Neuropsychopharmacology Reviews | Published:

Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies

Neuropsychopharmacologyvolume 44pages921 (2019) | Download Citation


The study of sexual dimorphism in psychiatric and neurodevelopmental disorders is challenging due to the complex interplay of diverse biological, psychological, and social factors. Males are more susceptible to neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and attention-deficit activity disorder. Conversely, after puberty, females are more prone to major depressive disorder and anxiety disorders compared to males. One major biological factor contributing to sex differences is the sex chromosomes. First, the X and Y chromosomes have unique and specific genetic effects as well as downstream gonadal effects. Second, males have one X chromosome and one Y chromosome, while females have two X chromosomes. Thus, sex chromosome constitution also differs between the sexes. Due to this complexity, determining genetic and downstream biological influences on sexual dimorphism in humans is challenging. Sex chromosome aneuploidies, such as Turner syndrome (X0) and Klinefelter syndrome (XXY), are common genetic conditions in humans. The study of individuals with sex chromosome aneuploidies provides a promising framework for studying sexual dimorphism in neurodevelopmental and psychiatric disorders. Here we will review and contrast four syndromes caused by variation in the number of sex chromosomes: Turner syndrome, Klinefelter syndrome, XYY syndrome, and XXX syndrome. Overall we describe an increased rate of attention-deficit hyperactivity disorder and autism spectrum disorder, along with the increased rates of major depressive disorder and anxiety disorders in one or more of these conditions. In addition to contributing unique insights about sexual dimorphism in neuropsychiatric disorders, awareness of the increased risk of neurodevelopmental and psychiatric disorders in sex chromosome aneuploidies can inform appropriate management of these common genetic disorders.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Riecher-Rossler A. Sex and gender differences in mental disorders. Lancet Psychiatry. 2017;4:8–9.

  2. 2.

    Rutter M, Caspi A, Moffitt TE. Using sex differences in psychopathology to study causal mechanisms: unifying issues and research strategies. J Child Psychol Psychiatry. 2003;44:1092–115.

  3. 3.

    Gobinath AR, Choleris E, Galea LA. Sex, hormones, and genotype interact to influence psychiatric disease, treatment, and behavioral research. J Neurosci Res. 2017;95:50–64.

  4. 4.

    Mandy W, Chilvers R, Chowdhury U, Salter G, Seigal A, Skuse D. Sex differences in autism spectrum disorder: evidence from a large sample of children and adolescents. J Autism Dev Disord. 2012;42:1304–13.

  5. 5.

    Rucklidge JJ. Gender differences in attention-deficit/hyperactivity disorder. Psychiatr Clin N Am. 2010;33:357–73.

  6. 6.

    Werling DM, Geschwind DH. Sex differences in autism spectrum disorders. Curr Opin Neurol. 2013;26:146–53.

  7. 7.

    Biederman J, Mick E, Faraone SV, Braaten E, Doyle A, Spencer T, et al. Influence of gender on attention-deficit hyperactivity disorder in children referred to a psychiatric clinic. Am J Psychiatry. 2002;159:36–42.

  8. 8.

    Arnett AB, Pennington BF, Willcutt EG, DeFries JC, Olson RK. Sex differences in ADHD symptom severity. J Child Psychol Psychiatry. 2015;56:632–9.

  9. 9.

    McLean CP, Asnaani A, Litz BT, Hofmann SG. Gender differences in anxiety disorders: prevalence, course of illness, comorbidity and burden of illness. J Psychiatr Res. 2011;45:1027–35.

  10. 10.

    Nolen-Hoeksema S. Sex differences in unipolar depression: evidence and theory. Psychol Bull. 1987;101:259–82.

  11. 11.

    Patten SB. Accumulation of major depressive episodes over time in a prospective study indicates that retrospectively assessed lifetime prevalence estimates are too low. BMC Psychiatry. 2009;9:19.

  12. 12.

    Angst J, Gamma A, Gastpar M, Lepine JP, Mendlewicz J, Tylee A, et al. Gender differences in depression. Epidemiological findings from the European DEPRES I and II studies. Eur Arch Psychiatry Clin Neurosci. 2002;252:201–9.

  13. 13.

    Kessler RC, McGonagle KA, Nelson CB, Hughes M, Swartz M, Blazer DG. Sex and depression in the National Comorbidity Survey. II: Cohort effects. J Affect Disord. 1994;30:15–26.

  14. 14.

    Bekker MH, van Mens-Verhulst J. Anxiety disorders: sex differences in prevalence, degree, and background, but gender-neutral treatment. Gend Med. 2007;4 Suppl B:S178–193.

  15. 15.

    Breslau N, Schultz L, Peterson E. Sex differences in depression: a role for preexisting anxiety. Psychiatry Res. 1995;58:1–12.

  16. 16.

    Bangasser DA, Valentino RJ. Sex differences in stress-related psychiatric disorders: neurobiological perspectives. Front Neuroendocrinol. 2014;35:303–19.

  17. 17.

    Solomon MB, Herman JP. Sex differences in psychopathology: of gonads, adrenals and mental illness. Physiol Behav. 2009;97:250–8.

  18. 18.

    Altemus M. Sex differences in depression and anxiety disorders: potential biological determinants. Horm Behav. 2006;50:534–8.

  19. 19.

    Cahill L. Equal not equal the same: sex differences in the human brain. Cerebrum. 2014;2014:5.

  20. 20.

    Cahill L. Fundamental sex difference in human brain architecture. Proc Natl Acad Sci USA. 2014;111:577–8.

