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Case Report
Fetal Diagn Ther 2009;26:5053
DOI: 10.1159/000236361
Cornelia de Lange Syndrome:
A Recognizable Fetal Phenotype
F.A. Wilmink
a
D.N.M. Papatsonis
a
E.W.M. Grijseels
b
M.W. Wessels
c


a
Department of Obstetrics and Gynecology, Amphia Hospital, Breda , Departments of
b
Obstetrics and Gynecology,
and
c
Clinical Genetics, Erasmus Medical Center, Rotterdam , The Netherlands

in 2003 because of stagnation at the first stage of labor. At a ges-
tational age of 40 weeks a healthy daughter of 3,975 g was born.
The parents were non-consanguineous and without dysmorphic
features or congenital anomalies. The family history did not men-
tion any congenital anomalies or relevant diseases. In this preg-
nancy there was no drug abuse or infection, and serologic screen-
ing for HIV, hepatitis B and syphilis was negative.
At routine sonography there was suspicion of a diaphragmat-
ic hernia ( fig. 1 ) and intrauterine growth retardation. Structural
Key Words
Cornelia de Lange syndrome Phenotype, fetal Hernia,
diaphragmatic Anomalies, limb NIPBL mutation
Abstract
We describe a fetus with Cornelia de Lange syndrome diag-
nosed after termination of pregnancy at 21 weeks. Prena-
tally, growth retardation, diaphragmatic hernia, cystic hy-
groma and a right hand with only three rays were diagnosed
by ultrasound in the second trimester of pregnancy. Postna-
tal magnetic resonance imaging confirmed the prenatal
findings, and the presence of the typical dysmorphic fea-
tures led to the diagnosis of Cornelia de Lange syndrome.
The diagnosis was confirmed by the finding of a truncating
mutation in the NIPBL gene. This case illustrates that the di-
agnosis Cornelia the Lange syndrome can be suspected pre-
natally in the second trimester, and can be diagnosed in fe-
tuses after induction or newborns at birth as the typical
phenotype is present early. Copyright 2009 S. Karger AG, Basel
Case Report
A 34-year-old gravida 2, para 1 woman visited our hospital for
routine sonographic scanning at a gestational age of 19 weeks.
Until then, the pregnancy had been uneventful. The obstetric his-
tory revealed a secondary cesarean section in the first pregnancy
Received: July 16, 2008
Accepted: September 15, 2008
Published online: October 10, 2009
D.N.M. Papatsonis, MD, PhD
Department of Obstetrics and Gynecology, Amphia Hospital Breda
Langendijk 75
NL4819 EV Breda (The Netherlands)
Tel. +31 76 595 1000, Fax +31 76 595 2467, E-Mail hoog.pap@wxs.nl
2009 S. Karger AG, Basel
10153837/09/02610050$26.00/0
Accessible online at:
www.karger.com/fdt
Fig. 1. Prenatal sonography showing the diaphragmatic hernia.
The stomach (S) is displaced upwards into the thorax causing a
mediastinal shift of the heart (H) to the right. The echodense line
of the diaphragm (D) is not continuous.
Cornelia de Lange Syndrome Fetal Diagn Ther 2009;26:5053 51
sonography in a third line referral center at a gestational age of 19
weeks confirmed that there was proportional intrauterine growth
retardation with the following growth parameters below the fifth
percentile: biparietal diameter 41.7 mm; head circumference
148.6 mm; abdominal circumference 122.2 mm, and femur length
25.1 mm. Multiple congenital anomalies were diagnosed: a cystic
hygroma, a left-sided diaphragmatic hernia with herniation of
stomach, small intestines and part of the liver, and a right hand
with only three rays. The heart appeared normal, but could not be
visualized optimally. Amniocentesis was performed, and a nor-
mal female karyotype 46,XX was obtained, whereas -fetoprotein
was increased at 29 mg/l (normal upper range for this gestational
age 20 mg/l).
After genetic counseling by the clinical geneticist and pedia-
trician the parents decided to terminate the pregnancy. Fifteen
hours after starting induction with vaginally administered miso-
prostol, a stillborn female fetus ( fig. 2 a) was delivered. Birth
weight was 290 g (normal weight at 21 weeks 360 g). Several con-
genital anomalies were present: hypertelorism; a depressed nasal
bridge; a short broad nose; long prominent philtrum; thin lips; a
small chin; dysplastic small ears, and a broad neck (most likely
caused by the cystic hygroma). The face was partly covered with
hair, especially above the upper lip and there was a synophrys
( fig. 2 b, c). The right hand was claw-like and had only 3 fingers: a
small thumb; one broad middle digit, and a finger-like attach-
ment ( fig. 3 ).
Coronal slides of the MRI scan ( fig. 4 ) showed the left part of
the liver and part of the small intestines protruding into the tho-
rax due to the diaphragmatic hernia. The brain was not yet gy-
rated, no abnormalities were described.
No consent for autopsy was given by the parents.
In view of the typical dysmorphic features and congenital
anomalies Cornelia de Lange syndrome (CdLS) was suspected.
Molecular analysis of the NIPBL gene by exon-by-exon sequenc-
ing revealed a de novo truncating disease causing mutation con-
sisting of a deletion of two nucleotides leading to a stop codon on
position 616 (p.ser616X).
Fig. 2. Fetus of 21 weeks with CdLS. a Full body picture. b , c Typ-
