REVIEW

CURRENT
OPINION Increased nuchal translucency in the presence of
normal chromosomes: what’s next?
Christina M.L. Alamillo a, Morris Fiddler b, and Eugene Pergament a

Purpose of review
First trimester screening is presently offered to all pregnant women as a means of prenatal screening for
Down syndrome, trisomy 18, and trisomy 13. Nuchal translucency measurement is a fundamental
component of the screening protocol. A woman whose fetus’ nuchal translucency is greater than the 95th
percentile is also at increased risk for a multiplicity of other adverse pregnancy and pediatric outcomes,
and as a consequence, counseling of patients about their testing options and range of pregnancy outcomes
has become complex and difficult.
Recent findings
The increased risk for chromosome abnormalities, congenital heart malformations, and pregnancy loss in
the presence of an increased nuchal translucency is well documented. What has not been clearly defined
is the incidence of other genetic syndromes, congenital defects, and adverse pregnancy and pediatric
outcomes in the presence of increased nuchal translucency. Currently, Noonan syndrome is the only
molecular genetic condition that has been shown to have a clear association with the finding of increased
nuchal translucency in the first trimester.
Summary
This article reviews the current literature on outcomes in pregnancies with an increased nuchal translucency
and a normal karyotype. We summarize the range of outcomes detected in the first trimester with
recommendations for further prenatal testing and counseling of patients.
Keywords
first trimester screening, nuchal translucency

INTRODUCTION semilunar valve acceleration time [2]) and/or an

Nuchal translucency has become a critical measure-
ment in assessing the genetic health of a pregnancy.
A nuchal translucency greater than the 99th
percentile at 11–14 weeks gestation has been associ-
ated with a markedly increased risk for a broad
spectrum of developmental anomalies, including
single gene mutations, chromosome abnormalities,
cardiac malformations, and fetal structural defects.
At the same time, a nuchal translucency measure-
ment of less than the 95th percentile at 11–14 weeks
gestation has a 97% chance of the pregnancy going
to term and resulting in a normal outcome [1].
The physiological cause(s) of increased nuchal
translucency is still poorly understood. Given the
phenotypic heterogeneity of fetuses with increased
nuchal translucency, a single physiological cause is
unlikely. Hypotheses include a relationship between
nuchal translucency thickness and cardiac dys-
function (right ventricular diastolic function and
aberrant lymphatic endothelial differentiation [3],
a finding that has also been seen in aneuploid fetuses
with increased nuchal translucency. De Mooij et al.
[3] hypothesized that the disturbance in lymphatic
differentiation can range from ‘delayed but physio-
logical development to a more severe disturbance’.
Additional studies are necessary to elucidate the
pathophysiological changes in fetuses with increased
nuchal translucency.
a
Northwestern Reproductive Genetics and bDePaul University, Chicago,
Illinois, USA
Correspondence to Christina M.L. Alamillo, MS, CGC, Northwestern
Reproductive Genetics, 680N, Lake Shore Drive, Suite 1230, Chicago,
IL 60611, USA. Tel: +1 312 981 4353; fax: +1 312 981 4404; e-mail:
christina.alamillo@ymail.com
Curr Opin Obstet Gynecol 2012, 24:102–108
DOI:10.1097/GCO.0b013e3283505b25

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April 2012

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 Increased nuchal translucency and normal chromosomes Alamillo et al.
KEY POINTS

At this time, Noonan syndrome is the only molecular
genetic condition that has been shown to have a clear
association with the finding of first trimester increased
nuchal translucency.

Since congenital heart defects are the most commonly
found congenital abnormalities following an increased
nuchal translucency, fetal echocardiogram is essential.