  21. 21.

    de Vries GJ, Forger NG. Sex differences in the brain: a whole body perspective. Biol Sex Differ. 2015;6:15.

  22. 22.

    De Vries GJ, Rissman EF, Simerly RB, Yang LY, Scordalakes EM, Auger CJ, et al. A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci. 2002;22:9005–14.

  23. 23.

    Ingalhalikar M, Smith A, Parker D, Satterthwaite TD, Elliott MA, Ruparel K, et al. Sex differences in the structural connectome of the human brain. Proc Natl Acad Sci USA. 2014;111:823–8.

  24. 24.

    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.

  25. 25.

    Green T, Naylor PE, Davies W. Attention-deficit hyperactivity disorder (ADHD) in phenotypically similar neurogenetic conditions: Turner syndrome and the RASopathies. J Neurodev Disord. 2017;9:25.

  26. 26.

    Fung LK, Reiss AL. Moving toward integrative, multidimensional research in modern psychiatry: lessons learned from fragile X syndrome. Biol Psychiatry. 2016;80:100–11.

  27. 27.

    Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L. A review of trisomy X (47,XXX). Orphanet J Rare Dis. 2010;5:8. A detailed review of the clinical phenotype in XXX syndrome.

  28. 28.

    Hong DS, Reiss AL. Cognitive and neurological aspects of sex chromosome aneuploidies. Lancet Neurol. 2014;13:306–18.

  29. 29.

    Hong DS, Reiss AL. Cognition and behavior in Turner syndrome: a brief review. Pediatr Endocrinol Rev. 2012;9 Suppl 2:710–2.

  30. 30.

    Printzlau F, Wolstencroft J, Skuse DH. Cognitive, behavioral, and neural consequences of sex chromosome aneuploidy. J Neurosci Res. 2017;95:311–9.

  31. 31.

    Savic I. Advances in research on the neurological and neuropsychiatric phenotype of Klinefelter syndrome. Curr Opin Neurol. 2012;25:138–43.

  32. 32.

    Boada R, Janusz J, Hutaff-Lee C, Tartaglia N. The cognitive phenotype in Klinefelter syndrome: a review of the literature including genetic and hormonal factors. Dev Disabil Res Rev. 2009;15:284–94.

  33. 33.

    Geschwind DH, Boone KB, Miller BL, Swerdloff RS. Neurobehavioral phenotype of Klinefelter syndrome. Ment Retard Dev Disabil Res Rev. 2000;6:107–16.

  34. 34.

    Hong D, Scaletta Kent J, Kesler S. Cognitive profile of Turner syndrome. Dev Disabil Res Rev. 2009;15:270–8.

  35. 35.

    Hutaff-Lee C, Cordeiro L, Tartaglia N. Cognitive and medical features of chromosomal aneuploidy. Handb Clin Neurol. 2013;111:273–9.

  36. 36.

    Leggett V, Jacobs P, Nation K, Scerif G, Bishop DV. Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review. Dev Med Child Neurol. 2010;52:119–29.

  37. 37.

    Raznahan A, Cutter W, Lalonde F, Robertson D, Daly E, Conway GS, et al. Cortical anatomy in human X monosomy. Neuroimage. 2010;49:2915–23.

  38. 38.

    Steinman K, Ross J, Lai S, Reiss A, Hoeft F. Structural and functional neuroimaging in Klinefelter (47,XXY) syndrome: a review of the literature and preliminary results from a functional magnetic resonance imaging study of language. Dev Disabil Res Rev. 2009;15:295–308.

  39. 39.

    Giedd JN, Clasen LS, Wallace GL, Lenroot RK, Lerch JP, Wells EM, et al. XXY (Klinefelter syndrome): a pediatric quantitative brain magnetic resonance imaging case–control study. Pediatrics. 2007;119:e232–40.

  40. 40.

    Lenroot RK, Lee NR, Giedd JN. Effects of sex chromosome aneuploidies on brain development: evidence from neuroimaging studies. Dev Disabil Res Rev. 2009;15:318–27.

  41. 41.

    Rovet J, Netley C, Bailey J, Keenan M, Stewart D. Intelligence and achievement in children with extra X aneuploidy: a longitudinal perspective. Am J Med Genet. 1995;60:356–63.

  42. 42.

    Rovet JF. The psychoeducational characteristics of children with Turner syndrome. J Learn Disabil. 1993;26:333–41.

  43. 43.

    Tartaglia N, Cordeiro L, Howell S, Wilson R, Janusz J. The spectrum of the behavioral phenotype in boys and adolescents 47,XXY (Klinefelter syndrome). Pediatr Endocrinol Rev. 2010;8 Suppl 1:151–9.

  44. 44.

    Visootsak J, Graham JM Jr. Social function in multiple X and Y chromosome disorders: XXY, XYY, XXYY, XXXY. Dev Disabil Res Rev. 2009;15:328–32.

  45. 45.

    Bishop DV, Jacobs PA, Lachlan K, Wellesley D, Barnicoat A, Boyd PA, et al. Autism, language and communication in children with sex chromosome trisomies. Arch Dis Child. 2011;96:954–9. This well-designed study compares autistic traits and language skills in individuals with KS, XXX syndrome, and XYY syndrome.

  46. 46.

    Bishop DV, Scerif G. Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin–neurexin hypothesis. Acta Paediatr. 2011;100:903–7.

  47. 47.

