With increasing use of prenatal screening, sex chromosome aneuploidies (SCAs) are more frequently detected. Individuals with SCAs have variable physical and medical findings, and developmental and behavioural outcomes.
Objective
This retrospective study describes the growth, development and clinical features of individuals with SCAs seen at the Genetics clinic in KK Women’s and Children’s Hospital, Singapore, between January 2011 and July 2014.
Results
Forty-seven patients were included in this study, comprising six groups: 47, XXY (Klinefelter syndrome); 47, XXY/46, XY; 47, XYY; 47, XYY/46, XY; 47, XXX; and other rare SCAs. The majority (39 patients, 82.9%) were detected prenatally. A developmental assessment was available for 44/47 (93.6%). Of these, 28 (63.6%) were delayed in at least one domain, though the delay was mild in the majority (17 patients) with improvement documented on follow-up. Among eight individuals diagnosed postnatally, global developmental delay was reported in 4 (50%), compared to none among those diagnosed prenatally. Growth appeared unaffected in most, with 11.9% (5 patients) having tall stature.
Conclusions
While 63.6% of our patients had developmental delay in at least one domain, commonly affecting speech and language, the delay was mild in the majority. No prenatally diagnosed patient had global developmental delay. This information is valuable in genetic counselling, especially prenatally. (201 words).
PienkowskiCCartaultACaula-LegrielS, et al.Klinefelter's syndrome and Turner’s syndrome. For a better management. Gynecol Obstet Fertil2011; 39(9): 521–524. https://doi.org/10.1016/j.gyobfe.2011.07.009
4.
CuiXCuiYShiL, et al.J. A basic understanding of Turner syndrome: incidence, complications, diagnosis, and treatment. Intractable Rare Dis Res2018; 7(4): 223–228. https://doi.org/10.5582/irdr.2017.01056
5.
BruiningHSwaabHKasM, et al.Psychiatric characteristics in a self-selected sample of boys with Klinefelter syndrome. Pediatrics2009; 123(5): e865–e870. https://doi.org/10.1542/peds.2008-1954
6.
WattendorfDJMuenkeM. Klinefelter syndrome. Am Fam Physician2005; 72(11): 2259–2262.
7.
SimpsonJLde la CruzFSwerdloffRS, et al.Klinefelter syndrome: expanding the phenotype and identifying new research directions. Genet Med2003; 5(6): 460–468. https://doi.org/10.1097/01.gim.0000095626.54201.d0
8.
SpazianiMGranatoSLiberatiN, et al.From mini-puberty to pre-puberty: early impairment of the hypothalamus–pituitary–gonadal axis with normal testicular function in children with non-mosaic Klinefelter syndrome. J Endocrinol Investig2021; 44(1): 127–138. https://doi.org/10.1007/s40618-020-01281-x
9.
PacenzaNPasqualiniTGottliebS, et al.Clinical presentation of klinefelter’s syndrome: differences according to age. Internet J Endocrinol2012; 2012: 324835. https://doi.org/10.1155/2012/324835
10.
RossJLTartagliaNMerryDE, et al.Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features. Gene Brain Behav2015; 14(2): 137–144. https://doi.org/10.1111/gbb.12200
11.
BerglundAStochholmKGravholtCH. Morbidity in 47,XYY syndrome: a nationwide epidemiological study of hospital diagnoses and medication use. Genet Med2020; 22: 1542–1551. https://doi.org/10.1038/s41436-020-0837-y
VisootsakJGrahamJM. Social function in multiple X and Y chromsome disorders: XYY, XYY, XXYY, XXXY. Dev Sisabil Res Rev2009; 15(4): 328–332. https://doi.org/10.1002/ddrr.76
14.
GropmanALPorterGFLasutschinkowPC, et al.Neurocognitive development and capabilities in boys with 49,XXXXY syndrome. Am J Med Genet2021; 185(12): 3541–3546. https://doi.org/10.1002/ajmg.a.61736
15.
TartagliaNRAyariNHutaff-LeeC, et al.Attention-deficit hyperactivity disorder symptoms in children and adolescents with sex chromosome aneuploidy: XXY, XXX, XYY, and XXYY. J Dev Behav Pediatr2012; 33(4): 309–318. https://doi.org/10.1097/DBP.0b013e31824501c8
16.
