Prenatal diagnosis of Turner syndrome
Dr Ivonne Bedei, Dr Amelie Hofmann-Werther, and Dr Afshin Pour Mirza provide detailed information about the prenatal diagnosis of Turner syndrome.
Dr Ivonne Bedei
Specialist Obstetrics and Gynecology, Fetal Medicine, Pediatric and Adolescent Gynecology, Maternal and Fetal Medicine at Klinikum Frankfurt Höchst, Germany, Mannheim University, Germany, Feto Maternal & GenetYX Center Dubai UAE.
Dr Amelie Hofmann-Werther
Specialist in Obstetrics and Gynecology, Cervical Dysplasia and Colposcopy, Master Class in Fetal Medicine, Feto Maternal & GenetYX Center Dubai, UAE.
Dr Afshin Pour Mirza
Specialist Obstetrics and Gynecology, Fetal Medicine, Feto Maternal & GenetYX Center Dubai, UAE.
Turner syndrome: Article abstract
Turner syndrome is a disorder with a great genotypic and phenotypic variability. Prenatally, the spectrum of the disease varies from a complete normal appearing fetus to a fetus with severe hydrops, with a high-risk of fetal demise, mainly before 28 weeks. After birth, again, the phenotype can be highly abnormal, with typical stigmas including short stature; webbed neck; lymphedema of the hands and feet; skeletal anomalies; delayed or absent pubertal development and infertility. Fetuses that appear normal at birth may be diagnosed in childhood for impaired growth, or during adolescence or early adulthood for delayed or absent pubertal development, infertility or POI.
The correlation between phenotype and genotype is hard to predict, even less in prenatal life, where prognosis is mostly linked with the presence or absence of sonographic anomalies and the reasons or indication for testing. Testing for SCA (sex chromosome anomalies), should always be accompanied by a qualified and non-directive genetic counselling, in order to try to decrease interruption of pregnancy for incomplete or false information about the disorder and the limitations of testing, including the low PPV.1
On the other hand, late diagnosis is also a major problem. Only one fifth is diagnosed prenatally or in the neonatal period. Another fifth is diagnosed in childhood, mainly for short stature. Over 50% are diagnosed in puberty or young adulthood, when most therapeutic possibilities cannot be applied anymore.2 So far, detection of Turner syndrome is not included in prenatal screening program in most countries, but is diagnosed, because invasive testing is performed for ultrasound anomalies, or, because testing is done for other reasons. For many years, different providers offer testing for SCA, including Turner syndrome, by NIPT (non-invasive prenatal testing.3-4 To overcome the problem of late detection, new approaches include the idea to use new genetic testing methods for a newborn screening.5
Turner syndrome: Introduction
Turner syndrome is diagnosed in about 1:2500 newborn girls. It accounts for approximately 10 % of abortions in the first trimester. More than 99% of fetuses with Turner syndrome die in utero, mostly before 28 weeks. Only about 1 % of these girls are born alive.6-7
Turner syndrome is caused by the complete or partial loss of one sex chromosome. The karyotype 45,X is found in about 50% of cases. Mosaicism between 45,X, and other karyotypes like 46 XX, 47XXX, 46XY, or others can also be found, as can be structural anomalies of one X chromosome, including ring chromosomes, isochromosomes and deletions or rearrangement of the short arm. These structural anomalies, like 45,X, are due to meiotic errors and, also like 45,X, often cause a more severe phenotype than mosaic forms. The origin of the X chromosome (paternal or maternal) also seems to cause phenotypic variations.8-9 In 60-80%, paternal non-disjunction is responsible. Maternal age, in contrast to Down syndrome, does not play a major role in the origination of Turner syndrome.