    Hong DS, Dunkin B, Reiss AL. Psychosocial functioning and social cognitive processing in girls with Turner syndrome. J Dev Behav Pediatr. 2011;32:512–20. A systematic study examining social cognition and function in a large group of young girls with TS.

  48. 48.

    Nielsen J, Wohlert M. Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Birth Defects Orig Artic Ser. 1990;26:209–23.

  49. 49.

    Herlihy AS, McLachlan RI. Screening for Klinefelter syndrome. Curr Opin Endocrinol Diabetes Obes. 2015;22:224–9.

  50. 50.

    Herlihy AS, Halliday JL, Cock ML, McLachlan RI. The prevalence and diagnosis rates of Klinefelter syndrome: an Australian comparison. Med J Aust. 2011;194:24–8.

  51. 51.

    Stochholm K, Juul S, Gravholt CH. Diagnosis and mortality in 47,XYY persons: a registry study. Orphanet J Rare Dis. 2010;5:15.

  52. 52.

    Otter M, Schrander-Stumpel CT, Curfs LM. Triple X syndrome: a review of the literature. Eur J Hum Genet. 2010;18:265–71.

  53. 53.

    Bellott DW, Hughes JF, Skaletsky H, Brown LG, Pyntikova T, Cho TJ, et al. Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators. Nature. 2014;508:494–9.

  54. 54.

    Migeon BR. Why females are mosaics, X-chromosome inactivation, and sex differences in disease. Gend Med. 2007;4:97–105.

  55. 55.

    Sharp A, Robinson D, Jacobs P. Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet. 2000;107:343–9.

  56. 56.

    Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005;434:400–4.

  57. 57.

    Berletch JB, Yang F, Xu J, Carrel L, Disteche CM. Genes that escape from X-inactivation. Hum Genet. 2011;130:237–45.

  58. 58.

    Rocca MS, Pecile V, Cleva L, Speltra E, Selice R, Di Mambro A, et al. The Klinefelter syndrome is associated with high recurrence of copy number variations on the X chromosome with a potential role in the clinical phenotype. Andrology. 2016;4:328–34.

  59. 59.

    Tuttelmann F, Gromoll J. Novel genetic aspects of Klinefelter’s syndrome. Mol Hum Reprod. 2010;16:386–95.

  60. 60.

    Migeon BR. X chromosome inactivation: theme and variations. Cytogenet Genome Res. 2002;99:8–16.

  61. 61.

    Modi DN, Sane S, Bhartiya D. Accelerated germ cell apoptosis in sex chromosome aneuploid fetal human gonads. Mol Hum Reprod. 2003;9:219–25.

  62. 62.

    Russell HF, Wallis D, Mazzocco MM, Moshang T, Zackai E, Zinn AR, et al. Increased prevalence of ADHD in Turner syndrome with no evidence of imprinting effects. J Pediatr Psychol. 2006;31:945–55.

  63. 63.

    Green T, Bade Shrestha S, Chromik LC, Rutledge K, Pennington BF, Hong DS, et al. Elucidating X chromosome influences on Attention Deficit Hyperactivity Disorder and executive function. J Psychiatr Res. 2015;68:217–25. This study establishes TS as a model for ADHD and elucidates similarities in behavioral profile between girls with TS and boys with ‘idiopathic ADHD’.

  64. 64.

    Green T, Saggar M, Ishak A, Hong DS, Reiss AL. X-chromosome effects on attention networks: insights from imaging resting-state networks in turner syndrome. Cereb Cortex. 2017;1–8.

  65. 65.

    Marco EJ, Skuse DH. Autism-lessons from the X chromosome. Soc Cogn Affect Neurosci. 2006;1:183–93.

  66. 66.

    Kilic BG, Ergur AT, Ocal G. Depression, levels of anxiety and self-concept in girls with Turner’s syndrome. J Pediatr Endocrinol Metab. 2005;18:1111–7.

  67. 67.

    Manning JT, Kilduff LP, Trivers R. Digit ratio (2D:4D) in Klinefelter’s syndrome. Andrology. 2013;1:94–9.

  68. 68.

    Ross JL, Samango-Sprouse C, Lahlou N, Kowal K, Elder FF, Zinn A. Early androgen deficiency in infants and young boys with 47,XXY Klinefelter syndrome. Horm Res. 2005;64:39–45.

  69. 69.

    Mandoki MW, Sumner GS, Hoffman RP, Riconda DL. A review of Klinefelter’s syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1991;30:167–72.

  70. 70.

    Tartaglia NR, Ayari N, Hutaff-Lee C, Boada R. Attention-deficit hyperactivity disorder symptoms in children and adolescents with sex chromosome aneuploidy: XXY, XXX, XYY, and XXYY. J Dev Behav Pediatr. 2012;33:309–18. This study systematically compares ADHD symptoms in KS, XXX syndrome, XYY syndrome, and XXYY syndrome.

  71. 71.

    Bruining H, Swaab H, Kas M, van Engeland H. Psychiatric characteristics in a self-selected sample of boys with Klinefelter syndrome. Pediatrics. 2009;123:e865–70.

  72. 72.

    Cederlof M, Ohlsson Gotby A, Larsson H, Serlachius E, Boman M, Langstrom N, et al. Klinefelter syndrome and risk of psychosis, autism and ADHD. J Psychiatr Res. 2014;48:128–30.

  73. 73.

    Bardsley MZ, Kowal K, Levy C, Gosek A, Ayari N, Tartaglia N, et al. 47, XYY syndrome: clinical phenotype and timing of ascertainment. J Pediatr. 2013;163:1085–94.

