Tiersch-Duplay ou Duckett;
pour l'hypospadias distal j'ai prfer la manire Snodgrass. Les rsultats ont t bons en termes de l'aspect
cosmtique et fonctionnel aprs la premire chirurgie dans 90% des patients atteints d'hypospadias distal et
45% de ceux avec d'hypospadias proximal. Chez les patients atteints de l'hypospadias proximal le taux
d'chec de l'uretroplastie est de 55%: 2 cas de dhiscences urethro-cutanes compltes et et 6 cas des
fistules. Les facteurs qui ont favoris de bons rsultats ont t: les patients sans antcdents de chirurgie du
pnis (avec des tissus mieux vasculariss), un cathter sus-pubien de drainage urinaire et l'interposition du
dartos vascularis entre la neourthre et les sutures de la peau. Pour les enfants avec hypospadias distal le
taux des complications postopratoires n'tait que de 10% (un cas de stnose urtrale). Il n'y avait pas
d'incidents ou de complications de la mise du trocart sus-pubien.

Une influence dcisive sur la russite de l'urtroplastie a la qualit des tissus du pnis. Une cicatrice du pnis
ncessite une adaptation de la technique (tubularisation du lambeau prputial avec un risque accru de fistule
ou d'une greffe de la muqueuse orale avec un risque de rtrcissement de l'urtre) en conditions de tissu de
voisinage mal vascularis ou en absence du prpuce. Le taux global de complications trouvs dans le group
tudi tait de 36%.

3. Identification des facteurs gntiques tiologiques impliqus dans les anomalies congnitales
urinaires sporadiques (non syndromiques).

Le dveloppement du rein et de la diffrenciation implique des interactions squentielles entre les cellules
pithliales et msenchymateuses, rgies par les produits d'expression de certains gnes. L'interaction
conduit la prolifration cellulaire, l'apoptose et la diffrenciation. La manque d'expression de ces gnes ou la
gnration des erreurs peuvent avoir lieu la suite des mutations conduisant l'ontogense rnale altre
avec divers degrs de gravit de la dysplasie du parenchyme rnal une agnsie rnale.

En cas des anomalies urinaires syndromique les tudes ont permis l'identification des patients atteints par les
gnes responsables. Mais la plupart des cas sont sporadiques, ce qui a entrav l'valuation du substrat
gntique et le travail sur ce terrain est laiss ouvert pour des futures tudes. Un des objectifs de cette
recherche a t mis sur la base de cette prmisse.

Nous avons recherch et valu l'existence des mutations gntiques spcifiques (PAX2, KAL, EYA1 et HNF-
1beta) dans les cellules urinaires de l'enfant prsentant des anomalies urinaires non syndromiques. Nous
avons inclus dans l'tude les patients avec des anomalies congnitales des voies urinaires (hydronphrose
congnitale, mgauretre congnitale). De ces patients, nous avons recueilli un chantillon de tissu (prise
d'urine) qui a t introduite toute suite aprs le prlevement dans l'azote liquide (-196C). Le matriel
biologique a t utilis pour des recherches gntiques.

Nous avons inclus dans l'tude 8 patients prsentant des anomalies urinaires obstructives (stnose de la
jonction pylo-urtrale et mgauretre). L'identification des gnes dont l'expression est altre qui sont
responsables des anomalies urinaires spcifiques a prmis formuler un conseil gntique et la dcision
thrapeutique fonde sur des arguments scientifiques pour le diagnostic antnatal des anomalies de
l'appareil urinaire. Dans les dosages effectus dans la population tudie nous avons constat que la gne
TCF2 est surexprim dans 4 des 6 cas d'anomalies gnito-urinaires obstructifs. Le nombre de cas est trop
faible pour permettre une recommandation, mais des nouvelles recherches dans cette direction sont
ncessaires. Pour les autres gnes tudies nous n'avons constat aucun changement significatif dans le
groupe des patients tudis.

Les donnes de notre tude (surexpression du gne TCF2) diffre de la littrature publie, ou est cit la
suppression ou l'absence d'expression de celle-ci. Des recherches approfondies permettront de dterminer si
ce type de l'expression des gnes peut tre utilis dans le diagnostique antnatal des anomalies urinaires.

4. L'valuation du rle des facteurs environnementaux dans des anomalies gnitales et des lsions
secondaires des gonades
L'augmentation de l'incidence des anomalies congnitales gnitales chez les garons dans les derniers 50 ans
a mis en discussion le rle des facteurs environnementaux qui perturbent l'embryogense normale. En
Grande-Bretagne l'incidence de la cryptorchidie est augmente de 2,7% 4,1% entre 1950 et 1980; pendant
la mme priode l'incidence en Danemark est augmente de 1,8% 8,4%. L'exposition parentale des
produits chimiques ayant des proprits strogniques ou anti-androgniques lors de la conception et
pendant la grossesse a augmente le risque de cryptorchidie et d'hypospadias. Les professions cites comme
tant risque sont les nettoyants, les techniciens de laboratoire, les friseurs et coiffeurs, les agriculteurs et les
travailleurs dans l'industrie des mtaux lourds. L'hypothse que les substances xnobiotiques peuvent
modifier les signaux hormonaux normaux a t tudie intensivement mais elle est encore mal documente.

