{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T02:37:55Z","timestamp":1783478275509,"version":"3.55.0"},"reference-count":99,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T00:00:00Z","timestamp":1713916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Klinefelter syndrome (KS), characterized by an additional X-chromosome in males, manifests in a wide range of neuroendocrine and psychiatric symptoms. Individuals with KS often face increased risks of hormonal dysfunction, leading to depression and anxiety, although extended research during pediatric and adolescent age is still limited. This critical phase, decisive for KS children, is influenced by a combination of genetic, environmental and familial factors, which impact brain plasticity. In this report, we reviewed, in a narrative form, the crucial KS psychopathological hallmarks in children. To better describe neuroendocrine and neuropsychiatric outcomes in children with KS, we presented the case of an 11-year-old prepubertal child with mosaic KS who was referred to our Center of Developmental Psychopathology due to a decline in his academic performance, excessive daytime fatigue and increased distractibility over the past few months. Family history revealed psychiatric conditions among first- and second-degree relatives, including recently divorced parents and a 15-year-old sister. Early-onset persistent depressive disorder and anxious traits were diagnosed. Timely identification of susceptible children, with thorough examination of familial psychiatric history, environmental influences and neurocognitive profile, alongside targeted interventions, could potentially mitigate lifelong psychopathology-related disabilities in pediatric and adolescent KS cases, including those with mosaic KS.<\/jats:p>","DOI":"10.3390\/children11050509","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T10:18:36Z","timestamp":1713953916000},"page":"509","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Klinefelter Syndrome: A Genetic Disorder Leading to Neuroendocrine Modifications and Psychopathological Vulnerabilities in Children\u2014A Literature Review and Case Report"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2683-0052","authenticated-orcid":false,"given":"Fabiola","family":"Panvino","sequence":"first","affiliation":[{"name":"Department of Human Neuroscience, Section of Child and Adolescent Neuropsychiatry, Sapienza University of Rome, Via dei Sabelli 108, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7020-1471","authenticated-orcid":false,"given":"Roberto","family":"Paparella","sequence":"additional","affiliation":[{"name":"Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisiana","family":"Gambuti","sequence":"additional","affiliation":[{"name":"Department of Human Neuroscience, Section of Child and Adolescent Neuropsychiatry, Sapienza University of Rome, Via dei Sabelli 108, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cerrito","sequence":"additional","affiliation":[{"name":"Department of Human Neuroscience, Section of Child and Adolescent Neuropsychiatry, Sapienza University of Rome, Via dei Sabelli 108, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Menghi","sequence":"additional","affiliation":[{"name":"Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginevra","family":"Micangeli","sequence":"additional","affiliation":[{"name":"Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0651-1816","authenticated-orcid":false,"given":"Carla","family":"Petrella","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6806-9715","authenticated-orcid":false,"given":"Marco","family":"Fiore","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5958-9364","authenticated-orcid":false,"given":"Luigi","family":"Tarani","sequence":"additional","affiliation":[{"name":"Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignazio","family":"Ardizzone","sequence":"additional","affiliation":[{"name":"Department of Human Neuroscience, Section of Child and Adolescent Neuropsychiatry, Sapienza University of Rome, Via dei Sabelli 108, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/andr.12909","article-title":"European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology","volume":"9","author":"Zitzmann","year":"2021","journal-title":"Andrology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Spaziani, M., Carlomagno, F., Tarantino, C., Angelini, F., Paparella, R., Tarani, L., Putotto, C., Badagliacca, R., Pozza, C., and Isidori, A.M. (2024). From Klinefelter Syndrome to High Grade Aneuploidies: Expanding the Gene-Dosage Effect of Supernumerary X