  74. 74.

    Ross JL, Tartaglia N, Merry DE, Dalva M, Zinn AR. Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features. Genes Brain Behav. 2015;14:137–44.

  75. 75.

    Ross JL, Zeger MP, Kushner H, Zinn AR, Roeltgen DP. An extra X or Y chromosome: contrasting the cognitive and motor phenotypes in childhood in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome. Dev Disabil Res Rev. 2009;15:309–17.

  76. 76.

    Cordeiro L, Tartaglia N, Roeltgen D, Ross J. Social deficits in male children and adolescents with sex chromosome aneuploidy: a comparison of XXY, XYY, and XXYY syndromes. Res Dev Disabil. 2012;33:1254–63.

  77. 77.

    Assaf M, Jagannathan K, Calhoun VD, Miller L, Stevens MC, Sahl R, et al. Abnormal functional connectivity of default mode sub-networks in autism spectrum disorder patients. Neuroimage. 2010;53:247–56.

  78. 78.

    Minshew NJ, Keller TA. The nature of brain dysfunction in autism: functional brain imaging studies. Curr Opin Neurol. 2010;23:124–30.

  79. 79.

    Bush G. Cingulate, frontal, and parietal cortical dysfunction in attention-deficit/hyperactivity disorder. Biol Psychiatry. 2011;69:1160–7.

  80. 80.

    Castellanos FX, Proal E. Large-scale brain systems in ADHD: beyond the prefrontal–striatal model. Trends Cogn Sci. 2012;16:17–26.

  81. 81.

    Cortese S, Kelly C, Chabernaud C, Proal E, Di Martino A, Milham MP, et al. Toward systems neuroscience of ADHD: a meta-analysis of 55 fMRI studies. Am J Psychiatry. 2012;169:1038–55.

  82. 82.

    Anagnostou E, Taylor MJ. Review of neuroimaging in autism spectrum disorders: what have we learned and where we go from here. Mol Autism. 2011;2:4.

  83. 83.

    Hong DS, Bray S, Haas BW, Hoeft F, Reiss AL. Aberrant neurocognitive processing of fear in young girls with Turner syndrome. Soc Cogn Affect Neurosci. 2014;9:255–64.

  84. 84.

    Hong DS, Hoeft F, Marzelli MJ, Lepage JF, Roeltgen D, Ross J, et al. Influence of the X-chromosome on neuroanatomy: evidence from Turner and Klinefelter syndromes. J Neurosci. 2014;34:3509–16.

  85. 85.

    Brandenburg-Goddard MN, van Rijn S, Rombouts SARB, Veer IM, Swaab H. A comparison of neural correlates underlying social cognition in Klinefelter syndrome and autism. Soc Cogn Affect Neurosci. 2014;9:1926–33.

  86. 86.

    Raznahan A, Lee NR, Greenstein D, Wallace GL, Blumenthal JD, Clasen LS, et al. Globally divergent but locally convergent X- and Y-chromosome influences on cortical development. Cereb Cortex. 2016;26:70–9. This well-designed study compares neural structure in diverse SCAs.

  87. 87.

    Lin A, Clasen L, Lee NR, Wallace GL, Lalonde F, Blumenthal J, et al. Mapping the stability of human brain asymmetry across five sex-chromosome aneuploidies. J Neurosci. 2015;35:140–5.

  88. 88.

    Raznahan A, Lue Y, Probst F, Greenstein D, Giedd J, Wang C, et al. Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies. Brain Struct Funct. 2015;220:3581–93. This study compares the effects of the sex-chromosomes and their downstream hormonal profiles on neurodevelopment in murine models of TS and KS, TD males, and TD females.

  89. 89.

    Raznahan A, Probst F, Palmert MR, Giedd JN, Lerch JP. High resolution whole brain imaging of anatomical variation in XO, XX, and XY mice. Neuroimage. 2013;83:962–8.

  90. 90.

    Lubs HA, Stevenson RE, Schwartz CE. Fragile X and X-linked intellectual disability: four decades of discovery. Am J Hum Genet. 2012;90:579–90.

  91. 91.

    Tzschach A, Grasshoff U, Beck-Woedl S, Dufke C, Bauer C, Kehrer M, et al. Next-generation sequencing in X-linked intellectual disability. Eur J Hum Genet. 2015;23:1513–8.

  92. 92.

    Caglayan AO. Genetic causes of syndromic and non-syndromic autism. Dev Med Child Neurol. 2010;52:130–8.

  93. 93.

    Chaste P, Leboyer M. Autism risk factors: genes, environment, and gene–environment interactions. Dialog Clin Neurosci. 2012;14:281–92.

  94. 94.

    Ross JL, Roeltgen DP, Stefanatos G, Benecke R, Zeger MP, Kushner H, et al. Cognitive and motor development during childhood in boys with Klinefelter syndrome. Am J Med Genet A. 2008;146A:708–19. One of the only studies to systematically assess ADHD symptoms in males with KS.

  95. 95.

    Boone KB, Swerdloff RS, Miller BL, Geschwind DH, Razani J, Lee A, et al. Neuropsychological profiles of adults with Klinefelter syndrome. J Int Neuropsychol Soc. 2001;7:446–56.

  96. 96.

    Geerts M, Steyaert J, Fryns JP. The XYY syndrome: a follow-up study on 38 boys. Genet Counsel. 2003;14:267–79.

  97. 97.

    Martinussen R, Hayden J, Hogg-Johnson S, Tannock R. A meta-analysis of working memory impairments in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2005;44:377–84.