A detailed level II ultrasound examination is critical in
the management plan for fetuses with increased nuchal
translucency in order to evaluate for signs of a genetic
syndrome, other congenital abnormalities, hydrops,
and fetal demise.
GENETIC DISORDERS TO CONSIDER
Many genetic syndromes have been associated
with an increased nuchal translucency; however,
the rarity of these syndromes raises the possibility
of chance and not a true relationship. A review
article by Souka et al. [4] states that ‘the prevalence
of major cardiac defects, diaphragmatic hernia,
exomphalos, body stalk anomaly, skeletal defects,
and certain genetic syndromes, such as congenital
adrenal hyperplasia, fetal akinesia deformation
sequence, Noonan syndrome, Smith-Lemli-Opitz
syndrome, and spinal muscular atrophy appears
to be substantially higher than in the general
population, and it is therefore likely that there is
a true association between these abnormalities
and increased nuchal translucency’. Bilardo et al.
&&
[5 ] emphatically claimed that ‘the association
with increased nuchal translucency is undisputed’.
&&
Pergament et al. [6 ] however, only confirmed an
association between increased nuchal translucency
and Noonan syndrome, but found no increased
incidence of fetuses predicted to be affected with
Smith-Lemli-Opitz syndrome, spinal muscular
atrophy, congenital adrenal hyperplasia, or 22q11
deletion syndrome.
Noonan syndrome
Noonan syndrome is one of the most commonly
identified genetic syndromes in fetuses with
increased nuchal translucency, increased nuchal
fold, or cystic hygroma. This autosomal dominant
condition, with a wide range in expressivity and
unknown penetrance, has a frequency of approxi-
mately 1 : 1000 to 1 : 2500. In fetuses with an
increased nuchal translucency, the incidence lies
&&
between 2% [7] and almost 5% [6 ]. Half of the
fetuses with Noonan syndrome have a mutation in
the PTPN11 gene [7], although this condition has
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been associated with mutations in seven other genes
(SOS1, RAF1, BRAF, MAP2K1/2, NRAS, and SHOC2).
The next most commonly involved locus is SOS1,
with much smaller percentages distributed across
other genes. Furthermore, some of the genes and
mutations overlap with syndromes having pheno-
typical features similar to Noonan syndrome (e.g.,
Leopard syndrome, CFC syndrome, and Costello
syndrome) [7].
There has been considerable debate as to when
to offer prenatal molecular testing for Noonan syn-
drome, either following a first trimester increased
nuchal translucency or following related second tri-
mester ultrasound findings, such as persistent nuchal
fold or cystic hygroma, hydrops fetalis, pleural effu-
sion, cardiac anomalies, polyhydramnios, or specific
& &
facial abnormalities [8 ,9 ]. Given that chorionic
villus sampling (CVS) is routinely offered to rule
out chromosome abnormalities in fetuses with
increased nuchal translucencies, it is reasonable
to consider testing the patient’s DNA for mutations
associated with Noonan syndrome. Houweling et al.
&&
[10 ] supported this approach, stating that ‘given
the high incidence of Noonan syndrome, we
strongly advocate that in case of increased nuchal
translucency and a normal karyotype, genetic coun-
seling and Noonan syndrome mutation detection is
offered, even in the absence of additional associated
abnormalities’. At this time, prenatal testing for
Noonan syndrome is available with costs ranging
from $400 to over $2500, depending on the metho-
dology of testing and number of genes included in
the panel. Although some panels include eight or
more genes that have been associated with Noonan
syndrome (as well as other syndromes), panels that
include PTPN11, SOS1, RAF1, and KRAS detect the
majority (70%) of cases of Noonan syndrome.
22q11 deletion syndrome
22q11 syndrome encompasses a spectrum of dis-
orders previously named DiGeorge and velocardio-
facial syndrome and is the most common contiguous
gene microdeletion syndrome with an estimated
population frequency of 1/4000 births. Conotruncal
heart defects are commonly seen in 22q11 syndrome,
and for that reason, prenatal analysis for 22q11
deletions has been recommended for all fetuses with
structural cardiac anomalies [11]. Although fetuses
with an increased nuchal translucency are at a sig-
nificantly increased risk for congenital heart defects,
offering 22q11 deletion analysis on the basis of
increased nuchal translucency alone in the first
&
trimester has been debated at length [12,13,14 ].
Donnenfeld et al. [12] found no instances of 22q11
in 80 chromosomally normal, nuchal translucency
www.co-obgyn.com 103
 Prenatal diagnosis
of more than 3.0 mm fetuses, and concluded that
‘routine 22q11 microdeletion analysis for fetuses
with excess nuchal translucency is not indicated’.
Two studies of 146 and 120 pregnancies with nuchal
