Table Of ContentBrandigietal.ItalianJournalofPediatrics2013,39:6
http://www.ijponline.net/content/39/1/6 ITALIAN JOURNAL
OF PEDIATRICS
CASE REPORT Open Access
Chromosome 18q-Syndrome and 1p terminal
duplication in a patient with bilateral vesico-
ureteral reflux: case report and literature revision
Elisa Brandigi*, Francesco Molinaro, Anna Lavinia Bulotta, Rossella Angotti, Maria Pavone and Mario Messina
Abstract
Background: Vesico-ureteral reflux (VUR)is a dynamic event inwhich a retrograde flow of urine is present into the
upper tracts. VUR may occur isolated or inassociation withother congenital abnormalitiesor as partof syndromic
entities. We present a patientwitha bilateral primary VUR, syndromic disease causedby a large deletion of18q
(18q21.3-qter) and terminal duplication of1p (1p36.32-p36.33).
Case report: The patientwas 8 years old female with a disease including moderategrowth retardation,
psychomotor retardation, facial dysmorphism, singleumbilical artery, umbilical hernia, urachal remnant,bilateral
congenital clubfeetand renal-urinary disease. Chromosomal analysis and Array-CGH revealed two heterozygous
chromosomal rearrangements: 1p terminal duplication and de novo 18q terminal deletion. She referred to our clinic
to evaluation of bilateral hydronephrosis and right renal cortexthinning. Voiding cystourethrography demonstrated
bilateral grade IV VUR and dimercaptosuccinicacid renal scintigraphy confirmed right renal cortex thinning and
showed a cortical uptake of 75% of theleft kidney and 25% oftheright kidney. The patient underwent
ureterovesical reimplantation after failure of 3 endoscopic submeatal Deflux injectionswithVUR resolution.
Conclusions: This is the firstreport involving a patient with18q-syndrome and contemporary presence of1p
chromosomal terminal duplication. The coexistence of two chromosomal rearrangements complicatestheclinical
picture and creates a chimeric disorder (marked by characteristicsof both chromosomal anomalies). Kidney
problems, primarily VUR is reported in15% of patients affected by 18-q syndrome and nocases is reported in the
literature regardinga correlation between VURand 1p36 chromosomal duplication.
Keywords: Vesico-ureteral reflux, Deletion of18q, Duplication of1p
Introduction present isn’t included among these syndromes despite
Vesico-ureteral reflux (VUR) is the most common somecasespresentingVURhavebeenreported[4].
disease of the urinary tract in children and affecting ap- The 18q-syndrome is chromosomal disorder resulting
proximately1%ofallchildren[1]. fromatotalorpartialdeletionofthelongarmofchromo-
The primary reflux may occur isolated or in association some 18 [5]. The syndrome constitutes one of the most
withothercongenitalabnormalitiesofkidney/urinarytract frequent autosomal syndrome in man and the clinical
oraspartofsyndromicentities[2]. phenotypeisvariablebecausethebreakpointvariesgreatly
SyndromicVURhasaninheritedMendeliantrasmission anditisgenerallycharacterizedbymentalretardation,de-
[3]. Several congenital syndromes associated withVUR as velopment delay, short stature and a specific pattern of
Renal coloboma o Brachio-otorenal syndrome were know cranofacialdysmorphisms,hearingloss,neurologicabnor-
[2]. The 18q syndrome affecting the patient that we malitiessuchhypoplasia,handsandfeetanomalies[5,6].
Chromosome 1p duplication is a very rare rearrange-
mentandthemostconsistentmanifestationsarelowbirth
weight, grow retardation, craniosynostosis, facial anomal-
*Correspondence:[email protected]
ies (flat nasal bridge, hiperthelorisme, cleft palade), hand
Divisionofpediatricsurgery,departmentofpediatrics,obstetricsand
reproductivemedicine,UniversityofSiena,Siena,Italy malformation,congenitalheartdiseases[7].
©2013Brandigietal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
Brandigietal.ItalianJournalofPediatrics2013,39:6 Page2of5
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We present a patient with a bilateral primary VUR, A renal dimercaptosuccinic acid (DMSA) scan per-
syndromic disease caused by a large deletion of 18q formed at 6 months confirmed right renal cortex thin-
(18q21.3-qter) and terminal duplication of 1p (1p36.32- ning and revealed a cortical uptake of 75% of the left
p36.33). kidneyand25%oftherightkidney.
Toourknowledgenopatienthassofarbeenreportedto Thepatientwasinitiallytreatedwithendoscopicsubmea-
beaffectedbyboth18q-syndromeand1p36duplication. talbilateralinjectionof0.5ccDefluxat30months.
