Background: Vesico-ureteral reflux (VUR) is a dynamic event in which a retrograde flow of urine is present into the

upper tracts. VUR may occur isolated or in association with other congenital abnormalities or as part of syndromic

entities. We present a patient with a bilateral primary VUR, syndromic disease caused by a large deletion of 18q

(18q21.3-qter) and terminal duplication of 1p (1p36.32-p36.33).

Case report: The patient was 8 years old female with a disease including moderate growth retardation,

psychomotor retardation, facial dysmorphism, single umbilical artery, umbilical hernia, urachal remnant, bilateral

congenital clubfeet and 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 cortex thinning. Voiding cystourethrography demonstrated

bilateral grade IV VUR and dimercaptosuccinic acid renal scintigraphy confirmed right renal cortex thinning and

showed a cortical uptake of 75% of the left kidney and 25% of the right kidney. The patient underwent

ureterovesical reimplantation after failure of 3 endoscopic submeatal Deflux injections with VUR resolution.

Conclusions: This is the first report involving a patient with 18q-syndrome and contemporary presence of 1p

chromosomal terminal duplication. The coexistence of two chromosomal rearrangements complicates the clinical

picture and creates a chimeric disorder (marked by characteristics of both chromosomal anomalies). Kidney

problems, primarily VUR is reported in 15% of patients affected by 18-q syndrome and no cases is reported in the

literature regarding a correlation between VUR and 1p36 chromosomal duplication

Angotti, Rossella

Brandigi, Elisa

Bulotta, Anna Lavinia

Messina, Mario

Molinaro, Francesco

Pavone, Maria

The Italian Journal of Pediatrics

PubMed

Elisa Brandigi

Francesco Molinaro

Anna Lavinia Bulotta

Rossella Angotti

Maria Pavone

Mario Messina

Springer - Publisher Connector

Chromosome 18q-Syndrome and 1p terminal duplication in a patient with bilateral vesico-ureteral reflux: case report and literature revision