translucency more than 3.5 and 3.0, respectively,
&&
also failed to find 22q11 microdeletions [6 ,13].
Testing for 22q11 microdeletions in the presence
of increased nuchal translucency may appear reason-
able, but the literature fails to support this practice.
Spinal muscular atrophy
Spinal muscular atrophy (SMA) is an autosomal
recessive disorder with a carrier frequency of
approximately 1/35–1/50 across all ethnic groups.
It is a degenerative condition and is classified
into four groups, from type 0, the most severe type
evident at birth, to type III, a mild type with child-
hood onset. Several reviews of pregnancy outcomes
associated with increased nuchal translucency have
included SMA on the list of genetic conditions to
&&
consider (e.g., Souka et al. [4] and Bilardo et al. [5 ]).
Nevertheless, there are only five documented cases
with increased nuchal translucency measurements
&
and a confirmed diagnosis of SMA [15 ], and there
are few studies specifically evaluating the risk of
SMA in pregnancies with increased nuchal trans-
lucencies. In a study of 120 fetuses with increased
nuchal translucency of at least 3.0 mm and a normal
karyotype, no fetuses predicted to be affected with
SMA were identified, although there was an un-
&&
usually high carrier frequency [6 ]. Conversely,
&
Zadeh et al. [15 ] recently reported on twelve infants
affected with SMA whose first trimester nuchal
translucency measurements ranged from 0.7 to
2.4 mm. These last two studies, therefore, failed to
demonstrate that increased nuchal translucency is
associated with SMA.
Skeletal anomalies
Skeletal anomalies are the most recent group of
genetic conditions under discussion in the literature
related to increased nuchal translucency in the
& &
first trimester [4,16,17 ,18–20]. Khalil et al. [17 ]
reported on 15 cases of skeletal dysplasias identified
prior to 14 weeks gestation, including ten different
dysplasias with a variety of inheritance patterns.
Accurate prenatal diagnosis was made only in
cases with a positive family history (one case each
of thanatophoric dysplasia and Roberts syndrome).
Common ultrasound findings in early pregnancy
included increased nuchal translucency, hydrops,
short femurs, abnormal skull shape and mineraliz-
ation, abnormal profile, and abnormal chest, a
combination not readily differentiated into an
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underlying syndrome based on ultrasound findings
alone. Tonni et al. [20] recently published a case
report of thanatophoric dysplasia type I associated
with increased nuchal translucency. At 16 and
19 weeks, ultrasound revealed skeletal findings that
were then confirmed to be thanatophoric dysplasia
type one by mutation analysis on a prenatal mole-
cular panel, pointing to the value of such a testing
strategy for providing specific prenatal diagnosis
and defined recurrence risk.
CONGENITAL ABNORMALITIES
The risk for congenital abnormalities increases
exponentially with nuchal translucency measure-
ment, from 2.5% for nuchal translucency between
95th percentile and 99th percentile to 45% for
a nuchal translucency of at least 6.5 mm [21,22].
A broad spectrum of congenital abnormalities has
been described in fetuses with an increased nuchal
translucency, with cardiac malformations being the
most common. Other abnormalities associated with
increased nuchal translucency and normal karyo-
type include orofacial clefts [22,23], diaphragmatic
hernia [4,24], exomphalos [4], body stalk anomaly
[4], fetal akinesia sequence [4], and megacystis [4].
Congenital heart defects
Multiple reports have described an association
between congenital heart defects (CHD) and nuchal
translucency. Compared to the general population,
the risk for CHD is approximately six times higher
in fetuses with a nuchal translucency of at least 99th
percentile [25]. Other studies found 34% to approxi-
mately 50% of fetuses with nuchal translucency
more than 95th percentile had a CHD [26,27].
Clur et al. [25] reported that 4.9% of fetuses with
increased nuchal translucency and normal karyo-
type had a major CHD (34 of 693 studied) with
an exponentially increasing incidence relative to
nuchal translucency measurement: from a 1.9%
risk at a nuchal translucency of 2.5–3.5 mm to a
27.7% risk at a nuchal translucency more than
6.5 mm. Vogel et al. [27] and Wald et al. [28] reported
increased detection and improved outcome when
increased nuchal translucency is used as a screen
for CHD. Nevertheless, the utility of nuchal
translucency measurement as a screening tool for
CHD has not been established as a standard measure
of care in a low risk population.
CHROMOSOME MICROARRAY
At the present time, molecular techniques for
prenatal karyotyping have been primarily applied
Volume 24
Number 2
April 2012
 Increased nuchal translucency and normal chromosomes Alamillo et al.