After this procedure, antibiotic prophylaxis (AP) with
Cefixime (10 mg/Kg/dose) was administered until six
Clinical report month. During this period the patient didn’t show UTI
The patient was a 8 years old female and she was the signs but her growth was retarded. When she was two
secondchildofahealthyandnonconsanguineouscouple. and a half years old an UTI occurred with high fever
The first-born is healthy. The patient was born at 40 and positive of urine culture. A VCUG confirmed per-
weeksgestationbyanormalspontaneousvaginaldelivery. sistent of left grade III VUR so, she was undertaken to a
W
Herbirthweightwas2700gr,birthlengthwas48cmand subsequent leftinjection of0,6 cc ofDeflux . Treatment
her head circumference was 31 cm (< III° percentile). She with AP was continued and the result of urine culture
wasnotedatbirthtohaveasingleumbilicalartery,umbil- performed every two months was negative. One year
ical hernia, renal-urinary disease and bilateral congenital after this procedure a new VCUG was performed and
clubfeet treated by an application of moulded plaster the result is the same of the previous examination. For
casts. thepersistentofapostoperativerefluxshewasundertaken
W
At the birth a renal ultrasonography was performed to attheageoffiveyearsold toa subsequent Deflux injec-
evaluate an hydronephrosis discovered during a prenatal tionwithafailureofthetreatment.Thepatient at 7years
ultrasonography. The renal ultrasonography showed a of age was underwent with bilateral Glenn-Anderson’s
bilateral hydronephrosis and right renal cortex thinning. ureterovesicalreimplantationwithVURresolution.
Voiding cystourethrography (VCUG) demonstrated bi- Standard karyotype was performed on peripheral blood
lateral grade IV VUR and urachal remnant later treated lymphocytes from the patient and both parents with
bya surgicalapproach (Figure 1). GAG,QFQbandingtechniques.
Figure1CUMimaging:IV°gradebilateralVUR.
Brandigietal.ItalianJournalofPediatrics2013,39:6 Page3of5
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TheKaryotypedesignationwas46,XX,del(18)(q21.3->qter) fromthepatientforthepublicationofthisreportandany
occurred de novo, as both parents had normal karyo- accompanyingimages.
type. Subsequently Array-CGH was done with Agilent
Human Genome CGH Microarray Kit 44B) and con-
firmed a del(18) (q21.3->qter) involving 53 genes in the Discussion
onechromosome18,butfurthermorerevealedthepres- The 18q-syndrome is characterized by a deletion that
ence of a terminal duplication of 1p (1p36.32-p36.33) involves the distal section of 18q and typically extends to
involving74genes. the tip of the long arm. The breakpoint involved varies
Additional physical features included: growth retard- greatly and the presence or absence of specific clinical fea-
ation, hypotonia, brachycephaly, midface hypoplasia, tures may depend on the size and position of the deleted
wide spaced front, hyperthelorisme, micrognatia, wide region[8].Theincreasinguseofmoleculartechniquessuch
philtrum, depressed and wide nasal bridge, small teeth, as array-CGH enables more accurate definition of the
deep-set eyes with downslanting palpebral fissures, nor- breakpoints. This, in turn, enables researchers to study
malears(Figure2). whichpartsofthechromosomecorrelatewiththedifferent
Her developmental milestones were delayed as she clinicalfeaturesofthecondition[9].
walkedattheageof2yearsand6month,herfirstwords It is generally characterized by mental retardation, de-
were spokenat theageof6years. velopment delay, short stature, hearing loss, white matter
Heart ultrasound, electroencephalogram, liver-spleen abnormalities of the brain, neurologic abnormalities such
ultrasound, visual and audiological examination were all hypoplasia, hands and feet malformation and ocular
normal. anomalies [5,6]. The facial dysmorphism may include
Our research is in compliance with the Helsinki brachycephaly, midface hypoplasia, everted lower lip,
Declaration and written informed consent was obtained narrow upper lip with absent philtrum, downturned
Figure2Facialfeaturesoftheproband.
Brandigietal.ItalianJournalofPediatrics2013,39:6 Page4of5
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corners of the mouth, depressed and wide nasal bridge, deep-set eyes with downslanting palpebral fissures,
smallteeth,deep-seteyeswithdownslantingpalpebralfis- umbilical hernia and RVU are related to 18q deletion
sures, epicanthus, strabismus, prominent anthelix and syndrome.
antitragus, and very narrow external ear canal [10]. The The patient also present hyperthelorisme, depressed and
associated anomalies include vertebral anomalies, geni- widenasalbridgeprobablyrelatedto1p36.3duplication.
tourinary changes, congenital heart defects, cleft lip and Patient’s clinical phenotype isn’t completely superim-
palate[10]. posable to the one present in 18q syndrome, for ex-
It is thought that the decreased growth may be due to ample, hearing abnormality, one of the most consistent
a growth hormone deficiency. This region contains the featureswith 66per cent ofchildren affected, itisabsent
genes myelinbasic protein(MBP)and thegalaninrecep- in this patient. This is probably consequent to the great
tor which are both candidates for the growth hormone breakpoint variability and to the simultaneous presence
insufficiency. The galanin receptor is involved in growth of1pduplication.