  98. 98.

    DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E, Dager SR, Schmitz C, et al. The developmental neurobiology of autism spectrum disorder. J Neurosci. 2006;26:6897–906.

  99. 99.

    Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, et al. Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry. 2011;168:904–12.

  100. 100.

    Christensen DL, Baio J, Van Naarden Braun K, Bilder D, Charles J, Constantino JN, et al. Prevalence and characteristics of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2012. MMWR Surveill Summ. 2016;65:1–23.

  101. 101.

    Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65:591–8.

  102. 102.

    Tartaglia NR, Wilson R, Miller JS, Rafalko J, Cordeiro L, Davis S, et al. Autism spectrum disorder in males with sex chromosome aneuploidy: XXY/Klinefelter syndrome, XYY, and XXYY. J Dev Behav Pediatr. 2017;38:197–207. This study systematically compares ASD symptoms in KS, XYY syndrome, and XXYY syndrome.

  103. 103.

    Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68:1095–102.

  104. 104.

    Mandy W, Lai MC. Annual Research Review: the role of the environment in the developmental psychopathology of autism spectrum condition. J Child Psychol Psychiatry. 2016;57:271–92.

  105. 105.

    Ornoy A, Weinstein-Fudim L, Ergaz Z. Genetic syndromes, maternal diseases and antenatal factors associated with autism spectrum disorders (ASD). Front Neurosci. 2016;10:316.

  106. 106.

    McCauley E, Feuillan P, Kushner H, Ross JL. Psychosocial development in adolescents with Turner syndrome. J Dev Behav Pediatr. 2001;22:360–5.

  107. 107.

    McCauley E, Sybert VP, Ehrhardt AA. Psychosocial adjustment of adult women with Turner syndrome. Clin Genet. 1986;29:284–90.

  108. 108.

    Rovet J, Ireland L. Behavioral phenotype in children with Turner syndrome. J Pediatr Psychol. 1994;19:779–90.

  109. 109.

    Lagrou K, Froidecoeur C, Verlinde F, Craen M, De Schepper J, Francois I, et al. Psychosocial functioning, self-perception and body image and their auxologic correlates in growth hormone and oestrogen-treated young adult women with Turner syndrome. Horm Res. 2006;66:277–84.

  110. 110.

    Mazzola F, Seigal A, MacAskill A, Corden B, Lawrence K, Skuse DH. Eye tracking and fear recognition deficits in Turner syndrome. Soc Neurosci. 2006;1:259–69.

  111. 111.

    McCauley E, Kay T, Ito J, Treder R. The Turner syndrome: cognitive deficits, affective discrimination, and behavior problems. Child Dev. 1987;58:464–73.

  112. 112.

    Romans SM, Stefanatos G, Roeltgen DP, Kushner H, Ross JL. Transition to young adulthood in Ullrich–Turner syndrome: neurodevelopmental changes. Am J Med Genet. 1998;79:140–7.

  113. 113.

    Ross JL, Kushner H, Zinn AR. Discriminant analysis of the Ullrich–Turner syndrome neurocognitive profile. Am J Med Genet. 1997;72:275–80.

  114. 114.

    Elgar K, Campbell R, Skuse D. Are you looking at me? Accuracy in processing line-of-sight in Turner syndrome. Proc Biol Sci. 2002;269:2415–22.

  115. 115.

    Lepage JF, Hong DS, Raman M, Marzelli M, Roeltgen DP, Lai S, et al. Brain morphology in children with 47, XYY syndrome: a voxel- and surface-based morphometric study. Genes Brain Behav. 2014;13:127–34.

  116. 116.

    Ross JL, Roeltgen DP, Kushner H, Zinn AR, Reiss A, Bardsley MZ, et al. Behavioral and social phenotypes in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome. Pediatrics. 2012;129:769–78. A well-designed study comparing ASD, ADHD and other behavioral traits in KS and XYY syndrome.

  117. 117.

    Ratcliffe S. Long term outcome in children of sex chromosome abnormalities. Arch Dis Child. 1999;80:192–5.

  118. 118.

    Simm PJ, Zacharin MR. The psychosocial impact of Klinefelter syndrome—a 10 year review. J Pediatr Endocrinol Metab. 2006;19:499–505.

  119. 119.

    van Rijn S, Swaab H, Aleman A, Kahn RS. Social behavior and autism traits in a sex chromosomal disorder: Klinefelter (47XXY) syndrome. J Autism Dev Disord. 2008;38:1634–41.

  120. 120.

    Geschwind DH, Dykens E. Neurobehavioral and psychosocial issues in Klinefelter syndrome. Learn Disabil Res Pract. 2004;19:166–73.

  121. 121.

    van Rijn S, Aleman A, Swaab H, Krijn T, Vingerhoets G, Kahn R. What it is said versus how it is said: comprehension of affective prosody in men with Klinefelter (47,XXY) syndrome. J Int Neuropsychol Soc. 2007;13:1065–70.

  122. 122.

    van Rijn S, Barendse M, van Goozen S, Swaab H. Social attention, affective arousal and empathy in men with Klinefelter syndrome (47,XXY): evidence from eyetracking and skin conductance. PLoS ONE. 2014;9:e84721.

  123. 123.

    van Rijn S, Swaab H, Aleman A, Kahn RS. X chromosomal effects on social cognitive processing and emotion regulation: a study with Klinefelter men (47,XXY). Schizophr Res. 2006;84:194–203.

  124. 124.