to second trimester pregnancies with ultrasound
anomalies. In the presence of a structural anomaly,
array comparative genome hybridization (aCGH)
has a detection rate 1–2% higher than that of con-
ventional chromosome analysis [29,30]. Faas et al.
[31] found that 16% of fetuses with ultrasound
anomalies and normal or balanced karyotype had
detectable submicroscopic aberrations, although
there were no fetuses referred because of an
increased nuchal translucency.
The association of increased nuchal translucency
with a submicroscopic copy number variant (CNV) is
based almost exclusively on individual clinic reports
[32–34]. Leung et al. [35] found CNVs in 12.5% (6/48)
of cases with nuchal translucency more than 3.5 mm
in first trimester screening, four of which (8.3%)
were considered to be pathogenic and clinically
significant. The authors concluded that the pre-
valence of submicroscopic chromosomal abnormal-
ities is increased in fetuses with nuchal translucency
more than 3.5 mm and a normal karyotype.
Schou et al. [36], on the contrary, did not detect
any chromosomal aberrations of clinical importance
by high resolution CGH in 100 fetuses with nuchal
translucencyof at least 99th percentile (mean nuchal
translucency ¼ 4.4 mm; range 3.5–9.7 mm). Given
the limited information available on the incidence
of abnormal aCGH results in fetuses with increased
nuchal translucency, it is yet to be established that
an isolated increased nuchal translucency warrants
prenatal microarray analysis.
CHANCE OF MISCARRIAGE AND FETAL
DEMISE
Increased nuchal translucency has been associated
with an increased risk of miscarriage or fetal demise,
even in euploid fetuses. The prevalence of mis-
carriage or fetal demise increased from 1.6% in
pregnancies with nuchal translucency between
95–99th percentile, to about 20% for nuchal trans-
lucencies measuring greater than 6.5 mm [4,22].
First trimester maternal serum markers including
PAPP-A and free beta hCG should also be evaluated,
given the association between low PAPP-A and
free beta hCG levels with miscarriage and other
pregnancy complications. In most cases, fetal loss
occurs before 20 weeks gestation and particularly in
the presence of fetal hydrops.
CHANCE OF MATERNAL AND FETAL
INFECTION
Persistence of unexplained increased nuchal
translucency or evolution to hydrops fetalis raises
&&
the possibility of congenital infection [5 ,21,37].
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Sebire et al. [37] identified recent maternal infection
in 1.4% of 462 euploid pregnancies with increased
nuchal translucency. None of the fetuses were
affected. Conversely, in the 63 cases of unexplained
second or third trimester nuchal edema or hydrops,
9.5% were associated with maternal infection, and
in all cases there was evidence of fetal infection [37].
Parvovirus B19 is the only specific pathogen associ-
ated with increased nuchal translucency, leading to
myocardial dysfunction or fetal anemia [38].
CHANCE OF A NORMAL PREGNANCY
OUTCOME
The most likely outcome in pregnancies with
increased nuchal translucency, even with measure-
ments as high as 5.4 mm, is a live birth with no
abnormalities. With a nuchal translucency ranged
from 4.5–5.4 mm, 50–71% had a positive pregnancy
outcome [4,22]. At nuchal translucency measure-
ments below the 99th percentile less than 3.5 mm),
there was a 92–93% chance of a good outcome
[4,22]. In the absence of a chromosome abnormality
and an unremarkable anatomic ultrasound evalu-
ation at 20 weeks gestation, the chance of a good
pregnancy outcome was similar to that of the
general population (95–96%), regardless of the
nuchal translucency measurement [4,22].
PEDIATRIC OUTCOME
There have been a limited number of studies
evaluating developmental outcomes in neonates
born following a first trimester nuchal translucency
measurement of 3.5 mm or greater. Senet et al. [39]
reported that the incidence of developmental delay
in children with enlarged nuchal translucency was
1.2%, which was not statistically different from
&&
controls. In the 2010 review by Bilardo et al. [5 ],
the incidence of developmental delay was 1.6%; 2/3
of the affected cases were also associated with suspi-
cious ultrasound features. Mula et al. [40] reported
that 3.7% of 108 children born following a nuchal
translucency more than 99th percentile exhibited
moderate to severe neurodevelopmental delay.
Conversely, Miltoft et al. [41] reported that there
was no increased risk of developmental delay at two
years of age when fetuses with a nuchal translucency
of at least 99th percentile but normal karyotype and
ultrasound were compared to fetuses with a nuchal
translucency less than 99th percentile (Fig. 1).
GENETIC COUNSELING
Women undergoing first trimester screening must
be informed that an increased nuchal translucency
www.co-obgyn.com 105
 Prenatal diagnosis