hormone response and is therefore a good candidate for Concerning VUR for which the patient referred to our
the growth hormone insufficiency [9,11]. Interestingly, clinic, most researchers now acknowledge that VUR is
thisregionisalmostidenticaltotheregionthathasbeen geneticallyheterogeneous[2].
identified to be responsible for the myelination pro- The initial evidence suggesting a genetic origin of pri-
blems. Thus, the gene or genes responsible for these two maryVURcamefromtwinstudies,showingan80%–100%
features are either the same gene or two tightly-linked concordance for VUR in monozygotic twins vs. a 35-50%
genes. Up until now, all people who have been shown to concordanceindizygotictwins[2].
have dysmyelination also have a growth hormone defi- Studiesof humanswithchromosomalabnormalitiessug-
ciency, so it has not yet been possible to uncouple these gest for not syndromic primary VUR candidate loci or
two features [9]. The common finding of narrow ear genesonchromosomes6p,10q26,19q13and13q33-34[2].
canals in 18q- has been linked, by three studies, to the M.L. Conte et al showed best evidence of linkage with
loss ofpartoftheregion18q22.3[9,12]. VUR onchromosome 3p12.3-3q24 andonchromosome
Acriticalregionforthemicrocephaly (smallhead)that 1p36.32-1p34.3.
is often present in 18q- has been shown to be located to None of 13 reported patients affected by chromosome
band18q21.33[8,9]. 1p36terminalduplicationsevidencedthepresenceofVUR.
Chromosome 1p duplications have been reported rarely No part of the chromosome 18 has yet been identified
andhiscontributetopatient’sphenotypeit’sdifficulttoesti- related to VUR despite is reported approximately in 15%
mate. A review of the literature suggests that there is not ofpatient affected bysyndrome18q.
possibletoestablishasyndrome.Themostconsistentman-
ifestations are low birth weight, grow retardation, Conclusion
craniofacial and hand anomalies, and congenital heart dis- The clinical case discussed it is the first reported to be
ease. Most males had abnormal genitalia, whereas females affected by both 18q-syndrome and 1p36 duplication
had normal genitalia [7]. Apart from not specific features (despite some children with 18q-syndrome have the in-
suchasmicrocephaly,growthretardation,anddevelopmen- volvementofanadditionalchromosome, usually adupli-
tal delay, the most striking feature reported in previous cation ofmaterialfrom anotherchromosome).
studiesismetopic,sagittalandcoronalsynostosis[13]. The coexistence of two chromosomal rearrangements
Such opposing phenotypes, cranial synostosis in dup(1) complicates the clinical picture and creates a chimeric
(p36)and largelate closing anterior fontanels indel(1)(p36) disorder marked by characteristics of both chromosomal
is probably corraleted to a gene that regulates suture clos- anomalies.
ureatchromosome1p36[13].Chromosome1p36rearran- Chromosome 1p duplications is a rare anomaly with
gements have been associated also with various neoplasms only 13 cases reports in literature his contribute to
suchasneuroblastomasuggestingthat1p36regioncontain patient’sphenotype it’sdifficult toestimate[6].
atumor-suppressorgeneinvolvedinmalignancy[13]. Concerning VUR that interest the syndromic disease
The coexistence of two chromosomal rearrangements presented, we know that none of 13 reported patients
complicates the clinical picture and creates a chimeric affected by chromosome 1p36 terminal duplications evi-
disorder marked by characteristics of both chromosomal denced the presenceofVUR andno part ofthe chromo-
anomalies. some 18 has yet been identified related to VUR despite
Thepatientreportedpresentsnotspecificcharacteristics is reported approximately in 15% of patient affected by
like growth and psychomotor retardation and also feet syndrome 18q.
malformationandmicrocephalyfoundinbothanomalies. Most researcher now acknowledge that VUR is genet-
The most clinical features as hypotonia, midface ically heterogeneous and no more these loci or genes
hypoplasia, micrognatia, wide philtrum, small teeth, hasbeen shown causally relatedtoprimaryVUR.
Brandigietal.ItalianJournalofPediatrics2013,39:6 Page5of5
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Continuous increasing knowledge of the genetic basis
of VUR should help us to further understand its
pathogenesis.
Consent
“Writteninformedconsentwasobtainedfromthepatient’s
guardian/parent/next in keen for publication of this report
andanyaccompanyingimages”.
Competinginterests
Theauthorsdeclarethattheyhavenocompetinginterests.
Authors’contributions
Allauthorsreadandapprovedthefinalmanuscript.
Received:7October2012Accepted:8January2013
Published:23January2013
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