    Otter M, Schrander-Stumpel CT, Didden R, Curfs LM. The psychiatric phenotype in triple X syndrome: new hypotheses illustrated in two cases. Dev Neurorehabil. 2012;15:233–8.

  125. 125.

    Lee NR, Wallace GL, Adeyemi EI, Lopez KC, Blumenthal JD, Clasen LS, 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. J Child Psychol Psychiatry. 2012;53:1072–81. This systematic study compares the effects of the Y chromosome and the effects of X-chromosome dose on social functioning in various supernumerary SCAs.

  126. 126.

    Wolraich ML, McKeown RE, Visser SN, Bard D, Cuffe S, Neas B, et al. The prevalence of ADHD: its diagnosis and treatment in four school districts across two states. J Atten Disord. 2014;18:563–75.

  127. 127.

    Barkley RA. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull. 1997;121:65–94.

  128. 128.

    Visser SN, Danielson ML, Bitsko RH, Holbrook JR, Kogan MD, Ghandour RM, et al. Trends in the parent-report of health care provider-diagnosed and medicated attention-deficit/hyperactivity disorder: United States, 2003–11. J Am Acad Child Adolesc Psychiatry. 2014;53:34–46 e32.

  129. 129.

    Willcutt EG. The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a meta-analytic review. Neurotherapeutics. 2012;9:490–9.

  130. 130.

    Biederman J, Faraone SV, Mick E, Williamson S, Wilens TE, Spencer TJ, et al. Clinical correlates of ADHD in females: findings from a large group of girls ascertained from pediatric and psychiatric referral sources. J Am Acad Child Adolesc Psychiatry. 1999;38:966–75.

  131. 131.

    Martel MM. Research review: a new perspective on attention-deficit/hyperactivity disorder: emotion dysregulation and trait models. J Child Psychol Psychiatry. 2009;50:1042–51.

  132. 132.

    Biederman J, Petty CR, Doyle AE, Spencer T, Henderson CS, Marion B, et al. Stability of executive function deficits in girls with ADHD: a prospective longitudinal follow up study into adolescence. Dev Neuropsychol. 2008;33:44–61.

  133. 133.

    Williams JK. Behavioral characteristics of children with Turner syndrome and children with learning disabilities. West J Nurs Res. 1994;16:26–35. discussion 35-29

  134. 134.

    Tamm L, Menon V, Reiss AL. Abnormal prefrontal cortex function during response inhibition in Turner syndrome: functional magnetic resonance imaging evidence. Biol Psychiatry. 2003;53:107–11.

  135. 135.

    Lepage JF, Dunkin B, Hong DS, Reiss AL. Impact of cognitive profile on social functioning in prepubescent females with Turner syndrome. Child Neuropsychol. 2013;19:161–72.

  136. 136.

    Temple CM, Sanfilippo PM. Executive skills in Klinefelter’s syndrome. Neuropsychologia. 2003;41:1547–59.

  137. 137.

    Kompus K, Westerhausen R, Nilsson LG, Hugdahl K, Jongstra S, Berglund A, et al. Deficits in inhibitory executive functions in Klinefelter (47, XXY) syndrome. Psychiatry Res. 2011;189:135–40.

  138. 138.

    Lee NR, Anand P, Will E, Adeyemi EI, Clasen LS, Blumenthal JD, et al. Everyday executive functions in Down syndrome from early childhood to young adulthood: evidence for both unique and shared characteristics compared to youth with sex chromosome trisomy (XXX and XXY). Front Behav Neurosci. 2015;9:264.

  139. 139.

    Lee NR, Wallace GL, Clasen LS, Lenroot RK, Blumenthal JD, White SL, et al. Executive function in young males with Klinefelter (XXY) syndrome with and without comorbid attention-deficit/hyperactivity disorder. J Int Neuropsychol Soc. 2011;17:522–30.

  140. 140.

    Ruud A, Arnesen P, Stray LL, Vildalen S, Vesterhus P. Stimulant medication in 47,XYY syndrome: a report of two cases. Dev Med Child Neurol. 2005;47:559–62.

  141. 141.

    Pennington BF, Puck M, Robinson A. Language and cognitive development in 47,XXX females followed since birth. Behav Genet. 1980;10:31–41.

  142. 142.

    Bender BG, Linden MG, Robinson A. Neuropsychological impairment in 42 adolescents with sex chromosome abnormalities. Am J Med. Genet. 1993;48: 169-73.

  143. 143.

    Nature Medicine Editorial. Accounting for sex in the genome. Nat Med. 2017;23:1243. This recent Nature Medicine editorial addresses the lack of inclusion of the X-chromosome in GWAS.

  144. 144.

    Wise AL, Gyi L, Manolio TA. eXclusion: toward integrating the X chromosome in genome-wide association analyses. Am J Hum Genet. 2013;92:643–7.

  145. 145.

    Bonas-Guarch S, Guindo-Martinez M, Miguel-Escalada I, Grarup N, Sebastian D, Rodriguez-Fos E, et al. Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes. Nat Commun. 2018;9:321.

  146. 146.

    Hoffmann TJ, Passarelli MN, Graff RE, Emami NC, Sakoda LC, Jorgenson E, et al. Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer. Nat Commun. 2017;8:14248.

  147. 147.

    Skare O, Gjessing HK, Gjerdevik M, Haaland OA, Romanowska J, Lie RT, et al. A new approach to chromosome-wide analysis of X-linked markers identifies new associations in Asian and European case–parent triads of orofacial clefts. PLoS ONE. 2017;12:e0183772.