ITALIAN JOURNAL 
OF PEDIATRICS
Brandigi et al. Italian Journal of Pediatrics 2013, 39:6
http://www.ijponline.net/content/39/1/6CASE REPORT Open AccessChromosome 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 MessinaAbstract
Background: Vesico-ureteral reflux (VUR) is a dynamic event in which a retrograde flow of urine is present into the
upper tracts. VUR may occur isolated or in association with other congenital abnormalities or as part of syndromic
entities. We present a patient with a bilateral primary VUR, syndromic disease caused by a large deletion of 18q
(18q21.3-qter) and terminal duplication of 1p (1p36.32-p36.33).
Case report: The patient was 8 years old female with a disease including moderate growth retardation,
psychomotor retardation, facial dysmorphism, single umbilical artery, umbilical hernia, urachal remnant, bilateral
congenital clubfeet and 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 cortex thinning. Voiding cystourethrography demonstrated
bilateral grade IV VUR and dimercaptosuccinic acid renal scintigraphy confirmed right renal cortex thinning and
showed a cortical uptake of 75% of the left kidney and 25% of the right kidney. The patient underwent
ureterovesical reimplantation after failure of 3 endoscopic submeatal Deflux injections with VUR resolution.
Conclusions: This is the first report involving a patient with 18q-syndrome and contemporary presence of 1p
chromosomal terminal duplication. The coexistence of two chromosomal rearrangements complicates the clinical
picture and creates a chimeric disorder (marked by characteristics of both chromosomal anomalies). Kidney
problems, primarily VUR is reported in 15% of patients affected by 18-q syndrome and no cases is reported in the
literature regarding a correlation between VUR and 1p36 chromosomal duplication.
Keywords: Vesico-ureteral reflux, Deletion of 18q, Duplication of 1pIntroduction
Vesico-ureteral reflux (VUR) is the most common
disease of the urinary tract in children and affecting ap-
proximately 1% of all children [1].
The primary reflux may occur isolated or in association
with other congenital abnormalities of kidney/urinary tract
or as part of syndromic entities [2].
Syndromic VUR has an inherited Mendelian trasmission
[3]. Several congenital syndromes associated with VUR as
Renal coloboma o Brachio-otorenal syndrome were know
[2]. The 18q syndrome affecting the patient that we* Correspondence: elisabrandigi@gmail.com
Division of pediatric surgery, department of pediatrics, obstetrics and
reproductive medicine, University of Siena, Siena, Italy
© 2013 Brandigi et al.; licensee BioMed Centra
Commons Attribution License (http://creativec
reproduction in any medium, provided the orpresent isn’t included among these syndromes despite
some cases presenting VUR have been reported [4].
The 18q-syndrome is chromosomal disorder resulting
from a total or partial deletion of the long arm of chromo-
some 18 [5]. The syndrome constitutes one of the most
frequent autosomal syndrome in man and the clinical
phenotype is variable because the breakpoint varies greatly
and it is generally characterized by mental retardation, de-
velopment delay, short stature and a specific pattern of
cranofacial dysmorphisms, hearing loss, neurologic abnor-
malities such hypoplasia, hands and feet anomalies [5,6].
Chromosome 1p duplication is a very rare rearrange-
ment and the most consistent manifestations are low birth
weight, grow retardation, craniosynostosis, facial anomal-
ies (flat nasal bridge, hiperthelorisme, cleft palade), hand
malformation, congenital heart diseases [7].l Ltd. This is an Open Access article distributed under the terms of the Creative
ommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
iginal work is properly cited.
Brandigi et al. Italian Journal of Pediatrics 2013, 39:6 Page 2 of 5
http://www.ijponline.net/content/39/1/6We present a patient with a bilateral primary VUR,
syndromic disease caused by a large deletion of 18q
(18q21.3-qter) and terminal duplication of 1p (1p36.32-
p36.33).
To our knowledge no patient has so far been reported to
be affected by both 18q-syndrome and 1p36 duplication.Clinical report
The patient was a 8 years old female and she was the
second child of a healthy and non consanguineous couple.
The first-born is healthy. The patient was born at 40
weeks gestation by a normal spontaneous vaginal delivery.
Her birth weight was 2700 gr, birth length was 48 cm and
her head circumference was 31 cm (< III° percentile). She
was noted at birth to have a single umbilical artery, umbil-
ical hernia, renal-urinary disease and bilateral congenital
clubfeet treated by an application of moulded plaster
casts.
At the birth a renal ultrasonography was performed to
evaluate an hydronephrosis discovered during a prenatal
ultrasonography. The renal ultrasonography showed a
bilateral hydronephrosis and right renal cortex thinning.
Voiding cystourethrography (VCUG) demonstrated bi-
lateral grade IV VUR and urachal remnant later treated
by a surgical approach (Figure 1).Figure 1 CUM imaging: IV° grade bilateral VUR.A renal dimercaptosuccinic acid (DMSA) scan per-
formed at 6 months confirmed right renal cortex thin-
ning and revealed a cortical uptake of 75% of the left
kidney and 25% of the right kidney.
The patient was initially treated with endoscopic submea-
tal bilateral injection of 0.5 cc Deflux at 30 months.
After this procedure, antibiotic prophylaxis (AP) with
Cefixime (10 mg/Kg/dose) was administered until six
month. During this period the patient didn’t show UTI
signs but her growth was retarded. When she was two
and a half years old an UTI occurred with high fever
and positive of urine culture. A VCUG confirmed per-
sistent of left grade III VUR so, she was undertaken to a
subsequent left injection of 0,6 cc of DefluxW. Treatment
with AP was continued and the result of urine culture
performed every two months was negative. One year
after this procedure a new VCUG was performed and
the result is the same of the previous examination. For
the persistent of a postoperative reflux she was undertaken
at the age of five years old to a subsequent DefluxW injec-
tion with a failure of the treatment. The patient at 7 years
of age was underwent with bilateral Glenn-Anderson’s
ureterovesical reimplantation with VUR resolution.
Standard karyotype was performed on peripheral blood
lymphocytes from the patient and both parents with
GAG, QFQ banding techniques.
Brandigi et al. Italian Journal of Pediatrics 2013, 39:6 Page 3 of 5
http://www.ijponline.net/content/39/1/6The Karyotype designation was 46,XX,del(18) (q21.3->qter)
occurred de novo, as both parents had normal karyo-
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
one chromosome 18, but furthermore revealed the pres-
ence of a terminal duplication of 1p (1p36.32-p36.33)
involving 74 genes.
Additional physical features included: growth retard-
ation, hypotonia, brachycephaly, midface hypoplasia,
wide spaced front, hyperthelorisme, micrognatia, wide
philtrum, depressed and wide nasal bridge, small teeth,
deep-set eyes with downslanting palpebral fissures, nor-
mal ears (Figure 2).
Her developmental milestones were delayed as she
walked at the age of 2 years and 6 month, her first words
were spoken at the age of 6 years.
Heart ultrasound, electroencephalogram, liver-spleen
ultrasound, visual and audiological examination were all
normal.
Our research is in compliance with the Helsinki