If detection of Turner syndrome is included in a general first trimester screening, overall detection rate is about 42%.10 Findings that are suggestive are a markedly increased nuchal translucency and lower PAPP-A. Nuchal translucency is markedly higher than in fetuses with Down syndrome, and also higher in 45,X than mosaic forms.10
A special challenge is prenatal diagnosis of a mosaic 45,X/46,XY. Prevalence is between 0,7-2,8/10000 amniocentesis. In 90%, this leads to the birth of a phenotypically normal male. 10% of affected fetuses have anomalies of penis and scrotum, or show a female phenotype with stigmata of Turner syndrome. Follow-up studies for longtime development, including fertility and development of germ cell tumors are very limited.11-12
NIPT: Noninvasive prenatal testing is using cell free “fetal” DNA, circulating in maternal blood. The phrase “fetal DNA” is a “misnomer, as the DNA is not directly derived from the fetus, but from apoptotic cell material of the placenta. For detection of trisomy 21, this approach gives excellent results, with detection rates of 99,7 %, and an FPR of 0,04%.13 Certain features of Turner syndrome limit the accuracy of the test and have to be announced with the patient or the couple before testing. The DR is 95,8% for an FPR of 0,14 %,13 but the the positive predictive value (PPV) is as low as 9 % in some studies14 and much lower as, for example, for Down syndrome. In general, it is less in fetuses without sonographic anomalies than in those with typical ultrasound findings. The false negative rate (FNR) is 70% for mosaic karyotypes without sonographic anomalies.15 Different reasons can account for this limited performance, for example: mosaicism of the fetus and/or the placenta, the presence of a vanishing twin, an altered maternal karyotype or a malignant tumor in the mother. Chromosomal mosaicism is found in about 1-2% of trophoblasts. Turner syndrome has the highest association with mosaicism. There can be confined placenta mosaicism (CPM), or true fetal mosaicism (TFM) (16). TFM that is not affecting the placenta will lead to a false negative result, in contrast, CPM will give a false positive result.
About 0,25% of phenotypically normal females have an altered karyotype, for example mosaic 45,X, or XXX. Also, there is a loss of the second X chromosome with increasing maternal age (16). At the age of 40 years, about 2,5 % of lymphocytes have lost one X chromosome. cffDNA disappears quickly after birth with a half-life of about 16 min. In the case of a vanishing twin, fetal DNA can be detected up to 16 weeks or more after demise.18-20 All these factors limit the performance of NIPT of Turner syndrome. There are hints, that SNP based NIPT could possibly eliminate or reduce the effect of abnormal maternal karyotype and the effect of a vanishing twin.21
Taking into account all these factors, and also the difficulty to predict the phenotype, the use of NIPT as a screening tool for Turner syndrome should be discouraged. If testing is considered, it should always be done after a detailed counselling and always in combination with a detailed ultrasound. The provider should always consider the psychical stress, that an abnormal result can cause in the parents, often leading to unnecessary invasive testing, consideration of termination of pregnancy and difficulties to recompose afterwards.
Certain anomalies rise the suspicion of Turner syndrome. That may be significant increased nuchal translucency, cystic hygroma, non-immune fetal hydrops, cardiac anomalies, mostly compromising the left outflow tract (CoA, HLHS, bicuspid aortic valve), renal anomalies, pleural effusions, brachycephaly and IUGR.22 Again, also a sonografically normal looking fetus can be affected by Turner syndrome.
Fetus with increased NT
Fetus with bilateral pleural effusions
Invasive testing: Prenatal confirmation of the diagnosis of Turner syndrome can be done either by CVS in early pregnancy, or later, by amniocentesis. Again, one has to consider limitations of chorionic villi, as there is a possibility of CPM. The results of short-term culture correlate with the trophoblast (outer layer of the placenta) and is mostly corresponding to the NIPT result, whereas the result of the long-term culture reflects the mesenchymal core of the placenta and thereby more the fetus itself. In doubt, or in cases with normal ultrasound, amniocentesis should be preferred to CVS.
Prognosis of a prenatally diagnosed Turner syndrome is strongly depended of the circumstances and indications for testing. If invasive testing was performed because of an abnormal ultrasound finding, diagnosis of Turner syndrome is associated with a severe manifestation and high risk of fetal demise. In contrast, fetuses with a diagnosis “by chance”, where the invasive testing was done for other reasons, like, for example, maternal age, have often few or no anomalies at birth.8 All prenatally diagnosed Turner syndromes must be confirmed after birth.23
- Jeon KC, Chen L-S. Decision to abort after a prenatal diagnosis of sex chromosome abnormality: a systematic review of the literature. Genet Med 2012:14(1):27-38)
2. Sävendahl L, Davenport ML. Delayed diagnosis of Turner´s syndrome: proposed guidelines for change. J Pediatr. 2000;137(4):455-459).
3. Dondorp W, de Wert G, Bombard Y, et al. Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. Eur J Hum Genet. 2015;23:1438-1450.
4. Schmid M, Klaritsch P, Arzt W, Burkhardt T, Duba H, Häusler M, et al. Cell-free DNA testing for fetal chromosomal anomalies in clinical practice: Austrian-German-Swiss recommendations for non-invasive prenatal tests (NIPT). Ultraschall Med – Eur J Ultrasound 2015;36:507–10).
