Nuchal Translucency


Nuchal Translucency and Genetic Conditions in Fetus

Posted on 22nd Feb 2017, by Dr. Anuradha Udumudi

Case Details

We received 25ml amniotic fluid sample requesting Karyotyping and FISH 21 test. Indication was specified as high nuchal translucency (NT) in ultrasound. In addition the requisition form also mentioned that biochemical screening result showed high risk for Down syndrome. Scan details and screening test results were not provided with the sample. Lab generally assumes that there is no family history in such cases.

Genetic tests and results

The received fluid sample was divided between cytogenetcis lab for Karyotyping and molecular cytogenetics lab for FISH 21. As cell culture of amniotic fetal cells is required for chromosomal analysis, karyotyping result would take anywhere from 12-14 days. Meanwhile FISH test, performed on interphase (resting) cells of amniotic fluid was done and report was available in 2 days. FISH 21 test result showed a normal result. The figure below shows two fluorescent probes hybridized to chromosome 21 ruling out trisomy 21.

Figure 1: Two Normal Signals indicating 2 normal 21 chromosomes

The karyotype result to our surprise showed Trisomy 13 (not trisomy 21) and the result was immediately communicated to the physician. The pregnancy was terminated and post termination features noted in the fetus were cleft lip and palate, polydactyly and rocker bottom feet.

Figure 2: Amniotic fluid Karyotype showing trisomy 13 (Patau syndrome)

This case demonstrates that elevated NT is not just a marker for Down syndrome but also a marker for other trisomies like Trisomy 13. The discussion below gives comprehensive information on association of high NT with spectrum of genetic conditions in fetus. Importance of genetic counseling in such cases is emphasized. Families will benefit by physician’s guidance based on the understanding of overall risk rather than just confining to Down syndrome risk.

Nuchal Translucency and it’s measurement

Nuchal Translucency is the normal fluid filled subcutaneous space between the back of the fetal skin and the overlying skin. It’s measurement involves measuring the back of the fetal neck between 10 weeks 3 days and 13 weeks 6 days, and then comparing the measurement to NT nomograms at a given gestational age. NT detection by ultrasound has emerged as a powerful prenatal screening strategy to diagnose a myriad of syndromes (Salman Guraya 2013).

The normal NT value measurement at 11 weeks gestation is up to 2mm. At 12-13 weeks the 50th percentile thickness is 1.7mm and the 95th percentile thickness is 2.8mm. Most authors use a thickness of >3 mm to define abnormal. Adverse outcomes are highlighted as much more common with an NT that exceeds a set threshold of 3.5mm (Souka et al 2005)


Elevated NT and risk of fetal chromosomal defects

The role of increased NT as a risk factor for Down syndrome in fetus is well known. The most popular first-trimester Down syndrome screening protocol includes three independent markers: maternal serum levels of PAPP-A, free or intact hCG, and measurement of fetal NT (Smith 2008). A fourth marker, measurement of nasal bone is also used in some screening programs; however more evidence based studies are needed to validate its importance.

In fetuses with increased nuchal translucency, only one half of the chromosomally abnormal group is affected by trisomy 21. The distribution of nuchal translucency is different for each type of chromosomal defect. In the majority of fetuses with trisomy 21, the nuchal translucency thickness was less then 4.5 mm, whereas in the majority of fetuses with trisomies 13 or 18 it was 4.5-8.4 mm, and in those with Turner syndrome it was 8.5 mm or more. (Kagan et al 2006). It is also reported that in fetuses with unbalanced chromosomal translocations, NT tends to be greater (Cheng et al 2005).

The wide range of risk discussed cannot be ruled out by FISH test, emphasizing the importance of fetal karyotyping which rules out all numerical and structural abnormalities of chromosomes and not just common aneuploidies detected by interphase FISH test. Irrespective of undertaking FISH test or not Karyotyping is a standard recommendation for fetuses with increased NT and high risk trisomy cases.

Elevated NT, Miscarriage risk and structural defects

In chromosomally normal fetuses with increased NT, the risk of miscarriage, intrauterine death, diagnosis of major structural defects (including congenital heart defects) leading to termination of pregnancy is elevated (Cheng 2011). It was demonstrated that the incidence of cardiac defects increased along with NT in a study involving 29,000 euploid pregnancies (Hyett et al 1999). Enlarged NT has been reported with other structural anomalies, including diaphragmatic hernia, exompholos, body stalk anomaly, fetal akinesia syndrome and skeletal dysplasias (Spencer K 2001). Associations of increased NT have also been described with cerebral hypoplasia (Bilardo et al 1998), facial cleft (Markov et al 2003)], spine disorganization (Clementschitsc et al 2003), and skin edema (Hiippala et al 2001. An increased NT has also been associated with parvovirus infection (Petrikovsky 1996).

Elevated NT, Normal Karyotype, risk of other genetic syndromes

Several genetic disorders are known to be associated with elevated NT such as congenital adrenal hyperplasia, fetal akinesia, deformation sequence, Noonan syndrome, Smith-lemli-Opitz syndrome and spinal muscular atrophy (De Domenico et al 2011), Mucopolysachariodosis VII (Geipel et al 2002), Smith-Lemli Opitz Syndrome (Sharp P et al 1997 and, Achondroplasia (Tonni et al 2005). DNA testing of specific single-gene mutations or advanced molecular tools like Next Generation Sequencing are required to diagnose these disorders, and to understand recurrence risk for future pregnancies.

End note

Although the commonest association of NT is with chromosomal defects, in fetuses with increased NT and a normal karyotype, the risk of an adverse outcome remains due to various other risks involved. Risk generally increases with increasing NT. (Salman Guraya 2017).

The role of genetic counseling is crucial in cases with increased NT. In addition to ruling out aneuploidy by FISH, karyotype of the fetus must be done to rule out structural abnormalities. Fetal outcome is favorable in the absence of any identified abnormalities and with resolution of NT thickening in the progressive scans.


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