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| Congenital Diaphragmatic Hernia in a Fetus with a De novo Terminal
Deletion of Chromosome 15q26.1 |
| Ruth C1*, Starcevic J2, Bartholomew ML3, Qin N4 and Slavin TP2,5 |
| 1Fetal Diagnostic Center, Kapiolani Medical Center for Women and Children |
| 2Department of Pediatrics, University of Hawaii, John A. Burns School of Medicine |
| 3Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Hawai‘i, John A. Burns School of Medicine |
| 4Genzyme Genetics, Orange, California |
| 5Kapiolani Medical Specialists, Honolulu, Hawaii |
| *Corresponding author: |
Ruth
Chelsey 1319 Punahou Street
Suite 540,
Honolulu
HI 96826808-983-6470
Fax: 808-983-8989
E-mail: chelsey.ruth@
kapiolani.org |
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| Received November 05, 2011; Accepted December 12, 2011; Published
december 16, 2011 |
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| Citation: Ruth C, Starcevic J, Bartholomew ML, Qin N, Slavin TP (2011) Congenital
Diaphragmatic Hernia in a Fetus with a De novo Terminal Deletion of Chromosome
15q26.1. Hereditary Genetics 1:101. doi:10.4172/2161-1041.1000101 |
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| Copyright: © 2011 Ruth C, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited. |
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| Abstract |
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| De novo terminal deletions of chromosome 15q26.1 are rare occurrences. Deletions of this region have been
previously linked to congenital diaphragmatic hernia (CDH) as well as congenital malformations and developmental
delay. This article presents a prenatal case of this de novo terminal deletion, detected by cytogenetic analysis and
confirmed by fluorescence in situ hybridization (FISH), in a fetus with CDH and intrauterine growth restriction (IUGR).
Genetic evaluation of pre- and postnatal cases of CDH should include at least a close examination of the terminal region
of chromosome 15q26. As with any de novo substantial loss of genetic material, the prognosis is likely to include
additional neurologic impairment and other congenital malformations in comparison to CDH patients without genomic
alterations. |
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| Keywords |
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| Congenital diaphragmatic hernia; Prenatal diagnosis;
15q deletion; Chromosomal deletion |
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| Introduction |
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| De novo terminal deletions of chromosome 15q26.1 are rare events
and/or seldom diagnosed. Likewise, few are reported in the literature.
We present a prenatal case of a de novo terminal deletion of one copy
of chromosome 15 in a fetus with CDH. This case report describes the
defined deleted region and discusses its association with CDH, while
presenting further support for the role of molecular genetic testing in
fetuses and infants with CDH. |
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| Case Report |
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| A 20-year-old gravida 2, para 1 mother and her 30-year-old
husband were referred to our fetal diagnostic center at 11 weeks 4
days gestation for first trimester nuchal translucency (NT) screening.
The initial ultrasound was significant for a NT measurement of 4 mm.
Given the increased NT thickness, the couple was counseled about the
option of chorionic villous sampling (CVS) to detect a possible fetal
chromosomal abnormality. They consented to the CVS procedure,
and cytogenetic analysis revealed an abnormal male karyotype with
a terminal deletion of the long arm of one copy of chromosome 15
(Figure 1). Fluorescence in situ hybridization studies using a whole
chromosome paint probe for chromosome 15 and a subtelomere probe
for the long arm of chromosome 15 (Vysis, Inc.) confirmed the terminal
deletion (Figure 2). Parental chromosome analyses were normal for the
nonconsanguineous couple. Therefore, the deletion in the fetus was de
novo in origin: 46,XY,del(15)(q26.1)dn.ish del(15)(wcp+, D15S396-). |
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Figure 1: Cytogenic analysis revealing one normal copy of chromosome 15 and
a terminal deletion of the long arm of the other copy of chromosome 15 (arrow). |
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Figure 2: Fluorescence in situ hybridization studies using a whole chromosome
paint probe for chromosome 15 (A) and a subtelomere probe for the long arm of
chromosome 15 (B) (Vysis, Inc). There is one subtelomeric signal on the long
arm of one copy of chromosome 15, indicating a terminal deletion on the other
copy of chromosome 15. |
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| The couple returned to our fetal diagnostic center at 17 weeks 0
days gestation for a fetal anatomy survey by ultrasound, which showed
intrauterine growth restriction (IUGR) and a left-sided CDH (Figure
3). Fetal head circumference was 131.6 mm (18th percentile), abdominal
circumference was 91.9 mm (<3rd percentile) and femur length was
20.6 mm (<3rd percentile). The stomach appeared in the chest, and the