  148. 148.

    Lim GY, Tam WW, Lu Y, Ho CS, Zhang MW, Ho RC. Prevalence of depression in the community from 30 countries between 1994 and 2014. Sci Rep. 2018;8:2861.

  149. 149.

    Gater R, Tansella M, Korten A, Tiemens BG, Mavareas VG, O’latawura MO. Sex differences in the prevalence and detection of depressive and anxiety disorders in general health care settings: report from the World Health Organization Collaborative Study on Psychological Problems in General Health Care. Arch Gen Psychiatry. 1998;55:405–13.

  150. 150.

    Kesler S, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence. J Affect Disord. 1994;29:85–96.

  151. 151.

    Taylor SE, Klein LC, Lewis BP, Gruenewald TL, Gurung RA, Updegraff JA. Biobehavioral responses to stress in females: tend-and-befriend, not fight-or-flight. Psychol Rev. 2000;107:411–29.

  152. 152.

    Tolin DF, Foa EB. Sex differences in trauma and posttraumatic stress disorder: a quantitative review of 25 years of research. Psychol Bull. 2006;132:959–92.

  153. 153.

    Young E, Korszun A. Sex, trauma, stress hormones and depression. Mol Psychiatry. 2010;15:23–28.

  154. 154.

    Altemus M, Sarvaiya N, Neill Epperson C. Sex differences in anxiety and depression clinical perspectives. Front Neuroendocrinol. 2014;35:320–30.

  155. 155.

    Freeman MP. Depression: what’s sex got to do with it? J Clin Psychiatry. 2006;67:1610–1.

  156. 156.

    Hankin BL, Mermelstein R, Roesch L. Sex differences in adolescent depression: stress exposure and reactivity models. Child Dev. 2007;78:279–95.

  157. 157.

    Kendler KS, Thornton LM, Prescott CA. Gender differences in the rates of exposure to stressful life events and sensitivity to their depressogenic effects. Am J Psychiatry. 2001;158:587–93.

  158. 158.

    Angold A, Costello EJ, Erkanli A, Worthman CM. Pubertal changes in hormone levels and depression in girls. Psychol Med. 1999;29:1043–53.

  159. 159.

    Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295:499–507.

  160. 160.

    Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L. Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry. 2004;61:62–70.

  161. 161.

    O’Hara MW. Social support, life events, and depression during pregnancy and the puerperium. Arch Gen Psychiatry. 1986;43:569–73.

  162. 162.

    O’Hara MW, Schlechte JA, Lewis DA, Varner MW. Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. J Abnorm Psychol. 1991;100:63–73.

  163. 163.

    Fernandez-Guasti A, Fiedler JL, Herrera L, Handa RJ. Sex, stress, and mood disorders: at the intersection of adrenal and gonadal hormones. Horm Metab Res. 2012;44:607–18.

  164. 164.

    Li SH, Graham BM. Why are women so vulnerable to anxiety, trauma-related and stress-related disorders? The potential role of sex hormones. Lancet Psychiatry. 2017;4:73–82.

  165. 165.

    Klein KO, Rosenfield R, Santen RJ, Gawlik A, Backeljauw P, Gravholt CH, et al. Estrogen replacement in Turner syndrome: literature review and practical considerations. J Clin Endocrinol Metab. 2018;103:1790–1803.

  166. 166.

    Seney ML, Ekong KI, Ding Y, Tseng GC, Sibille E. Sex chromosome complement regulates expression of mood-related genes. Biol Sex Differ. 2013;4:20.

  167. 167.

    Arnold AP. A general theory of sexual differentiation. J Neurosci Res. 2017;95:291–300. A comprehensive view of mammalian sexual differentiation accounting for the effects of the sex-chromosomes and their downstream hormonal influences on male versus female phenotype.

  168. 168.

    Rickert VI, Hassed SJ, Hendon AE, Cunniff C. The effects of peer ridicule on depression and self-image among adolescent females with Turner syndrome. J Adolesc Health. 1996;19:34–8.

  169. 169.

    Schmidt PJ, Cardoso GM, Ross JL, Haq N, Rubinow DR, Bondy CA. Shyness, social anxiety, and impaired self-esteem in Turner syndrome and premature ovarian failure. JAMA. 2006;295:1374–6.

  170. 170.

    Cardoso G, Daly R, Haq NA, Hanton L, Rubinow DR, Bondy CA, et al. Current and lifetime psychiatric illness in women with Turner syndrome. Gynecol Endocrinol. 2004;19:313–9.

  171. 171.

    Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab. 2010;95:1487–95.

  172. 172.

    Shea AK, Wolfman W. The role of hormone therapy in the management of severe postpartum depression in patients with Turner syndrome. Menopause. 2017;24:1309–12.

  173. 173.

    Turriff A, Levy HP, Biesecker B. Prevalence and psychosocial correlates of depressive symptoms among adolescents and adults with Klinefelter syndrome. Genet Med. 2011;13:966–72.

  174. 174.

    Ross JL, Kushner H, Kowal K, Bardsley M, Davis S, Reiss AL, et al. Androgen treatment effects on motor function, cognition, and behavior in boys with Klinefelter syndrome. J Pediatr. 2017;185:193–9 e194.

  175. 175.

    Linden MG, Bender BG, Harmon RJ, Mrazek DA, Robinson A. 47,XXX: what is the prognosis? Pediatrics. 1988;82:619–30.

  176. 176.

    Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732–41.

  177. 177.