Chromosomes. J. Clin. Endocrinol. Metab., dgad730.","DOI":"10.1210\/clinem\/dgad730"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1210\/jc.2002-021491","article-title":"Prenatal and Postnatal Prevalence of Klinefelter Syndrome: A National Registry Study","volume":"88","author":"Bojesen","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1542\/peds.96.4.672","article-title":"Sex chromosome tetrasomy and pentasomy","volume":"96","author":"Linden","year":"1995","journal-title":"Pediatrics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1210\/jc.2012-2382","article-title":"Klinefelter Syndrome\u2014A Clinical Update","volume":"98","author":"Groth","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s40618-016-0541-6","article-title":"Klinefelter syndrome (KS): Genetics, clinical phenotype and hypogonadism","volume":"40","author":"Bonomi","year":"2017","journal-title":"J. Endocrinol. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1210\/er.2017-00212","article-title":"Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology","volume":"39","author":"Gravholt","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1111\/andr.12208","article-title":"The Klinefelter syndrome: Current management and research challenges","volume":"4","author":"Nieschlag","year":"2016","journal-title":"Andrology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e1329","DOI":"10.1210\/clinem\/dgad281","article-title":"Altered Thyroid Feedback Loop in Klinefelter Syndrome: From Infancy through the Transition to Adulthood","volume":"108","author":"Carlomagno","year":"2023","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ibror.2018.11.008","article-title":"The human hypothalamus in mood disorders: The HPA axis in the center","volume":"6","author":"Bao","year":"2019","journal-title":"IBRO Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/1750-1172-1-42","article-title":"Klinefelter syndrome and other sex chromosomal aneuploidies","volume":"1","author":"Visootsak","year":"2006","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"109","DOI":"10.2174\/1871530318666180703160250","article-title":"Neuropsychiatric Aspects in Men with Klinefelter Syndrome","volume":"19","author":"Giagulli","year":"2019","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/ajmg.1320480312","article-title":"Neuropsychological impairment in 42 adolescents with sex chromosome abnormalities","volume":"48","author":"Bender","year":"1993","journal-title":"Am. J. Med. Genet."},{"key":"ref_14","first-page":"151","article-title":"The spectrum of the behavioral phenotype in boys and adolescents 47,XXY (Klinefelter syndrome)","volume":"8","author":"Tartaglia","year":"2010","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1136\/adc.80.2.192","article-title":"Long term outcome in children of sex chromosome abnormalities","volume":"80","author":"Ratcliffe","year":"1999","journal-title":"Arch. Dis. Child."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1097\/MED.0000000000000157","article-title":"Neuropsychology and socioeconomic aspects of Klinefelter syndrome: New developments","volume":"22","author":"Wallentin","year":"2015","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1530\/EJE-21-1239","article-title":"Association between domains of quality of life and patients with Klinefelter syndrome: A systematic review","volume":"187","author":"Mehmet","year":"2022","journal-title":"Eur. J. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/ajmg.c.31797","article-title":"Neuropsychological functions, sleep, and mental health in adults with Klinefelter syndrome","volume":"184","author":"Fjermestad","year":"2020","journal-title":"Am. J. Med. Genet. Part C"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jcomdis.2019.02.003","article-title":"Speech and language in children with Klinefelter syndrome","volume":"78","author":"Ponchard","year":"2019","journal-title":"J. Commun. Disord."},{"key":"ref_20","first-page":"138","article-title":"Advances in research on the neurological and neuropsychiatric phenotype of Klinefelter syndrome","volume":"25","author":"Savic","year":"2012","journal-title":"Curr. Opin. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1017\/S1355617718000723","article-title":"Phonemic and Semantic Verbal Fluency in Sex Chromosome Aneuploidy: Contrasting the Effects of Supernumerary X versus Y Chromosomes on Performance","volume":"24","author":"Udhnani","year":"2018","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e623","DOI":"10.1097\/DBP.0000000000001111","article-title":"Novel Neurocognitive Profile in a Minority of Boys with 47,XXY (Klinefelter Syndrome)","volume":"43","author":"Hamzik","year":"2022","journal-title":"J. Dev. Behav. Pediatr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1002\/ajmg.a.38621","article-title":"International investigation of neurocognitive and behavioral phenotype in 47,XXY (Klinefelter syndrome): Predicting individual differences","volume":"176","author":"Stapleton","year":"2018","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1177\/002221940103400105","article-title":"Developmental Dyscalculia Is a Familial Learning Disability","volume":"34","author":"Shalev","year":"2001","journal-title":"J. Learn. Disabil."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1111\/1467-8624.7402003","article-title":"Family Risk of Dyslexia Is Continuous: Individual Differences in the Precursors of Reading Skill","volume":"74","author":"Snowling","year":"2003","journal-title":"Child Dev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/1098-2779(2000)6:2<107::AID-MRDD4>3.0.CO;2-2","article-title":"Neurobehavioral phenotype of Klinefelter syndrome","volume":"6","author":"Geschwind","year":"2000","journal-title":"Ment. Retard. Dev. Disabil. Res. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/ddrr.83","article-title":"The cognitive phenotype in Klinefelter syndrome: A review of the literature including genetic and hormonal factors","volume":"15","author":"Boada","year":"2009","journal-title":"Dev. Disabil. Res. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1002\/ajmg.a.36483","article-title":"Expanding the phenotypic profile of boys with 47, XXY: The impact of familial learning disabilities","volume":"164","author":"Stapleton","year":"2014","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/jnr.23951","article-title":"Cognitive, behavioral, and neural consequences of sex chromosome aneuploidy","volume":"95","author":"Printzlau","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ics.2006.06.016","article-title":"The cognitive phenotype of Turner syndrome: Specific learning disabilities","volume":"1298","author":"Mazzocco","year":"2006","journal-title":"Int. Congr. Ser."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1080\/87565649109540499","article-title":"Developmental changes in performance on tests of purported frontal lobe functioning","volume":"7","author":"Levin","year":"1991","journal-title":"Dev. Neuropsychol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1080\/87565648509540320","article-title":"Neuropsychological development of behavior attributed to frontal lobe functioning in children","volume":"1","author":"Passler","year":"1985","journal-title":"Dev. Neuropsychol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1080\/87565649109540483","article-title":"A normative-developmental study of executive function: A window on prefrontal function in children","volume":"7","author":"Welsh","year":"1991","journal-title":"Dev. Neuropsychol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1016\/S0028-3932(03)00061-7","article-title":"Executive skills in Klinefelter\u2019s syndrome","volume":"41","author":"Temple","year":"2003","journal-title":"Neuropsychologia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1177\/2167702616672038","article-title":"Strengths and Weaknesses in the Intellectual Profile of Different Subtypes of Specific Learning Disorder: A Study on 1049 Diagnosed Children","volume":"5","author":"Toffalini","year":"2017","journal-title":"Clin. Psychol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1017\/S1355617701744013","article-title":"Neuropsychological profiles of adults with Klinefelter syndrome","volume":"7","author":"Boone","year":"2001","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1002\/ajmg.c.31806","article-title":"Psychological functioning, brain morphology, and functional neuroimaging in Klinefelter syndrome","volume":"184","author":"Gravholt","year":"2020","journal-title":"Am. J. Med. Genet. Part C"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e88","DOI":"10.1210\/clinem\/dgad487","article-title":"Executive Dysfunction in Klinefelter Syndrome: Associations with Brain Activation and Testicular Failure","volume":"109","author":"Ghasemi","year":"2023","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/jclp.22871","article-title":"Emotion regulation in adults with Klinefelter syndrome (47,XXY): Neurocognitive underpinnings and associations with mental health problems","volume":"76","author":"Swaab","year":"2020","journal-title":"J. Clin. Psychol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.schres.2007.03.015","article-title":"Psychiatric morbidity and X-chromosomal origin in a Klinefelter sample","volume":"93","author":"Boks","year":"2007","journal-title":"Schizophr. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1097\/GIM.0b013e3182227576","article-title":"Prevalence and psychosocial correlates of depressive symptoms among adolescents and adults with Klinefelter syndrome","volume":"13","author":"Turriff","year":"2011","journal-title":"Genet. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1542\/peds.96.2.302","article-title":"Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities","volume":"96","author":"Bender","year":"1995","journal-title":"Pediatrics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1080\/09297049.2016.1252320","article-title":"The effect of early life stress on the cognitive phenotype of children with an extra X chromosome (47,XXY\/47,XXX)","volume":"24","author":"Barneveld","year":"2018","journal-title":"Child Neuropsychol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e12465","DOI":"10.1111\/gbb.12465","article-title":"The nature of social cognitive deficits in children and adults with Klinefelter syndrome (47,XXY)","volume":"17","author":"Swaab","year":"2018","journal-title":"Genes Brain Behav."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"van Rijn, S. (2018). Salivary testosterone in relation to social cognition and social anxiety in children and adolescents with 47,XXY (Klinefelter syndrome). PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0200882"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1017\/S1355617715000302","article-title":"Social Attention in 47,XXY (Klinefelter Syndrome): Visual Scanning of Facial Expressions Using Eyetracking","volume":"21","year":"2015","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1192\/bjp.bp.105.008961","article-title":"Klinefelter\u2019s syndrome (karyotype 47,XXY) and schizophrenia-spectrum pathology","volume":"189","author":"Aleman","year":"2006","journal-title":"Br. J. Psychiatry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1002\/(SICI)1096-8628(19990416)88:2<200::AID-AJMG18>3.0.CO;2-3","article-title":"Psychosocial competence of unselected young adults with sex chromosome abnormalities","volume":"88","author":"Bender","year":"1999","journal-title":"Am. J. Med. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1139\/cjpp-2021-0457","article-title":"Serum prokineticin-2 in prepubertal and adult Klinefelter individuals","volume":"100","author":"Fiore","year":"2022","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Paparella, R., Ferraguti, G., Fiore, M., Menghi, M., Micangeli, G., Tarani, F., Ligotino, A., Messina, M.P., Ceccanti, M., and Minni, A. (2024). Serum Lipocalin-2 Levels as a Biomarker in Pre- and Post-Pubertal Klinefelter Syndrome Patients: A Pilot Study. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25042214"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e865","DOI":"10.1542\/peds.2008-1954","article-title":"Psychiatric Characteristics in a Self-Selected Sample of Boys with Klinefelter Syndrome","volume":"123","author":"Bruining","year":"2009","journal-title":"Pediatrics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/ajmg.b.30163","article-title":"Klinefelter\u2019s syndrome (XXY) as a genetic model for psychotic disorders","volume":"135B","author":"DeLisi","year":"2005","journal-title":"Am. J. Med. Genet. Part B"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.neuroimage.2004.08.018","article-title":"Automated morphometric study of brain variation in XXY males","volume":"23","author":"Shen","year":"2004","journal-title":"NeuroImage"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1002\/ajmg.b.30454","article-title":"Dysregulation of X-linked gene expression in Klinefelter\u2019s syndrome and association with verbal cognition","volume":"144B","author":"Vawter","year":"2007","journal-title":"Am. J. Med. Genet. Part B"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.neubiorev.2004.11.005","article-title":"Neurobiology of emotion and high risk for schizophrenia: Role of the amygdala and the X-chromosome","volume":"29","author":"Aleman","year":"2005","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1001\/archpsyc.61.2.162","article-title":"Increased Incidence of Diagnosed Depressive Illness in HypogonadalOlder Men","volume":"61","author":"Shores","year":"2004","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1001\/archgenpsychiatry.2007.33","article-title":"Low Free Testosterone Concentration as a Potentially Treatable Cause of Depressive Symptoms in Older