title: Only a minority of sex chromosome abnormalities are detected by a national prenatal screening program for Down syndrome.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  The SCA detection rate resulting from DS screening was below 50% for all four groups of SCAs.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mette Hansen
authors.initials: MH
authors.lastname: Viuff
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Stochholm
authors.affiliation: Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Uldbjerg
authors.affiliation: Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Birgitte Bruun
authors.initials: BB
authors.lastname: Nielsen
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark ch.gravholt@dadlnet.dk.
authors.forename: Claus Højbjerg
authors.initials: CH
authors.lastname: Gravholt
mesh_terms: D016022:Case-Control Studies; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000097:blood; D041321:Chromosomes, Human, X / Q000235:genetics; D003718:Denmark; D004314:Down Syndrome / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D005865:Gestational Age; D006801:Humans; D007621:Karyotyping; D007713:Klinefelter Syndrome / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008403:Mass Screening; D008423:Maternal Age; D048208:Nuchal Translucency Measurement; D011247:Pregnancy; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism; D011296:Prenatal Diagnosis; D012042:Registries; D012729:Sex Chromosome Aberrations; D025064:Sex Chromosome Disorders / Q000175:diagnosis* / Q000235:genetics; D058533:Sex Chromosome Disorders of Sex Development / Q000175:diagnosis* / Q000235:genetics; D012730:Sex Chromosomes / Q000235:genetics*; D014314:Trisomy / Q000175:diagnosis* / Q000235:genetics; D014424:Turner Syndrome / Q000175:diagnosis* / Q000235:genetics; D014997:XYY Karyotype / Q000175:diagnosis* / Q000235:genetics; D055815:Young Adult
chemical_list: D018997:Chorionic Gonadotropin, beta Subunit, Human; D011266:Pregnancy-Associated Plasma Protein-A
keywords: chromosomal abnormalities; embryology; epidemiology; pregnancy termination; sex chromosomes