Pregnancy with
NT ≥ 3.0mm
identified
between 10-14
weeks
gestational age

Store an un- Normal

banded slide chromosome
and fetal DNA result on CVS or
sample for amniocentesis
future testing sample

12-16 weeks 18-22 weeks

gestation gestation

Prenatal testing History of an Detailed Level II

Pregnancy at Detailed Fetal
for Noonan affected anatomical
increased risk ultrasound echocardiogram
syndrome parvovirus ultrasound
for genetic examination to
condition based contact or monitor for
on family maternal hydrops and
history, carrier symptoms intrauterine
screening fetal demise
results, and/or
US findings

Noonan No Maternal Congenital No Congenital Hydrops No

syndrome Noonan screening for heart congenital anomalies fetalis congenital
mutation syndrome parvovirus defect heart identified identified anomalies
identified mutation infection identified defect identified
identified identified

Parental Consider Testing for

Standard High
testing for molecular 22q11
hydrops probability of
mutation testing for deletion Congenital Consider infectious normal
identified at risk anomalies prenatal screening pregnancy
in the condition suggest a array CGH including outcome
fetus specific testing for
syndrome parvovirus

Consider
options for
molecular
testing

FIGURE 1. Recommended guidelines for follow-up of euploid pregnancies with increased nuchal translucencies.
may be indicative of risk factors other than including miscarriage or fetal demise. Parents often
aneuploidy. The overall incidence of any adverse inquire about monitoring the pregnancy by ultra-
outcome in fetuses with an increased nuchal sound to determine if the nuchal translucency
translucency is approximately 20% [22], however, has normalized over the course of the pregnancy.
the chance of a positive pregnancy outcome has Although the nuchal translucency thickness may
been reported as high as 96% when fetal karyotype decrease, there is insufficient data to state that
and 20 week level II anatomical evaluation is normal nuchal translucency normalization over time dec-
[22]. Genetic counseling, therefore, should assess reases the risk of an adverse outcome. Although an
the chance of a healthy outcome as well as review increased nuchal translucency persists in only 3% of
the range of abnormal findings. fetuses [22], these fetuses have a 10% risk either of
It is critical to review the risks of specific hydrops/IUFD or a genetic syndrome [4].
outcomes pertaining to the nuchal translucency If molecular genetic testing for Noonan syn-
&&
measurement in the fetus [4,5 ,22]. Particularly in drome is pursued, it is important to discuss the
the case of an extremely enlarged nuchal translu- range in clinical severity of Noonan syndrome when
cency (at least 6.5 mm), parents should be informed a mutation in one of the associated genes is found,
of the relatively high chance of adverse outcome, from apparently asymptomatic individuals to more

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April 2012

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 Increased nuchal translucency and normal chromosomes Alamillo et al.
severely affected individuals with cardiac anomalies
and significantly reduced IQ. This highlights the
need for additional studies regarding genotype/
phenotype correlations for the specific mutation
identified. Furthermore, parental testing should
always be offered to asymptomatic parents, given
the range in expressivity of the mutations and for
recurrence risk counseling.
Since the majority of skeletal dysplasias cannot
be definitively diagnosed by ultrasound, molecular
testing should be considered when an increased
nuchal translucency and significant skeletal
anomalies are observed. For recessively inherited
skeletal dysplasias, the recurrence risk is 25%, but
for disorders caused by de novo mutations, less than
1%. If termination of pregnancy occurs, the fetal
autopsy should provide diagnostic information
based on pathology and radiology evaluations.
Molecular testing of fetal DNA is important,
although genetic heterogeneity of skeletal dyspla-
sias makes this a daunting challenge. Testing for
thanatophoric dysplasia is one exception, since
ultrasound generally reveals classic features such
as trident fingers and short ribs. Since there are
only a few mutations known to cause thanatophoric
dysplasia in the FGFR3 gene, prenatal molecular
diagnosis is relatively simple for this condition.
Increasingly, arrays that test for mutations across
multiple genes are becoming available. As is the case
with most genetic conditions, the importance of
identifying familial mutations lies in facilitating
the option of using targeted molecular testing in
subsequent pregnancies.
CONCLUSION
The range of outcomes in pregnancies with
increased nuchal translucency and normal karyo-
type should be clearly and carefully explained to
parents, ideally by a genetic counselor or other
prenatal genetic professional knowledged in the
current literature. Parents should be informed of
all recommended follow-up guidelines, as well as
options for further testing if applicable. Above all,
the chance of a good pregnancy outcome should be
stressed when genetic testing results and level II
ultrasound findings are within normal limits.
Acknowledgements
None.
Conflicts of interest
This paper has not been submitted for publication
elsewhere. The authors of this review have no conflicts
of interest.
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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Volume 24
Number 2
April 2012