Les enfants ns en hiver auraient un risque accru des malformations gnitales par rapport aux autres enfants,
les mcanismes physiopathologiques impliqus sont endocriniens, lis la quantit de lumire ambiante qui
influence la production des hormones hypophysaires.

Bas sur les donns ci-dessus, je dfinis un objectif d'valuation des facteurs environnementaux impliqus
dans des malformations gnitales et des cas de dysfonctionnement testiculaires secondaires identifis l'aide
du programme de dpistage (exposition professionnelle des parents des substances ayant des effets
endocriniens, le taux de lumire ambiante circaanual et l'haute temprature du scrotum). Nous avons tudi
la sensibilit au temprature plus leve que la physiologique de chaque type de cellule dans le cycle de la
spermatogense pour valuer le rle de la temprature dans l'tiologie de l'infertilit chez les patients
atteints de cryptorchidie. Nous avons ralis une exposition exprimentale des testicules de souri au
temprature leve et tudi les rpercussions d'eux sur la spermatogense.

L'exposition des testicules des animaux de laboratoire l'fft de l'haute temprature atteinte leur fonction
exocrine. Il n'est pas vident comment voluent les paramtres de la sperme au cours d'un cycle de
spermatogense d'une dure de 40 jours chez les souris. Les ffts de la chaleur sur les spermatozodes dans
l'pididyme sont mis en vidence 6 heures aprs l'exposition la temprature. Les ffts dans les testicules
pendant la spermatogense sont mis en vidence dans les jours 7, 14, 21, 28 et 40 aprs l'exposition, les jours
correspondant aux principales tapes de la spermatogense.

Bien que toutes les tapes de la spermatogense sont touchs, la sensibilit maximale semble tre
caractristique dans les stades prcoces (montr exprimentalement par la prise des chantillons 21 ans et
28 jours).

L'information est utile en essayant d'extrapoler les rsultats de cette recherche dans la pathologie humaine.
Le principal inconvnient de cette experience est que nous avons fait une exposition aigue, limite, des
testicules la chaleur, tandis que les testicules en cryptorchide sont expos chroniquement (permanent).
Toutefois, l'exprience a montr la sensibilit thermique des certaines cellules prcurseurs de la cycle de
spermatogense.

Les rsultats de cette tude ont t prsents en 2009 pendant le Congrs de la Socit Internationale
d'Urologie Shanghai, en Chine.

5. Cration d'une base de donnes et des applications informatiques pour la gestion des donnes des
patients et tude du rle tiologique des facteurs environnementaux

"Data mining" aide les organisations qui ont une grande quantit d'informations, traitement de cette
information, la recherche et l'extraction de rgles peine visibles, pour crer de nouvelles connaissances de
domaine. Les avantages de cette technologie sont la capacit de travailler avec de grandes quantits
d'information, de trouver des groupes de donnes significatives et la capacit d'utiliser les attributs discrets
ou continus. Utilisation commune des data mining est dans la stratgie de marketing, ou prdire les
donnes.

Le projet de recherche a mis au point trois types d'applications: les applications de passation des marchs
(mobile) de donnes, des applications, la centralisation des donnes et des applications d'analyse de donnes.
Ils sont utiles pour recueillir les donnes des patients dans un avis campagne de dpistage, ils sont envoys
une base de donnes et d'analyser la relation entre divers paramtres et les conditions trouves au cours des
consultations d'enregistrement.

Le but de la recherche tait de crer des applications qui permettent une bonne gestion de l'information
recueillie au cours de la campagne de consultation pour dtecter les anomalies gnito-urinaires congnitales.

Les logiciels ont t dvelopps en utilisant diverses technologies de pointe, y compris les technologies pour
les applications mobiles (Java Mobile, de Microsoft. NET Compact Framework), les technologies de bureau
(Microsoft. NET Framework), de la technologie serveur (Microsoft ASP.NET, Apache Tomcat, Microsoft IIS 6.0
Google Web Toolkit) et de la technologie de base de donnes classique pour la gestion des donnes (Microsoft
SQL Server) et l'analyse des donnes (Analysis Server de Microsoft). ScanUrgent application mobile. NET peut
tre utilis sur les systmes installs avec les versions Windows PocketPC mobiles de 5,0. Pour excuter
l'application on ncessite Microsoft. NET Framework 2.0. Ce cadre peut tre tlcharg partir du site
Microsoft. Pour installer l'appareil mobile qui peut copier directement sur la carte en utilisant l'appareil ou en
utilisant l'application ActiveSync mis disposition par Microsoft.