5. Murdock DR, Donovan FX, Chandrasekharappa SC, Banks N, Bondy C, Muenke M, et al. Whole-exome Sequencing for Diagnosis of Turner syndrome: Towards Next Generation Sequencing and Newborn Screening. J Clin Endocrinol Metab. 2017
6. Hook EB, Warburton D. The distribution of chromosomal genotypes associated with Turner´s syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism. Hum Genet. 1983;64:24-7
7. Alpman A, Cogulu O, Akgul M, Arikan EA, Durmaz B, Karaca E, Sadol S, Ozkinay C, Ozkinay F 2009 Prenatally diagnosed Turner syndrome and cystic hygroma: incidence and reasons for referrals. Fetal Diagn Ther 25:58-61)
8. Bondy C. Recent Developments in Diagnosis and Care for girls with Turner syndrome. Advances in Endocrinology Volume 2014, Article ID 231089.
9. Ibarra-Ramirez M, Martinez-de-Villareal LE. Clinical and genetic aspects of Turner´s syndrome. Medicina Universitaria. 2016;18(70):42-48).
10. Viuff MH, Stochholm K, Uldbjerg N, Nielsen BB, the Danish Fetal Medicine Study Group, and Gravholt CH. Only a minority of sex chromosome abnormalities are detected by a national prenatal sceening program for Down syndrome.Human Reproduction, Vol.30, No 10pp.2419-2426,2015).
11. Sybert VP, McCauley E. Turner´s Syndrome N Engl J Med 2004; 351:1227-1238,
12. Chang HJ, Clark RD, Bachman H. The Phenotype of 45,X/46,XY Mosaicism: An Analysis of 92 Prenatally Diagnosed Cases. Am. J. Genet. 46:156-167, 1990).
13. Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol 2017; 50:302-314).
14. Reiss RE, Discenza M, Foster J, Dobson L, Wilkins-Haug L. Sex chromosome aneuploidy detection by noninvasive prenatal testing: helpful or hazardous? Prenatal Diagnosis 2017, 37; 515-520
15. Grati FR, Bajaj K, Zanalfa V, Malvestiti F, Malvestiti B, Marcato L. Implications of fetoplacental mosaicism on cell-free DNA testing for sex chromosome aneuploidies. Prenatal Diagnosis 2017. 37. 1017-1027).
16. Malvestiti F, Agrati C, Grimi B, et al. Interpreting mosaicism in chorionic vili: results of a monocentric series of 1001 mosaics in chorionic villi with follow-up amniocentesis. Prenatal Diagnosis 2015, 35, 1117-1127)
17. Russell LM, Strike P, Browne CE, Jacobs PA. X Chromosome loss and aging. Cytogenet Genome Res 116:181-185(2007).
18. Zhang B, Lu B-Y, Zheng F-X, Zhou Q, Cheng Y-P, Zhang X-Q. Noninvasive prenatal screening for fetal common sex chromosome aneuploidies from maternal blood. J Med Res. 2017 Apr; 45(2): 621-630.
19. Bevilacqua E, Ordonez E, Hurtado I, Rueda L, Mazzone E, Cirigliano V, Jani JC. Screening for Sex Chromosome Aneuploidy by Cell-Free DNA Testing: Patient Choice and Performance. Fetal Diagn Ther DOI: 10.1159/000479507.
20. Chitty LS, Hudgins L, Norton ME. Current controversies in prenatal diagnosis 2: Cell-free DNA prenatal screening should be used to identify all chromosome abnormalities. Prenatal Diagnosis. 2018;38:160-165)
21. Samango-Sprouse C, Banjevic M, Ryan A, Sigurjonsson S, Zimmermann B, Hill M, Hall MP, Westmeyer M, Saucier J, Demko Z, Rabinowitz M. SNP-based non-invasive prenatal testing detects sex chromosome aneuploidies with high accuracy. Prenat Diagn. 2013 July; 33(7): 643-649.
22. Bronstein M, Zimmer EZ & Blazer S. A characteristic cluster of fetal sonographic markers that are predictive of fetal Turner syndrome in early pregnancy. American Journal of Obstetrics and Gynecology 2003 188 1016-1020.
23. Gravholt CH et al. Clinical practice guideline for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner syndrome Meeting. European Journal of Endocrinology 2017;177:3 G1-G70).