Declaration and written informed consent was obtainedFigure 2 Facial features of the proband.from the patient for the publication of this report and any
accompanying images.Discussion
The 18q-syndrome is characterized by a deletion that
involves the distal section of 18q and typically extends to
the tip of the long arm. The breakpoint involved varies
greatly and the presence or absence of specific clinical fea-
tures may depend on the size and position of the deleted
region [8]. The increasing use of molecular techniques such
as array-CGH enables more accurate definition of the
breakpoints. This, in turn, enables researchers to study
which parts of the chromosome correlate with the different
clinical features of the condition [9].
It is generally characterized by mental retardation, de-
velopment delay, short stature, hearing loss, white matter
abnormalities of the brain, neurologic abnormalities such
hypoplasia, hands and feet malformation and ocular
anomalies [5,6]. The facial dysmorphism may include
brachycephaly, midface hypoplasia, everted lower lip,
narrow upper lip with absent philtrum, downturned
Brandigi et al. Italian Journal of Pediatrics 2013, 39:6 Page 4 of 5
http://www.ijponline.net/content/39/1/6corners of the mouth, depressed and wide nasal bridge,
small teeth, deep-set eyes with downslanting palpebral fis-
sures, epicanthus, strabismus, prominent anthelix and
antitragus, and very narrow external ear canal [10]. The
associated anomalies include vertebral anomalies, geni-
tourinary changes, congenital heart defects, cleft lip and
palate [10].
It is thought that the decreased growth may be due to
a growth hormone deficiency. This region contains the
genes myelin basic protein (MBP) and the galanin recep-
tor which are both candidates for the growth hormone
insufficiency. The galanin receptor is involved in growth
hormone response and is therefore a good candidate for
the growth hormone insufficiency [9,11]. Interestingly,
this region is almost identical to the region that has been
identified to be responsible for the myelination pro-
blems. Thus, the gene or genes responsible for these two
features are either the same gene or two tightly-linked
genes. Up until now, all people who have been shown to
have dysmyelination also have a growth hormone defi-
ciency, so it has not yet been possible to uncouple these
two features [9]. The common finding of narrow ear
canals in 18q- has been linked, by three studies, to the
loss of part of the region 18q22.3 [9,12].
A critical region for the microcephaly (small head) that
is often present in 18q- has been shown to be located to
band 18q21.33 [8,9].
Chromosome 1p duplications have been reported rarely
and his contribute to patient’s phenotype it’s difficult to esti-
mate. A review of the literature suggests that there is not
possible to establish a syndrome. The most consistent man-
ifestations are low birth weight, grow retardation,
craniofacial and hand anomalies, and congenital heart dis-
ease. Most males had abnormal genitalia, whereas females
had normal genitalia [7]. Apart from not specific features
such as microcephaly, growth retardation, and developmen-
tal delay, the most striking feature reported in previous
studies is metopic, sagittal and coronal synostosis [13].
Such opposing phenotypes, cranial synostosis in dup(1)
(p36)and large late closing anterior fontanels in del(1)(p36)
is probably corraleted to a gene that regulates suture clos-
ure at chromosome 1p36 [13]. Chromosome 1p36 rearran-
gements have been associated also with various neoplasms
such as neuroblastoma suggesting that 1p36 region contain
a tumor-suppressor gene involved in malignancy [13].
The coexistence of two chromosomal rearrangements
complicates the clinical picture and creates a chimeric
disorder marked by characteristics of both chromosomal
anomalies.
The patient reported presents not specific characteristics
like growth and psychomotor retardation and also feet
malformation and microcephaly found in both anomalies.
The most clinical features as hypotonia, midface
hypoplasia, micrognatia, wide philtrum, small teeth,deep-set eyes with downslanting palpebral fissures,
umbilical hernia and RVU are related to 18q deletion
syndrome.
The patient also present hyperthelorisme, depressed and
wide nasal bridge probably related to 1p36.3 duplication.
Patient’s clinical phenotype isn’t completely superim-
posable to the one present in 18q syndrome, for ex-
ample, hearing abnormality, one of the most consistent
features with 66 per cent of children affected, it is absent
in this patient. This is probably consequent to the great
breakpoint variability and to the simultaneous presence
of 1p duplication.
Concerning VUR for which the patient referred to our
clinic, most researchers now acknowledge that VUR is
genetically heterogeneous [2].
The initial evidence suggesting a genetic origin of pri-
mary VUR came from twin studies, showing an 80%–100%
concordance for VUR in monozygotic twins vs. a 35-50%
concordance in dizygotic twins [2].
Studies of humans with chromosomal abnormalities sug-
gest for not syndromic primary VUR candidate loci or
genes on chromosomes 6p, 10q26, 19q13 and 13q33-34 [2].
M.L. Conte et al showed best evidence of linkage with
VUR on chromosome 3 p12.3-3q24 and on chromosome
1p36.32-1p34.3.
None of 13 reported patients affected by chromosome
1p36 terminal duplications evidenced the presence of VUR.
No part of the chromosome 18 has yet been identified
related to VUR despite is reported approximately in 15%
of patient affected by syndrome 18q.
Conclusion
The clinical case discussed it is the first reported to be
affected by both 18q-syndrome and 1p36 duplication
(despite some children with 18q-syndrome have the in-
volvement of an additional chromosome, usually a dupli-
cation of material from another chromosome).
The coexistence of two chromosomal rearrangements
complicates the clinical picture and creates a chimeric
disorder marked by characteristics of both chromosomal
anomalies.
Chromosome 1p duplications is a rare anomaly with
only 13 cases reports in literature his contribute to
patient’s phenotype it’s difficult to estimate [6].
Concerning VUR that interest the syndromic disease
presented, we know that none of 13 reported patients
affected by chromosome 1p36 terminal duplications evi-
denced the presence of VUR and no part of the chromo-
some 18 has yet been identified related to VUR despite
is reported approximately in 15% of patient affected by
syndrome 18q.
Most researcher now acknowledge that VUR is genet-
ically heterogeneous and no more these loci or genes
has been shown causally related to primary VUR.
Brandigi et al. Italian Journal of Pediatrics 2013, 39:6 Page 5 of 5
http://www.ijponline.net/content/39/1/6Continuous increasing knowledge of the genetic basis
of VUR should help us to further understand its
pathogenesis.
Consent
“Written informed consent was obtained from the patient’s
guardian/parent/next in keen for publication of this report
and any accompanying images”.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
All authors read and approved the final manuscript.
Received: 7 October 2012 Accepted: 8 January 2013
Published: 23 January 2013
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Cite this article as: Brandigi et al.: Chromosome 18q-Syndrome and 1p
terminal duplication in a patient with bilateral vesico-ureteral reflux:
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Crossref