Pour recueillir des donnes ScanUrgent application mobile. NET fournit un formulaire pour l'enregistrement
des donnes descriptives de l'utilisateur du patient (2 onglets nomms E1 et E2) et un formulaire de saisie de
donnes au questionnaire (3 onglets appel C1, C2, C3).

Pour amliorer l'exprience utilisateur et le nom des donnes prcdemment utilis de prcdentes sessions
sont enregistres et peuvent tre slectionnes dans la liste, pas besoin de les retaper. Le nom de session se
rfre un groupe d'enregistrements, qui peut tre un groupe de quelques lves, test une certaine date.
L'exprience utilisateur est amliore par l'optimisation de la collecte de donnes et d'analyse et rduit la
possibilit d'erreur dans les donnes.

Les applications peuvent tre utilises pour recueillir des donnes sur les malformations gnitales et
urinaires chez les enfants, la dcouverte des motifs lis la problmatique tudie. L'analyse des donnes est
base sur un modle d'arbre de dcision. Les grappes de reflter les variables d'entre et de leur impact sur le
diagnostic.

6. Conclusions

i Compte tenu du nombre important d'enfants apparemment en bonne sant trouvs tre porteurs de
maladies congnitales (9,3% des enfants examins) du programme de dpistage des anomalies gnito-
urinaires pour congnitales est efficace et ncessaire. La forte incidence de la maladie gnitale non
diagnostique doit attirer l'attention des mdecins de famille et les pdiatres sur ces organes au cours des
examens de routine qu'ils effectuent.

ii. Les cots financiers et les fournitures matrielles ncessaires pour faire un tel programme sont
suffisamment bas, un appareil chographie portable et le cabinet pour examination.

iii. Le traitement des enfants atteints de malformations gnito-urinaires peut se faire dans des conditions
optimales dans l'unit mdicale indpendante, un service d'urologie pdiatrique. Ceci peut tre reprsent
dans une clinique d'urologie par les efforts coopratifs d'une quipe qui comprend des experts de nombreux
domaines des dcideurs mdicaux et administratifs.

iv. Les patients pdiatriques peuvent bnficier de mthodes mini-invasives de diagnostic et thrapeutique
de l'urologie caractristiques des adultes. Dans notre tude le traitements laparoscopiques et endoscopiques
chez les enfants a abouti des rsultats comparables ceux des techniques traditionnelles. Les maladies pour
lesquelles nous avons pu appliquer les techniques de diagnostic non invasive et de traitement sont la
dysplasie rnale, le syndrome de la jonction pielo-urtrale, les valves urtrales postrieures, le reflux vsico-
urtral et la cryptorchidie. Par voie laparoscopique nous avons fait la nphrectomie, la pyeloplastie et
l'orchidectomie.

v. La hydronphrose par syndrome de la jonction pielo-urtral est la maladie la plus haute incidence dans les
annes clinique, un tiers des enfants oprs ayant cette condition.

vi. Les enfants avec valve urtrale postrieure eu le plus mauvais pronostic, 66% taient dj en insuffisance
rnale chronique terminale.

vii. Nous avons enregistr un trs faible taux d'chec chirurgical: seulement 3 de 177 enfants avec des
rinterventions chirurgicales (1,6%). Les exceptions sont les patients avec hypospadias proximal, le taux de
rintervention tait de 50%.

viii. La gne TCF2 est surexprim dans la plupart des cas d'anomalies urinaires obstructifs analys
indpendamment de la normalisation avec les deux gnes mnage et HPRT1 RPLPO. Par consquent des
niveaux levs de TCF2 gne peuvent devenir un marqueur important dans l'valuation de l'enfant avec
ontogense urinaires imparfaites.

ix. Lexposition des testicules la temprature suprieure affecte tous les types de cellules prcurseurs des
spermatozodes. La sensibilit maximale semble tre caractristique des premiers stades de la
spermatogense. Augmentation de la temprature des testicules est l'une des causes de diminution de la
fertilit chez les patients atteints de cryptorchidie bilatrale.

x.Les garons ns en hiver sont plus susceptibles d'avoir des testicules anormale de migration par rapport
ceux qui sont ns en t, la diffrence tant statistiquement significative.

xi. J'ai russi montrer un lien entre l'exposition professionnelle pendant la grossesse et les malformations
gnitales.

xii. Dans le cadre d'un programme de consultation afin de dtecter des malformations congnitales
d'enregistrement de plusieurs paramtres sur les sujets examins l'aide de l'infrastructure cre permettra
de collecte et de traitement par "data mining" pour tablir le rle causal des facteurs environnementaux. En
outre, cette plate-forme intgre fournit une vue graphique de rgles et les conclusions trouves, ce qui
facilite une perspective globale, les prcieuses donnes recueillies.