FETAL AND PEDIATRIC PATHOLOGY

, VOL. , NO. , –

http://dx.doi.org/./..

CASE REPORT

VATER/VACTERL Association and Caudal Regression with

Xq-q. Microdeletion: A Case Report
Surasak Puvabanditsina , James Van Gurpb , Melissa Februarya , Marwa Khalila ,
Julia Maynea , Jennifer Ai McConnella , and Rajeev Mehtaa
a
Pediatrics, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA; b Pathology,
Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

ABSTRACT ARTICLE HISTORY

We report a term female neonate with vertebral anomalies, anal and ure- Received  October 
thral atresia, esophageal atresia with tracheoesophageal fistula (TEF), Revised  November 
renal agenesis, pulmonary hypoplasia, genital and sacral appendages, Accepted  December 
and a single umbilical artery. Genetic studies revealed a 20.91 Mb inter- KEYWORDS:
stitial deletion of the long arm of X chromosome: Xq25-q27.3. This is a VATER/VACTERL association;
new case of VATER/VACTERL association with Xq25 microdeletion. Xq-q. deletion; neonate;
congenital anomalies

Introduction
VATER/VACTERL association is typically defined by the presence of at least three of the fol-
lowing congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheoe-
sophageal fistula, renal anomalies, and limb abnormalities [1]. Although diagnostic criteria
vary, most clinicians and researchers require the presence of at least three component fea-
tures for making the diagnosis. Others have stressed emphasis on certain “core” features such
as tracheoesophageal fistula (TEF) or anorectal malformations (ARM) [2]. The prevalence is
estimated at approximately 1 in 10,000 to 1 in 40,000 live-born infants [1]. Shortly after the
initial description, it was proposed that the diagnostic criteria should also include vascular
anomalies (as part of the “V” in VACTERL), including single umbilical artery, or SUA, as part
of the definition. Cardiac malformations (“C”) and additional Limb (“L”) anomalies other
than strict radial anomalies were also added. It is nowadays standard in medical genetics to
define the clinical diagnosis of VATER/VACTERL association when three main components
are present. Microdeletion in Xq25 has infrequently been reported [3]. We are the first to
report a neonate with VATER/VACTERL association and caudal regression associated with
Xq25–27.3 microdeletion.

Case report
A 2015 female was delivered at 37 weeks’ gestation to a 22-year-old primigravida African
American. Apgar scores were 4 and 5 at 1 and 5 minutes, respectively. Pregnancy was com-
plicated with intrauterine growth restriction and anhydramnios. Obstetric sonogram at 20
weeks’ gestation revealed absence of bladder and kidneys, and single umbilical artery. Genetic

CONTACT Surasak Puvabanditsin surasak@aol.com Rutgers-Robert Wood Johnson Medical School, Pediatrics,  Robert
Wood Johnson Place, New Brunswick, NJ , USA.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ipdp.
©  Taylor & Francis Group, LLC
134 S. PUVABANDITSIN ET AL.

Figure . Chest and abdominal x-rays showing bell-shaped thorax, lower lumbar hemivertebrae, and
dysmorphic sacral vertebrae and coccyx.

study had not been performed during the pregnancy. Physical examination revealed a weight
of 2015 g <3rd percentile, length 45 cm (5th percentile), and head circumference 28 cm (<3rd
percentile). Multiple anomalies were noted: Potter’s facies (retrognathia, abnormal ear loba-
tion, and a flattened nasal tip), compression deformities of the upper and lower extremities,
absence of anus, sacral appendage, genital appendage with absent urethral opening, and a right
buttock dimple. The patient was intubated in the delivery room. Attempts to place a nasogas-
tric (NG) tube failed. Chest and abdominal radiographs showed a bell-shaped chest, the tip of
the NG tube was in the upper esophagus (at the level of T3), and there was air in the stomach
and intestine (Figure 1). In addition, there was a left sided hemivertebra at L5, dysmorphism
of the sacral and coccygeal vertebrae, narrow pubic and ischial bones, and dislocation of the
 FETAL AND PEDIATRIC PATHOLOGY 135

Figure . Note compression deformities of the face: flat nasal tip, retrognathia and deformed ear lobation.

left hip. The patient expired at 19 hours of age because of respiratory failure secondary to
pneumothorax and pulmonary hypoplasia.

Autopsy findings
External examination showed compression deformities of the face and extremities including
Potter facies (flattened nasal tip, retrognathia, and abnormal ear lobulation), rocker-bottom
left foot, compression deformities of the hands and right foot, and contractures of hips and
knees. In addition, there was an imperforate anus, compressed and phallic appearing genital
appendage (2 × 4 cm in size) without any urethral opening, compressed sacral appendage (2
× 2 cm in size), and a dimple on left buttock (Figures 2–5).

Figure . Note rocker buttom feet.

136 S. PUVABANDITSIN ET AL.

Figure . (a,b,c) Note (phallic-like) genital appendage with opening of the skin at the tip. No urethral open-
ing was noted.

Figure . Note an imperforate anus, a sacral appendage and a dimple on the right buttock.
 FETAL AND PEDIATRIC PATHOLOGY 137

Figure . Photograph shows small chest with lung hypoplasia.

Internal examination revealed esophageal atresia (middle 1/3rd ), malrotation of the small
bowel, dilated distal colon communicating with the posterior wall of the bladder, and absence
of bladder neck, urethra, kidneys, ureters and renal arteries (Figures 6 and 7). Examination
of the umbilical cord showed a single umbilical artery. The ovary, fallopian tubes and uterus
were identified. Both lungs were hypoplastic; combined lung weight was 17.5 gm (normal:
50). Left lung weighed 9.5 g and right lung 8 g (Figure 8). Consent for autopsy of the brain
was refused.