heart was displaced to the right. The lung to head ratio was 2.1. There
was no liver herniation into the chest. |
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Figure 3: Sagittal ultrasound image of the fetal chest and abdomen revealing
congenital diaphragmatic hernia at 17 weeks gestation. The stomach (STOM)
appears in the chest consistent with CDH. |
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| The family was counseled on the combined abnormal findings of the
fetal karyotype, CDH, and early IUGR. Termination of the pregnancy was elected at 18 weeks 2 days gestation. Fetopsy was declined by the
family. |
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| Discussion |
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| Congenital diaphragmatic hernia, a severe birth defect involving incomplete or abnormal diaphragmatic closure, is frequently
associated with life-threatening pulmonary hypoplasia and postnatal
pulmonary hypertension. Half of the cases present with other nonpulmonary
congenital anomalies and at least 5-10% of cases have a
specific underlying chromosomal etiology [1]. |
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| Biggio et al. [2] presented a patient with a 46,XX,del(15)(q26.1)
karyotype who was born with a CDH, coarctation of the aorta, and
dysmorphic features. They hypothesized that MEF2A, a myocytespecific
enhancer factor, which maps to 15q26, may play a crucial
role in the control of muscle differentiation and development of the
diaphragm [2]. |
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| Slavotinek et al. [3] screened patients with CDH and additional
phenotypic characteristics of Fryns syndrome. They used array
comparative genomic hybridization (CGH) to identify more
occult chromosomal aberrations. Results showed submicroscopic
chromosome deletions in three probands who had normal karyotypes
and were previously diagnosed with Fryns syndrome. Two of the three
probands were found to have microdeletions in 15q26.6 while the other
had a deletion in 8p23.1 [3]. Furthermore, You et al. [4] observed
dorsolateral Bochdalek-type congenital diaphragmatic hernias in
mice with NR2F2 gene deletions, and therefore, suggested that NR2F2
is a likely contributor to the formation of CDH in patients with 15q
deletions. |
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| Klaassens et al. [5] reported a patient with CDH with an
approximately 5-Mb deletion at 15q26.1-26.2. This region contained
four known genes of which two, NR2F2 and CHD2, were particularly
interesting candidates for CDH. Likewise, Lopez et al.[6] reported two
cases of CDH and congenital heart disease with one patient having a
15q26.1 deletion confirmed by FISH and array CGH [6]. |
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| Klaassens et al. [1] described two patients with a deletion of 15q26
with a common phenotype of IUGR, CDH, cardiac anomalies, and
characteristic facial features similar to those seen in Fryns syndrome
.They believed that this constellation of birth defects warranted further
investigation to evaluate for 15q26 deletions. Also, Jaillard et al.[7]
presented a female patient with multiple congenital malformations,
including CDH and a heart defect, who was detected to have a terminal
6.9-Mb deletion of chromosome 15q associated with a structurally
abnormal chromosome X. |
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| Clugston et al. [8] used rodent diaphragms to study the expression
of CDH candidate genes from 15q26, as well as FOG2 and GATA4, two
genes in other CDH critical regions at 8q22-q23 and 8p23.1, respectively
[8]. They concluded that the 15q26 critical region contains a cluster
of genes, such as MEF2A, NR2F2, and CHD2, that are expressed in
rodent diaphragm development, thus supporting other reports that
deletions in this region are associated with CDH [8]. |
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| In contrast, there are many other patients described in the literature
with 15q26.1 deletions who do not have CDH but have variable
phenotype presentations, including facial dysmorphisms, short neck,
complex heart defects, developmental delay, failure to thrive/ growth
restriction, cholestatic liver disease, severe feeding issues, and kidney
and spinal cord abnormalities [9-11]. Therefore, haploinsufficiency of
this region does not show complete penetrance for CDH. |
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| The chromosomal region 15q26.1 has many genes and presumed
genetic regulatory regions. As such, the list of candidates that may
be involved with CDH is large. In this particular case, the deleted
region consisted of up to 59 genes and/or known gene regulatory loci,
including all of the genes previously mentioned in this article: MEF2A,
NR2F2, and CHD2. Unfortunately, array CGH was not available in our
case to define the deleted region further. The terminal deletion in this
case was visible by chromosome analysis, so it may be much larger than
deletions in other reported patients. |
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| While the fetus in this case showed CDH and IUGR, other
malformations could not be observed given the early ultrasound
examination and termination of pregnancy without autopsy.