Italian Journal of Pediatrics

Background: Vesico-ureteral reflux (VUR) is a dynamic event in which a retrograde flow of urine is present into the upper tracts. VUR may occur isolated or in association with other congenital abnormalities or as part of syndromic entities. We present a patient with a bilateral primary VUR, syndromic disease caused by a large deletion of 18q (18q21.3-qter) and terminal duplication of 1p (1p36.32-p36.33).
Case report: The patient was 8 years old female with a disease including moderate growth retardation, psychomotor retardation, facial dysmorphism, single umbilical artery, umbilical hernia, urachal remnant, bilateral congenital clubfeet and 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 cortex thinning. Voiding cystourethrography demonstrated bilateral grade IV VUR and dimercaptosuccinic acid renal scintigraphy confirmed right renal cortex thinning and showed a cortical uptake of 75% of the left kidney and 25% of the right kidney. The patient underwent ureterovesical reimplantation after failure of 3 endoscopic submeatal Deflux injections with VUR resolution.
Conclusions: This is the first report involving a patient with 18q-syndrome and contemporary presence of 1p chromosomal terminal duplication. The coexistence of two chromosomal rearrangements complicates the clinical picture and creates a chimeric disorder (marked by characteristics of both chromosomal anomalies). Kidney problems, primarily VUR is reported in 15% of patients affected by 18-q syndrome and no cases is reported in the
literature regarding a correlation between VUR and 1p36 chromosomal duplication