Cytogenetic and molecular studies

Single nucleotide polymorphism (SNP) microarray analysis performed using the Affymetrix
Cytoscan HD platform revealed a 20.91 Mb interstitial deletion at Xq25 -> q27.3 [arr
Xq25q27.3 (122, 650,458–143,564,589) x1 (Figures 9 and 10). This deletion interval includes
numerous OMIM genes (start: THOCS2 TO END: SPANX2). Disease-associated OMIM
genes in the deleted interval are: XIAP, SH2DIA, OCRL, CDHHC9, AIFM1, IGSF1, FRMD7,
GPC3, GPC4, PHF6, HPRT1, SLC9A6, FHL1, CD40LG, ZIC3, F9, SOX3.

Discussion
VATER/VACTERL association is typically defined by the presence of at least three of the
following congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheo-
esophageal fistula, renal anomalies, and limb abnormalities [1, 2]. VATER/VACTERL associ-
ation is usually sporadic and related to perturbation of blastogenesis. The VATER/VACTERL
association was first described in early 1970s as a non-random co-occurrence of congenital
138 S. PUVABANDITSIN ET AL.

Figure . Photograph shows dilated colon communicating with the urinary bladder (C-Colon; B-Urinary
bladder).

Figure . The SNP microarray (Reveal) analysis shows a . Mb copy loss on Xqq. [,,–
,,](arrows).
 FETAL AND PEDIATRIC PATHOLOGY 139

malformations. Although most patients with VACTERL association have had normal chro-
mosomal studies, a few reports have been published VACTERL association patients with
chromosomal abnormalities (13q, 10q, 16q, Xp22) [4]. VATER/VACTERL association have
been associated with mutations in FGF8, HOXD13, ZIC3, PTEN, FANCB, FOXF1, PCSK5,
and TRAP1 genes [5, 6]. VACTERL syndrome has been reported in a deletion of the ZIC3
gene (300265) on chromosome Xq26 [7, 8]. ZIC3 plays a role in the development of the
foregut, urogenital and hindgut malformations, central nervous system anomalies, hetero-
taxy, and complex congenital heart diseases [7]. The ZIC3 gene typically associated with X-
linked heterotaxy(left-right asymmetry defects) including complex cardiac anomalies, altered
lung lobation, splenic and hepatobiliary abnormalities, and gut malposition [8]. This gene has
been implicated in polyalanine expansion diseases, and that ZIC3 mutations may be present
in patients with VATER/VACTERL association in combination with heterotaxy.
Variable phenotypes in female patients with Xq deletion have been observed. These obser-
vations most likely suggest that skewed X-inactivation is the underlining mechanism [9–11].
Without the X-inactivation study, we could not be certain that the Xq deletion in the female
patient is responsible for the clinical findings.
Caudal regression syndrome (CRS) is a congenital malformation of the lower spinal seg-
ments associated with aplasia or hypoplasia of the sacrum and lumbar spine. Prevalence is
estimated at around 1/50,000 and 1/100,000 of pregnancies. Most cases of caudal regression
are sporadic or associated with maternal diabetes. Maternal diabetes is a major risk factor for
developing this syndrome, which is up to 200 fold more frequent than in the general popula-
tion. CRS has also been associated with the VATER/VACTERL association [12]. The patho-
genesis is believed to result from impaired development of the mesoderm prior to 4 weeks
gestation but the etiology of CRS remains unclear [13]. The etiology seems to be multifac-
torial, and includes maternal diabetes, vascular hypoperfusion, and genetic predisposition.
Recent advances in the understanding of axial mesoderm patterning during early embryonic
development suggest that sirenomelia represents the most severe end of the caudal regression
spectrum [14]. The experimental and epidemiologic studies suggest a common pathogenic
mechanism of VACTERL association and syrinomelia [15].
The deleted region (Xq25q27.3) seen in our patient encompasses GPC3 gene. GPC3 plays
a key role in regulating cell proliferation in embryonic mesodermal tissues. The GPC3 gene,
encoded a heparin sulphate proteoglycan belonging to the glypican family, has been identified
in patients with renal (renal dysplasia, cystic disease of the kidney), genital abnormalities, and
vertebral abnormalities (abnormal number or shape of vertebra) known as Simpson–Golabi–
Behmel syndrome [16, 17].
Other significant disorders associated with Online Mendelian Inheritance in Man (OMIM)
genes in the deleted region in our case are: OCRL, GPC4, PHF6, SOX3. The deletion of OCRL
gene has been detected in patient with Lowe syndrome (disorders of kidneys, eyes, and ner-
vous system) [18]. The GPC4 gene is adjacent to the 3 end of GPC3 and may also play a
role in Simpson–Golabi–Behmel syndrome [19]. Mutations of PHF6 gene is associated with
Borjeson—Forssman–Lehmann syndrome (mental retardation, epilepsy, hypogonadism and
obesity [20]. Mutations in the SOX3 gene have been associated with X-linked hypopituitarism
(XH) and X-linked mental retardation [21, 22].
In summary we report a neonate with VATER/VACTERL association, including vertebral
anomalies, anal atresia, esophageal atresia and traheoesophageal fistula (TEF), renal agenesis
and limb abnormalities. Anomalies of the caudal end of the trunk [Caudal regression: partial
agenesis of the lower lumbar and sacrococcygeal spines, sacral appendage, deformities of the
140 S. PUVABANDITSIN ET AL.

pelvis, anomalies of the lower extremities and genitourinary anomalies (urethral atresia, gen-
ital appendage)] and malposition of the intestine (Heterotaxy spectrum) were also present.
The cytogenetic study revealed deletion of the responsible genes (ZIC3, GPC3) at Xq25q27.3
region.

Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content
and writing of the article.

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