Therefore, we cannot compare and contrast the phenotypic findings
with those previously reported in other patients with 15q26.1 deletions.
However, this case supports this chromosomal region’s association
with CDH. Furthermore, as seen in some of the above case reports,
molecular methods and FISH studies helped narrow down the genes
and/or regulatory regions that are likely involved with CDH from
15q26 deletions. |
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| Based on this case, as well as a review of the literature, we
recommend paying close attention to the 15q26 region in prenatal cases
with clinical findings of CDH. Deletions of this region contain many
genes and/or regulatory elements that, in addition to CDH, would be
expected to involve other congenital malformations and neurologic
impairment. Such deletions may lead to an overall poorer prognosis
than that of isolated cases of CDH without genomic alterations. |
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| Therefore, as some small deletions or rearrangements of this region
can sometimes be missed by karyotype, molecular methods such as
chromosomal microarray, could be considered first tier genetic testing
for CDH as their results may change pre- and postnatal counseling as
well as overall prognosis. |
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| References |
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- Klaassens M, Galjaard RJ, Scott DA, Bruggenwirth HT, van Opstal D, et
al.(2007) Prenatal detection and outcome of congenital diaphragmatic hernia
(CDH) associated with deletion of chromosome 15q26: two patients and review
of the literature. Am j med genet A 143: 2204-2212.
- Biggio JR, Descartes MD, Carroll AJ, Holt RL (2004) Congenital diaphragmatic
hernia: is 15q26.1-26.2 a candidate locus? American journal of medical
genetics Part A 126A:183-185.
- Slavotinek A, Lee SS, Davis R, Shrit A, Leppig KA, et al. (2005) Fryns syndrome
phenotype caused by chromosome microdeletions at 15q26.2 and 8p23.1. J
med genet 42: 730-736.
- You LR, Takamoto N, Yu CT, Tanaka T, Kodama T, et al. (2005) Mouse lacking
COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic
hernia. Proc Natl Acad Sci USA 102: 16351-16356.
- Klaassens M, van Dooren M, Eussen HJ, Douben H, den Dekker AT, et al (2005)
Congenital diaphragmatic hernia and chromosome 15q26: determination of a
candidate region by use of fluorescent in situ hybridization and array-based
comparative genomic hybridization. Am J Hum Genet 76: 877-882.
- Lopez I, Bafalliu JA, Bernabe MC, Garcia F, Costa M, et al. (2006) Prenatal
diagnosis of de novo deletions of 8p23.1 or 15q26.1 in two fetuses with
diaphragmatic hernia and congenital heart defects. Prenatal diagnosis 26: 577-
580.
- Jaillard S, Loget P, Lucas J, Dubourg C, Le Bouar G, et al. (2011) Terminal
6.9 Mb deletion of chromosome 15q, associated with a structurally abnormal
X chromosome in a patient with congenital diaphragmatic hernia and heart
defect. European journal of medical genetics 54 :186-188.
- Clugston RD, Zhang W, Greer JJ (2008) Gene expression in the developing
diaphragm: significance for congenital diaphragmatic hernia, American journal
of physiology Lung cellular and molecular physiology 294: L665-675.
- Tonnies H, Schulze I, Hennies H, Neumann LM, Keitzer R, et al (2001) De
novo terminal deletion of chromosome 15q26.1 characterised by comparative
genomic hybridisation and FISH with locus specific probes. Journal of medical
genetics 38: 617-621.
- Bhakta KY, Marlin SJ, Shen JJ, Fernandes CJ (2005) Terminal deletion of
chromosome 15q26.1: case report and brief literature review. Journal of
perinatology : official journal of the California Perinatal Association 25: 429-432.
- Davidsson J, Collin A, Bjorkhem G, Soller M (2008) Array based
characterization of a terminal deletion involving chromosome subband 15q26.2:
an emerging syndrome associated with growth retardation, cardiac defects and
developmental delay. BMC medical genetics 9: 2.
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