ical facial characteristics of CdLS are present at 21 weeks of ges-
tation: synophrys and facial hair covered with vernix, hyper-
telorism, depressed nasal bridge, short broad nose, long philtrum,
thin lips, small chin, dysplastic small ears, and broad neck (caused
by the cystic hygroma).
Fig. 3. Right claw-like hand with only three rays: a small thumb,
one broad middle digit, and finger-like attachment which is
placed at the side.
Fig. 4. Postnatal MRI (coronal slide): the left part of the liver (ar-
row) is protruding into the thorax because of the diaphragmatic
hernia, and there is a mediastinal shift.
Wilmink /Papatsonis /Grijseels /Wessels Fetal Diagn Ther 2009;26:5053 52
Discussion
CdLS is characterized by prenatal and postnatal
growth retardation, typical facial features, upper limb
malformations, and delayed psychomotor development
[1, 2] . About half of the cases of CdLS are due to autoso-
mal dominant mutations in the NIPBL gene (CdLS type
1) [3, 4] . Five percent of cases are due to X-linked muta-
tions in SMC1L1 SMC1A (CdLS type 2) [5, 6] , and one
autosomal dominant mutation has been described in the
SMC3 gene (CdLS type 3). All three genes encode com-
ponents of the cohesin complex. The syndrome is usu-
ally sporadic as it is caused by de novo mutations, where-
as patients rarely reproduce. However, rare familial oc-
currences have been reported.
Typical craniofacial features of CdLS include micro-
brachycephaly, synophrys, long eye lashes, short broad
nose with anteverted nares, a broad or depressed nasal
bridge, long philtrum, small or square chin, thin lips with
down-turned corners, high palate and widely spaced or
absent teeth [2, 7, 8] . Upper limb malformations range
from normal limbs to severe reduction defects mostly at
the ulnar side, with limited involvement of the lower ex-
tremities. Pre- and postnatal growth retardation, hyper-
trychosis, mental retardation, specific behavioral abnor-
malities, a low-pitched voice, and malformations involv-
ing the gastrointestinal, cardiac or neurodevelopmental
system are other common features. CdLS types 2 and 3
have a milder phenotype than type 1, and in some cases
are limited to nonsyndromic mental retardation.
Prenatal diagnosis of CdLS has rarely been reported,
but is usually suspected based upon ultrasound findings,
which is confirmed postnatally [913] . Prenatal diagnosis
of CdLS is difficult for several reasons: (i) most cases oc-
cur de novo without family history; (ii) the ultrasound
findings can be suggestive but are not pathognomonic for
CdLS, and (iii) the disease genes are very large and dif-
ficult to sequence, certainly within the small time win-
dow between the suspicion of CdLS based upon ultra-
sound findings near mid pregnancy and 24 weeks of ges-
tation until which termination of pregnancy is legally and
ethically permitted. Consequently, a definite prenatal di-
agnosis of CdLS supported by molecular studies of the
NIPBL gene has not yet been reported.
Intrauterine growth retardation is present in the vast
majority of CdLS fetuses, but is an aspecific finding.
More specific findings, suggesting CdLS, are ulnar re-
duction defects of the upper limbs with a limited number
of rays, often asymmetric and unilateral in combination
with a cardiac defect and/or a diaphragmatic hernia.
However, in a recent epidemiological study, as much as
68% of cases of CdLS with major malformations were not
detected by routine prenatal ultrasonography [12] . In-
creased nuchal translucency has been described in sev-
eral cases with CdLS [10, 14] . Abnormal levels of maternal
serum markers have also been reported in CdLS preg-
nancies. Pregnancy-associated plasma protein-A levels
are significantly lower for women who give birth to a
child with CdLS than in normal pregnancies [15] . Two
other biochemical maternal serum markers, free -sub-
unit of human chorionic gonadotropin ( -HCG) and in-
hibin A, are also reduced in CdLS pregnancies, albeit to
a lesser extent [15, 16] . In our family no first-trimester
screening (nuchal tranlucency measurement or assay of
serum pregnancy-associated plasma protein-A level) was
performed.
Although prenatal recognition of facial dysmorphic
features has become possible with the latest generation of
echographic equipment, this still requires considerable
technical experience and theoretical knowledge about the
dysmorphic features of the specific syndrome. Therefore,
growth retardation and major anomalies including upper
limb defects, diaphragmatic hernia, congenital heart mal-
formation and increased nuchal translucency remain the
clue to the prenatal suspected diagnosis of CdLS. A defi-
nite prenatal diagnosis of CdLS based upon the finding of
a disease-associated mutation in the NIPBL gene is not
possible in most cases since molecular NIPBL studies usu-
ally take longer than 2 months, whereas the suspicion of
CdLS is only raised in the second or third trimester of the
pregnancy. After birth or termination of pregnancy the
typical features of CdLS are easily recognized, even in fe-
tuses of 21 weeks, as illustrated by our case.

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