    Vogelzangs N, Beekman AT, de Jonge P, Penninx BW. Anxiety disorders and inflammation in a large adult cohort. Transl Psychiatry. 2013;3:e249.

  178. 178.

    Dantzer R, O’Connor JC, Lawson MA, Kelley KW. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology. 2011;36:426–36.

  179. 179.

    Carta MG, Hardoy MC, Carpiniello B, Murru A, Marci AR, Carbone F, et al. A case control study on psychiatric disorders in Hashimoto disease and Euthyroid Goitre: not only depressive but also anxiety disorders are associated with thyroid autoimmunity. Clin Pract Epidemiol Ment Health. 2005;1:23.

  180. 180.

    Ainiala H, Loukkola J, Peltola J, Korpela M, Hietaharju A. The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology. 2001;57:496–500.

  181. 181.

    Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008;8:737–44.

  182. 182.

    Case LK, Wall EH, Dragon JA, Saligrama N, Krementsov DN, Moussawi M, et al. The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease. Genome Res. 2013;23:1474–85.

  183. 183.

    Bianchi I, Lleo A, Gershwin ME, Invernizzi P. The X chromosome and immune associated genes. J Autoimmun. 2012;38:J187–92.

  184. 184.

    Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2:777–80.

  185. 185.

    Sawalha AH, Harley JB, Scofield RH. Autoimmunity and Klinefelter’s syndrome: when men have two X chromosomes. J Autoimmun. 2009;33:31–34.

  186. 186.

    Jorgensen KT, Rostgaard K, Bache I, Biggar RJ, Nielsen NM, Tommerup N, et al. Autoimmune diseases in women with Turner’s syndrome. Arthritis Rheum. 2010;62:658–66.

  187. 187.

    Staii A, Mirocha S, Todorova-Koteva K, Glinberg S, Jaume JC. Hashimoto thyroiditis is more frequent than expected when diagnosed by cytology which uncovers a pre-clinical state. Thyroid Res. 2010;3:11.

  188. 188.

    Vanderpump MP. The epidemiology of thyroid disease. Br Med Bull. 2011;99:39–51.

  189. 189.

    Witkowska-Sedek E, Borowiec A, Kucharska A, Chacewicz K, Ruminska M, Demkow U, et al. Thyroid autoimmunity in girls with Turner syndrome. Adv Exp Med Biol. 2017;1022:71–6.

  190. 190.

    Livadas S, Xekouki P, Fouka F, Kanaka-Gantenbein C, Kaloumenou I, Mavrou A, et al. Prevalence of thyroid dysfunction in Turner’s syndrome: a long-term follow-up study and brief literature review. Thyroid. 2005;15:1061–6.

  191. 191.

    Rose NR. The genetics of autoimmune thyroiditis: the first decade. J Autoimmun. 2011;37:88–94.

  192. 192.

    Seminog OO, Seminog AB, Yeates D, Goldacre MJ. Associations between Klinefelter’s syndrome and autoimmune diseases: English national record linkage studies. Autoimmunity. 2015;48:125–8.

  193. 193.

    Liu K, Kurien BT, Zimmerman SL, Kaufman KM, Taft DH, Kottyan LC, et al. X chromosome dose and sex bias in autoimmune diseases: increased prevalence of 47,XXX in systemic lupus erythematosus and Sjogren’s Syndrome. Arthritis Rheumatol. 2016;68:1290–1300.

  194. 194.

    Scofield RH, Bruner GR, Namjou B, Kimberly RP, Ramsey-Goldman R, Petri M, et al. Klinefelter’s syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. 2008;58:2511–7.

  195. 195.

    Souyris M, Cenac C, Azar P, Daviaud D, Canivet A, Grunenwald S, et al. TLR7 escapes X chromosome inactivation in immune cells. Sci Immunol. 2018;3. A recent study which examines the link between escape from X chromosome inactivation and increased prevalence of SLE in KS.

  196. 196.

    Konig IR, Loley C, Erdmann J, Ziegler A. How to include chromosome X in your genome-wide association study. Genet Epidemiol. 2014;38:97–103.

  197. 197.

    Merikangas KR, He JP, Burstein M, Swanson SA, Avenevoli S, Cui L, et al. Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey Replication-Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2010;49:980–9.

  198. 198.

    Goldacre MJ, Seminog OO. Turner syndrome and autoimmune diseases: record-linkage study. Arch Dis Child. 2014;99:71–3.

Download references


We thank Leah Naomi Slang, BS, and Alexandra Ishak, BS, for assistance with editing. TG was supported by funding from the NICHD (HD090209) and the Stanford WSDM Seed Grants for Biological/Medical Research on Sex Differences and/or Women’s Health. ALR was supported by funding from the NIMH (MH099630), NICHD (HD049653). ALR is an unpaid medical advisor for the Turner Syndrome Society and Turner Syndrome Foundation.

Author information

Author notes

  1. These authors contributed equally: Tamar Green, Shira Flash


  1. Center for Interdisciplinary Brain Sciences Research, Stanford University, Stanford, CA, 94305, USA

    • Tamar Green
    • , Shira Flash
    •  & Allan L. Reiss
  2. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA

    • Tamar Green
    •  & Allan L. Reiss
  3. Department of Radiology, Stanford University, Stanford, CA, 94305, USA

    • Allan L. Reiss


  1. Search for Tamar Green in:

  2. Search for Shira Flash in:

  3. Search for Allan L. Reiss in:

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Tamar Green.

About this article

Publication history