BojesenAJuulSGravholtCH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab2003; 88(2): 622–626. https://doi.org/10.1210/jc.2002-021491
17.
DavisSMTeerlinkCCLynchJA, et al.An extra X chromosome among adult women in the million veteran program: a more benign perspective of trisomy X. Am J Med Genet C Semin Med Genet2024; 5: e32083. https://doi.org/10.1002/ajmg.c.32083
18.
TubmanAPapadakisJLFinlaysonC, et al.Finding acceptance: how adolescents and young adults with Klinefelter syndrome navigate identity, disclosure, and support. J Genet Counsel2025; 34(3): e70074. https://doi.org/10.1002/jgc4.70074
19.
NielsenJWohlertM. Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in arhus, Denmark. Hum Genet1991; 87(1): 81–83. https://doi.org/10.1007/BF01213097
20.
Samango-SprouseCKirkizlarEHallMP, et al.Incidence of X and Y chromosomal aneuploidy in a large child bearing population. PLoS One2016; 11(8): e0161045. https://doi.org/10.1371/journal.pone.0161045
21.
TartagliaNDavisSHowellS, et al.Medical findings in infants prenatally identified with sex chromosome trisomy in year one of life. medRxiv Update in: Pediatrics2025; 156(4): e2024068133. https://doi.org/10.1542/peds.2024-068133
22.
HowellSDavisSMThompsonT, et al.Noninvasive prenatal screening (NIPS) results for participants of the eXtraordinarY babies study: screening, counseling, diagnosis, and discordance. J Genet Counsel2023; 32(1): 250–259. https://doi.org/10.1002/jgc4.1639
23.
PietersJJKooperAJvan KesselAG, et al.Incidental prenatal diagnosis of sex chromosome aneuploidies: health, behavior, and fertility. ISRN Obstet Gynecol2011; 2011: 807106. https://doi.org/10.5402/2011/807106
24.
SimpsonNHAddisLBrandlerWM, et al.Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia. Dev Med Child Neurol2014; 56(4): 346–353. https://doi.org/10.1111/dmcn.12294
25.
PrintzlauFWolstencroftJSkuseDH. Cognitive, behavioral, and neural consequences of sex chromosome aneuploidy. J Neurosci Res2017; 95(1-2): 311–319. https://doi.org/10.1002/jnr.23951
26.
LeeNRWallaceGLAdeyemiEI, et al.Dosage effects of X and Y chromosomes on language and social functioning in children with supernumerary sex chromosome aneuploidies: implications for idiopathic language impairment and autism spectrum disorders. JCPP (J Child Psychol Psychiatry)2012; 53(10): 1072–1081. https://doi.org/10.1111/j.1469-7610.2012.02573.x
27.
LenrootRKLeeNRGieddJN. Effects of sex chromosome aneuploidies on brain development: evidence from neuroimaging studies. Dev Disabil Res Rev2009; 15(4): 318–327. https://doi.org/10.1002/ddrr.86
28.
TukeMARuthKSWoodAR, et al.Mosaic Turner syndrome shows reduced penetrance in an adult population study. Genet Med2019; 21(4): 877–886. https://doi.org/10.1038/s41436-018-0271-6
29.
Le GallJNizonMPichonO, et al.Sex chromosome aneuploidies and copy-number variants: a further explanation for neurodevelopmental prognosis variability?Eur J Hum Genet2017; 25(8): 930–934. https://doi.org/10.1038/ejhg.2017.93
30.
OttesenAMAksglaedeLGarnI, et al.Increased number of sex chromosomes affects height in a nonlinear fashion: a study of 305 patients with sex chromosome aneuploidy. Am J Med Genet2010; 152A(5): 1206–1212. https://doi.org/10.1002/ajmg.a.33334
31.
TallaksenHBLJohannsenEBJustJ, et al.The multi-omic landscape of sex chromosome abnormalities: current status and future directions. Endocr Connect2023; 12(9): e230011. https://doi.org/10.1530/EC-23-0011
