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Cited by 78Prenatal Screening and DiagnosticsGenetic and Clinical Aspects of Sex Determination and Chromosomal AbnormalitiesDown syndrome and intellectual disability research

Only a minority of sex chromosome abnormalities are detected by a national prenatal screening program for Down syndrome

Viuff, Mette Hansen, Stochholm, Kirstine, Uldbjerg, Niels, Nielsen, Birgitte Bruun, the Danish Fetal Medicine Study Group, Gravholt, Claus Højbjerg·2015·Human Reproduction
DOI 10.1093/humrep/dev192
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Abstract

STUDY QUESTION: How does a national prenatal screening program for Down syndrome (DS) perform in detecting sex chromosome abnormalities (SCAs)-Turner syndrome (TS), Klinefelter syndrome, 47,XXX and 47,XYY syndromes. SUMMARY ANSWER: The SCA detection rate resulting from DS screening was below 50% for all four groups of SCAs. WHAT IS KNOWN ALREADY: The detection rates of SCAs are higher in countries with DS screening. TS is associated with greater nuchal translucency (NT) and lower pregnancy-associated plasma protein-A (PAPP-A). However, specific detection rates of SCAs using prenatal DS screening have not been determined. No clear trend in PAPP-A, free beta human chorionic gonadotropin (β-hCG) and NT has been found in the remaining SCAs. Several lines of inquiry suggest that it would be advantageous for individuals with SCA to be detected early in life, leading to prevention or treatment of accompanying conditions. There is limited information about pre- and perinatal status that distinguishes SCA embryogenesis from normal fetal development. STUDY DESIGN, SIZE, DURATION: A register-based case-control study from the Danish Central Cytogenetic Register (DCCR), cross-linked with the Danish Fetal Medicine Database (DFMD), was performed from 2008 to 2012. Groups of SCAs were compared with DS and then matched with non-SCA controls to assess differences between these groups in prenatal markers and birth outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included cases with prenatal and post-natal SCA karyotypes (n = 213), DS (n = 802) and 168 056 controls. We screened 275 037 individuals examined prenatally. We retrieved information regarding maternal age, NT, β-hCG and PAPP-A, as well as details regarding maternal and newborn characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: The DS screening procedure detected 87 per 100 000 TS (42% of expected), 19 per 100 000 Klinefelter syndrome (13% of expected), 16 per 100 000 47,XXX (16% of cases) and 5 per 100 000 47,XYY (5% of expected) SCAs, with an overall detection rate of 27%. Compared with controls, all four SCA groups showed significantly higher NT and lower PAPP-A compared with controls (all P < 0.01) and similar to DS. The legal abortion rate was high for all four syndromes (47,XXX: 24%; 47,XYY: 29%; Klinefelter syndrome: 48%, TS: 84%). For SCA fetuses carried to term, only TS fetuses had consistently lower birthweights and placenta weights than non-SCA controls (both P = 0.0001). A few SCA cases localized in DCCR could not be found in DFMD (n = 16). LIMITATIONS, REASON FOR CAUTION: Controls were matched on sex of the fetus of cases, meaning that all electively aborted fetuses (before week 12) were excluded, possibly reducing the diversity in the control group. We were not able to localize all diagnosed cases of SCA and DS in DFMD. Although these cases were present in DCCR, we were not able to account for the discrepancy. In addition, we suspect that several SCA children have not been diagnosed yet and future post-natal diagnosis of these cases would reduce the diagnostic yield reported here even further. WIDER IMPLICATIONS OF THE FINDINGS: The prenatal detection rate is below 50% for all SCAs. The approach used for detecting DS cannot be extended to also include SCAs. In addition, all SCAs have low PAPP-A and increased NT, thus probably reflecting an abnormal embryogenesis. Growth retardation of TS fetuses is if anything more pronounced than previously reported, both when evaluating fetus and placenta. STUDY FUNDING/COMPETING INTERESTS: This study received support from Aarhus University and the Novo Nordisk Foundation. The authors have no competing interests that may be relevant to the study.

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Crossref · 10.1093/humrep/dev192

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  • Abnormal results in prenatal serum screening may suggest TS, but these tests may be normal together with normal nuchal translucency thickness.

    “Abnormal results in prenatal serum screening (PAPP-A as part of combined first trimester screening, triple or quadruple test) even though not specifically intended to screen for TS, may also suggest this condition.59,60 However, these tests may be normal together with normal nuchal translucency thickness.59”

    From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [59]

  • Up to 42% of TS fetuses are being detected prenatally by first trimester screening.

    “Up to 42% of TS fetuses are being detected prenatally by first trimester screening.59”

    From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [59]

  • In countries where termination of pregnancy is allowed, rates of termination of pregnancy following prenatal diagnosis of TS vary between 15.4% and 100%.

    “In countries where termination of pregnancy is allowed, rates of termination of pregnancy following prenatal diagnosis of TS vary between 15.4% and 100%.59,81,82”

    From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [59]

  • Growth failure in TS begins early, often in utero, characterized by mild intrauterine growth restriction and lower placental weight.

    “Growth failure in TS begins early, often in utero, characterized by mild intrauterine growth restriction,137 and with lower placental weight,59”

    From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [59]

  • Average birth weight is ~300-1000 grams below mean and length 1-2 cm below mean for healthy infants of similar gestational age and country of birth.

    “resulting in average birth weight ∼300-1000 grams and length 1-2 cm below mean values for healthy infants of similar gestational age and country of birth.59,138,139”

    From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [59]

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Authors
Viuff, M. H., Stochholm, K., Uldbjerg, N., Nielsen, B. B., the Danish Fetal Medicine Study Group, & Gravholt, C. H.
Affiliations
Aarhus University Hospital (DK)
Corresponding author
Gravholt, Claus Højbjerg
ORCID
Venue
Human Reproduction
Publisher
Oxford University Press (OUP)
Published
2015-08-06
Volume
30
Issue
10
Pages
2419-2426
ISSN
  • 0268-1161 (ISSN-L)
  • 1460-2350
DOI
10.1093/humrep/dev192
OpenAlex
W1613419203
Cited by
78
References
42
Citations by year
2026: 2 · 2025: 12 · 2024: 6 · 2023: 14 · 2022: 7 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 6 · 2017: 3 · 2016: 4 · 2015: 2
FWCI
4.99
Type
journal article
Language
en
Open access
closed
Locations
  • Human Reproduction (publishedVersion)
  • PubMed (publishedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
Funders
  • Department of Clinical Medicine, Aarhus University Hospital
  • Novo Nordisk Foundation
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Screening and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Keywords
sex chromosome abnormalities, Down syndrome screening, Turner syndrome, Klinefelter syndrome, 47,XXX syndrome, 47,XYY syndrome, nuchal translucency, PAPP-A, free beta-hCG, birth outcomes, sex chromosome aneuploidy
MeSH terms
Denmark, Down Syndrome, Female, Gestational Age, Humans, Karyotyping, Klinefelter Syndrome, Male, Mass Screening, Maternal Age, Pregnancy, Pregnancy-Associated Plasma Protein-A, Prenatal Diagnosis, Registries, Sex Chromosome Aberrations, Sex Chromosomes, Trisomy, Turner Syndrome, XYY Karyotype, Case-Control Studies, Chorionic Gonadotropin, beta Subunit, Human, Sex Chromosome Disorders, Chromosomes, Human, X, Nuchal Translucency Measurement, Young Adult, Sex Chromosome Disorders of Sex Development

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