MOLINARO, FRANCESCO

BULOTTA, ANNA LAVINIA

MESSINA, MARIO

Archivio della Ricerca - Università degli Studi di Siena

ITALIAN JOURNAL OF PEDIATRICSBrandigi et al. Italian Journal of Pediatrics 2013, 39:6http://www.ijponline.net/content/39/1/6CASE REPORT Open AccessChromosome 18q-Syndrome and 1p terminalduplication in a patient with bilateral vesico-ureteral reflux: case report and literature revisionElisa Brandigi*, Francesco Molinaro, Anna Lavinia Bulotta, Rossella Angotti, Maria Pavone and Mario MessinaAbstractBackground: Vesico-ureteral reflux (VUR) is a dynamic event in which a retrograde flow of urine is present into theupper tracts. VUR may occur isolated or in association with other congenital abnormalities or as part of syndromicentities. We present a patient with a bilateral primary VUR, syndromic disease caused by a large deletion of 18q(18q21.3-qter) and terminal duplication of 1p (1p36.32-p36.33).Case report: The patient was 8 years old female with a disease including moderate growth retardation,psychomotor retardation, facial dysmorphism, single umbilical artery, umbilical hernia, urachal remnant, bilateralcongenital clubfeet and renal-urinary disease. Chromosomal analysis and Array-CGH revealed two heterozygouschromosomal rearrangements: 1p terminal duplication and de novo 18q terminal deletion. She referred to our clinicto evaluation of bilateral hydronephrosis and right renal cortex thinning. Voiding cystourethrography demonstratedbilateral grade IV VUR and dimercaptosuccinic acid renal scintigraphy confirmed right renal cortex thinning andshowed a cortical uptake of 75% of the left kidney and 25% of the right kidney. The patient underwentureterovesical reimplantation after failure of 3 endoscopic submeatal Deflux injections with VUR resolution.Conclusions: This is the first report involving a patient with 18q-syndrome and contemporary presence of 1pchromosomal terminal duplication. The coexistence of two chromosomal rearrangements complicates the clinicalpicture and creates a chimeric disorder (marked by characteristics of both chromosomal anomalies). Kidneyproblems, primarily VUR is reported in 15% of patients affected by 18-q syndrome and no cases is reported in theliterature regarding a correlation between VUR and 1p36 chromosomal duplication.Keywords: Vesico-ureteral reflux, Deletion of 18q, Duplication of 1pIntroductionVesico-ureteral reflux (VUR) is the most commondisease of the urinary tract in children and affecting ap-proximately 1% of all children [1].The primary reflux may occur isolated or in associationwith other congenital abnormalities of kidney/urinary tractor as part of syndromic entities [2].Syndromic VUR has an inherited Mendelian trasmission[3]. Several congenital syndromes associated with VUR asRenal coloboma o Brachio-otorenal syndrome were know[2]. The 18q syndrome affecting the patient that we* Correspondence: elisabrandigi@gmail.comDivision of pediatric surgery, department of pediatrics, obstetrics andreproductive medicine, University of Siena, Siena, Italy© 2013 Brandigi et al.; licensee BioMed CentraCommons Attribution License (http://creativecreproduction in any medium, provided the orpresent isn’t included among these syndromes despitesome cases presenting VUR have been reported [4].The 18q-syndrome is chromosomal disorder resultingfrom a total or partial deletion of the long arm of chromo-some 18 [5]. The syndrome constitutes one of the mostfrequent autosomal syndrome in man and the clinicalphenotype is variable because the breakpoint varies greatlyand it is generally characterized by mental retardation, de-velopment delay, short stature and a specific pattern ofcranofacial dysmorphisms, hearing loss, neurologic abnor-malities such hypoplasia, hands and feet anomalies [5,6].Chromosome 1p duplication is a very rare rearrange-ment and the most consistent manifestations are low birthweight, grow retardation, craniosynostosis, facial anomal-ies (flat nasal bridge, hiperthelorisme, cleft palade), handmalformation, congenital heart diseases [7].l Ltd. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly cited.Brandigi et al. Italian Journal of Pediatrics 2013, 39:6 Page 2 of 5http://www.ijponline.net/content/39/1/6We present a patient with a bilateral primary VUR,syndromic disease caused by a large deletion of 18q(18q21.3-qter) and terminal duplication of 1p (1p36.32-p36.33).To our knowledge no patient has so far been reported tobe affected by both 18q-syndrome and 1p36 duplication.Clinical reportThe patient was a 8 years old female and she was thesecond child of a healthy and non consanguineous couple.The first-born is healthy. The patient was born at 40weeks gestation by a normal spontaneous vaginal delivery.Her birth weight was 2700 gr, birth length was 48 cm andher head circumference was 31 cm (< III° percentile). Shewas noted at birth to have a single umbilical artery, umbil-ical hernia, renal-urinary disease and bilateral congenitalclubfeet treated by an application of moulded plastercasts.At the birth a renal ultrasonography was performed toevaluate an hydronephrosis discovered during a prenatalultrasonography. The renal ultrasonography showed abilateral hydronephrosis and right renal cortex thinning.Voiding cystourethrography (VCUG) demonstrated bi-lateral grade IV VUR and urachal remnant later treatedby a surgical approach (Figure 1).Figure 1 CUM imaging: IV° grade bilateral VUR.A renal dimercaptosuccinic acid (DMSA) scan per-formed at 6 months confirmed right renal cortex thin-ning and revealed a cortical uptake of 75% of the leftkidney and 25% of the right kidney.The patient was initially treated with endoscopic submea-tal bilateral injection of 0.5 cc Deflux at 30 months.After this procedure, antibiotic prophylaxis (AP) withCefixime (10 mg/Kg/dose) was administered until sixmonth. During this period the patient didn’t show UTIsigns but her growth was retarded. When she was twoand a half years old an UTI occurred with high feverand positive of urine culture. A VCUG confirmed per-sistent of left grade III VUR so, she was undertaken to asubsequent left injection of 0,6 cc of DefluxW. Treatmentwith AP was continued and the result of urine cultureperformed every two months was negative. One yearafter this procedure a new VCUG was performed andthe result is the same of the previous examination. Forthe persistent of a postoperative reflux she was undertakenat the age of five years old to a subsequent DefluxW injec-tion with a failure of the treatment. The patient at 7 yearsof age was underwent with bilateral Glenn-Anderson’sureterovesical reimplantation with VUR resolution.Standard karyotype was performed on peripheral bloodlymphocytes from the patient and both parents withGAG, QFQ banding techniques.Brandigi et al. Italian Journal of Pediatrics 2013, 39:6 Page 3 of 5http://www.ijponline.net/content/39/1/6The Karyotype designation was 46,XX,del(18) (q21.3->qter)occurred de novo, as both parents had normal karyo-type. Subsequently Array-CGH was done with AgilentHuman Genome CGH Microarray Kit 44B) and con-firmed a del(18) (q21.3->qter) involving 53 genes in theone chromosome 18, but furthermore revealed the pres-ence of a terminal duplication of 1p (1p36.32-p36.33)involving 74 genes.Additional physical features included: growth retard-ation, hypotonia, brachycephaly, midface hypoplasia,wide spaced front, hyperthelorisme, micrognatia, widephiltrum, depressed and wide nasal bridge, small teeth,deep-set eyes with downslanting palpebral fissures, nor-mal ears (Figure 2).Her developmental milestones were delayed as shewalked at the age of 2 years and 6 month, her first wordswere spoken at the age of 6 years.Heart ultrasound, electroencephalogram, liver-spleenultrasound, visual and audiological examination were allnormal.Our research is in compliance with the HelsinkiDeclaration and written informed consent was obtainedFigure 2 Facial features of the proband.from the patient for the publication of this report and anyaccompanying images.DiscussionThe 18q-syndrome is characterized by a deletion thatinvolves the distal section of 18q and typically extends tothe tip of the long arm. The breakpoint involved variesgreatly and the presence or absence of specific clinical fea-tures may depend on the size and position of the deletedregion [8]. The increasing use of molecular techniques suchas array-CGH enables more accurate definition of thebreakpoints. This, in turn, enables researchers to studywhich parts of the chromosome correlate with the differentclinical features of the condition [9].It is generally characterized by mental retardation, de-velopment delay, short stature, hearing loss, white matterabnormalities of the brain, neurologic abnormalities suchhypoplasia, hands and feet malformation and ocularanomalies [5,6]. The facial dysmorphism may includebrachycephaly, midface hypoplasia, everted lower lip,narrow upper lip with absent philtrum, downturnedBrandigi et al. Italian Journal of Pediatrics 2013, 39:6 Page 4 of 5http://www.ijponline.net/content/39/1/6corners of the mouth, depressed and wide nasal bridge,small teeth, deep-set eyes with downslanting palpebral fis-sures, epicanthus, strabismus, prominent anthelix andantitragus, and very narrow external ear canal [10]. Theassociated anomalies include vertebral anomalies, geni-tourinary changes, congenital heart defects, cleft lip andpalate [10].It is thought that the decreased growth may be due toa growth hormone deficiency. This region contains thegenes myelin basic protein (MBP) and the galanin recep-tor which are both candidates for the growth hormoneinsufficiency. The galanin receptor is involved in growthhormone response and is therefore a good candidate forthe growth hormone insufficiency [9,11]. Interestingly,this region is almost identical to the region that has beenidentified to be responsible for the myelination pro-blems. Thus, the gene or genes responsible for these twofeatures are either the same gene or two tightly-linkedgenes. Up until now, all people who have been shown tohave dysmyelination also have a growth hormone defi-ciency, so it has not yet been possible to uncouple thesetwo features [9]. The common finding of narrow earcanals in 18q- has been linked, by three studies, to theloss of part of the region 18q22.3 [9,12].A critical region for the microcephaly (small head) thatis often present in 18q- has been shown to be located toband 18q21.33 [8,9].Chromosome 1p duplications have been reported rarelyand his contribute to patient’s phenotype it’s difficult to esti-mate. A review of the literature suggests that there is notpossible to establish a syndrome. The most consistent man-ifestations are low birth weight, grow retardation,craniofacial and hand anomalies, and congenital heart dis-ease. Most males had abnormal genitalia, whereas femaleshad normal genitalia [7]. Apart from not specific featuressuch as microcephaly, growth retardation, and developmen-tal delay, the most striking feature reported in previousstudies is metopic, sagittal and coronal synostosis [13].Such opposing phenotypes, cranial synostosis in dup(1)(p36)and large late closing anterior fontanels in del(1)(p36)is probably corraleted to a gene that regulates suture clos-ure at chromosome 1p36 [13]. Chromosome 1p36 rearran-gements have been associated also with various neoplasmssuch as neuroblastoma suggesting that 1p36 region containa tumor-suppressor gene involved in malignancy [13].The coexistence of two chromosomal rearrangementscomplicates the clinical picture and creates a chimericdisorder marked by characteristics of both chromosomalanomalies.The patient reported presents not specific characteristicslike growth and psychomotor retardation and also feetmalformation and microcephaly found in both anomalies.The most clinical features as hypotonia, midfacehypoplasia, micrognatia, wide philtrum, small teeth,deep-set eyes with downslanting palpebral fissures,umbilical hernia and RVU are related to 18q deletionsyndrome.The patient also present hyperthelorisme, depressed andwide nasal bridge probably related to 1p36.3 duplication.Patient’s clinical phenotype isn’t completely superim-posable to the one present in 18q syndrome, for ex-ample, hearing abnormality, one of the most consistentfeatures with 66 per cent of children affected, it is absentin this patient. This is probably consequent to the greatbreakpoint variability and to the simultaneous presenceof 1p duplication.Concerning VUR for which the patient referred to ourclinic, most researchers now acknowledge that VUR isgenetically heterogeneous [2].The initial evidence suggesting a genetic origin of pri-mary VUR came from twin studies, showing an 80%–100%concordance for VUR in monozygotic twins vs. a 35-50%concordance in dizygotic twins [2].Studies of humans with chromosomal abnormalities sug-gest for not syndromic primary VUR candidate loci orgenes on chromosomes 6p, 10q26, 19q13 and 13q33-34 [2].M.L. Conte et al showed best evidence of linkage withVUR on chromosome 3 p12.3-3q24 and on chromosome1p36.32-1p34.3.None of 13 reported patients affected by chromosome1p36 terminal duplications evidenced the presence of VUR.No part of the chromosome 18 has yet been identifiedrelated to VUR despite is reported approximately in 15%of patient affected by syndrome 18q.ConclusionThe clinical case discussed it is the first reported to beaffected by both 18q-syndrome and 1p36 duplication(despite some children with 18q-syndrome have the in-volvement of an additional chromosome, usually a dupli-cation of material from another chromosome).The coexistence of two chromosomal rearrangementscomplicates the clinical picture and creates a chimericdisorder marked by characteristics of both chromosomalanomalies.Chromosome 1p duplications is a rare anomaly withonly 13 cases reports in literature his contribute topatient’s phenotype it’s difficult to estimate [6].Concerning VUR that interest the syndromic diseasepresented, we know that none of 13 reported patientsaffected by chromosome 1p36 terminal duplications evi-denced the presence of VUR and no part of the chromo-some 18 has yet been identified related to VUR despiteis reported approximately in 15% of patient affected bysyndrome 18q.Most researcher now acknowledge that VUR is genet-ically heterogeneous and no more these loci or geneshas been shown causally related to primary VUR.Brandigi et al. Italian Journal of Pediatrics 2013, 39:6 Page 5 of 5http://www.ijponline.net/content/39/1/6Continuous increasing knowledge of the genetic basisof VUR should help us to further understand itspathogenesis.Consent“Written informed consent was obtained from the patient’sguardian/parent/next in keen for publication of this reportand any accompanying images”.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsAll authors read and approved the final manuscript.Received: 7 October 2012 Accepted: 8 January 2013Published: 23 January 2013References1. Hsieh MH, Madden-Fuentes RJ, Lindsay NE, Roth DR: Treatment ofpediatric vesicoureteral reflux using endoscopic injection of hyaluronicacid/dextranomer gel: intermediate-term experience by a singlesurgeon. Urology 2010, 76(1):199–203.2. Conte ML, Bertoli-Avella AM, de Graaf BM, Punzo F, Lama G, La Manna A,Grassia C, Rambaldi PF, Oostra BA, Perrotta S: A genome search for primaryvesicoureteral reflux shows further evidence for genetic heterogeneity.Pediatr Nephrol 2008, 23(4):587–595.3. Morales Martínez A, Calvo Medina R, Chaffanel Peláez M, Bueno FernándezA, Míguelez Lago C, Acedo del Olmo EC: Embryology and genetics ofprimary vesicoureteral reflux and associated renal dysplasia. Arch Esp Urol2008, 61(2):99–111.4. Puri P, Gosemann JH, Darlow J, Barton DE: Genetics of vesicoureteralreflux. Nat Rev Urol 2011, 8(10):539–552.5. Kohonen-Corish M, Strathdee G, Overhauser J, McDonald T, Jammu V:A new deletion of 18q23 with few typical features of the 18q-syndrome. J Med Genet 1996, 33(3):240–243.6. Dostal A, Nemeckova J, Gaillyova R: The 18q deletion syndrome andanalysis of the critical region for orofacial cleft at 18q22.3.J Craniomaxillofac Surg 2009, 37(5):272–275.7. Garcia-Heras J, Corley N, Garcia MF, Kukolich MK, Smith KG, Day DW: Denovo partial duplications 1p: report of two new cases and review.Am J Med Genet 1999, 82(3):261–264.8. Kline AD, White ME, Wapner R, Rojas K, Biesecker LG, Kamholz J, Zackai EH,Muenke M, Scott CI Jr, Overhauser J: Molecular analysis of the18q- syndrome and correlation with phenotype. Am J Hum Genet 1993,52(5):895–906. Review.9. Feenstra I, Vissers LE, Orsel M, van Kessel AG, Brunner HG, Veltman JA, vanRavenswaaij-Arts CM: Genotype-phenotype mapping of chromosome 18qdeletions by high-resolution array CGH: an update of the phenotypicmap. Am J Med Genet A 2007, 143A(16):1558–1567.10. : High-resolution array CGH: an update of the phenotypic map. Am J MedGenet A 2007, 143A(16):1858–1867.11. Manolakos E, Kosyakova N, Thomaidis L, Neroutsou R, Weise A, Mihalatos M,Orru S, Kokotas H, Kitsos G, Liehr T, Petersen MB: Complex chromosomerearrangement in a child with microcephaly, dysmorphic facial featuresand mosaicism for a terminal deletion del(18)(q21.32-qter) investigatedby FISH and array-CGH: Case report. Mol Cytogenet 2008, 1:24.12. Ghidoni PD, Hale DE, Cody JD, Gay CT, Thompson NM, McClure EB, DanneyMM, Leach RJ, Kaye CI: Growth hormone deficiency associated in the 18qdeletion syndrome. Am J Med Genet 1997, 69(1):7–12.13. Tonk VS, Wilson GN, Yatsenko SA, Stankiewicz P, Lupski JR, Schutt RC,Northup JK, Velagaleti GV: Molecular cytogenetic characterization of afamilial der(1)del(1)(p36.33)dup(1)(p36.33p36.22) with variablephenotype. Am J Med Genet A 2005, 139A(2):136–140.doi:10.1186/1824-7288-39-6Cite this article as: Brandigi et al.: Chromosome 18q-Syndrome and 1pterminal duplication in a patient with bilateral vesico-ureteral reflux:case report and literature revision. Italian Journal of Pediatrics 2013 39:6.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color ﬁgure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submit

Chromosome 18q-Syndrome and 1p terminal duplication in a patient with bilateral vesicoureteral reflux: case report and literature revision

Chromosome 18q-Syndrome and 1p terminal

duplication in a patient with bilateral vesicoureteral

reflux: case report and literature revision

Chromosome 18q-Syndrome and 1p terminal duplication in a patient with bilateral vesicoureteral reflux: case report and literature revision

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