Men","volume":"65","author":"Almeida","year":"2008","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/S0006-3223(01)01148-9","article-title":"Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men","volume":"50","author":"Seidman","year":"2001","journal-title":"Biol. Psychiatry"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Miers, A., Ziermans, T., and Van Rijn, S. (2017). Connecting the Dots between Schizotypal Symptoms and Social Anxiety in Youth with an Extra X Chromosome: A Mediating Role for Catastrophizing. Brain Sci., 7.","DOI":"10.3390\/brainsci7090113"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.jpeds.2017.02.036","article-title":"Androgen Treatment Effects on Motor Function, Cognition, and Behavior in Boys with Klinefelter Syndrome","volume":"185","author":"Ross","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1002\/ajmg.a.35769","article-title":"Positive effects of short course androgen therapy on the neurodevelopmental outcome in boys with 47,XXY syndrome at 36 and 72 months of age","volume":"161","author":"Sadeghin","year":"2013","journal-title":"Am. J. Med. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Wechsler, D. (2003). Wechsler Intelligence Scale for Children\u2014Fourth Edition (WISC-IV), The Psychological Corporation.","DOI":"10.1037\/t15174-000"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1098\/rstb.1982.0082","article-title":"Specific impairments of planning","volume":"298","author":"Shallice","year":"1982","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_64","unstructured":"Korkman, M., Kirk, U., and Kemp, S. (2007). NEPSY-II: Clinical and Interpretative Manual, Harcourt Assessment."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Kovacs, M. (2011). Children\u2019s Depression Inventory 2nd Edition: Technical Manual, Multi-Health Systems.","DOI":"10.1037\/t04948-000"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1097\/00004583-199707000-00021","article-title":"Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): Initial Reliability and Validity Data","volume":"36","author":"Kaufman","year":"1997","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"March, J.S. (2013). Multidimensional Anxiety Scale for Children\u20142nd Edition: Technical Manual, Multi-Health Systems.","DOI":"10.1037\/t05050-000"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/j.1365-2869.1996.00251.x","article-title":"The Sleep Disturbance Scale for Children (SDSC) Construction and validation of an instrument to evaluate sleep disturbances in childhood and adolescence","volume":"5","author":"Bruni","year":"1996","journal-title":"J. Sleep Res."},{"key":"ref_69","unstructured":"Achenbach, T.M., and Rescorla, L.A. (2001). Manual for ASEBA School-Age Forms & Profiles, University of Vermont, Research Center for Children, Youth & Families."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1023\/A:1022602400621","article-title":"The revised Conners\u2019 Parent Rating Scale (CPRS-R): Factor structure, reliability, and criterion validity","volume":"26","author":"Conners","year":"1998","journal-title":"J. Abnorm. Child Psychol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1023\/A:1022606501530","article-title":"Revision and restandardization of the Conners Teacher Rating Scale (CTRS-R): Factor structure, reliability, and criterion validity","volume":"26","author":"Conners","year":"1998","journal-title":"J. Abnorm. Child Psychol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.1210\/clinem\/dgad205","article-title":"Testicular Dysfunction in 47,XXY Boys: When It All Begins. A Semilongitudinal Study","volume":"108","author":"Pozza","year":"2023","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/j.fertnstert.2013.12.051","article-title":"Phenotypic differences in mosaic Klinefelter patients as compared with non-mosaic Klinefelter patients","volume":"101","author":"Samplaski","year":"2014","journal-title":"Fertil. Steril."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0140-6736(04)16678-6","article-title":"Klinefelter\u2019s syndrome","volume":"364","author":"Lanfranco","year":"2004","journal-title":"Lancet"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13039-022-00588-z","article-title":"Klinefelter syndrome mosaicism in boys with neurodevelopmental disorders: A cohort study and an extension of the hypothesis","volume":"15","author":"Vorsanova","year":"2022","journal-title":"Mol. Cytogenet."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Ferraguti, G., Terracina, S., Micangeli, G., Lucarelli, M., Tarani, L., Ceccanti, M., Spaziani, M., D\u2019Orazi, V., Petrella, C., and Fiore, M. (2023). NGF and BDNF in pediatrics syndromes. Neurosci. Biobehav. Rev., 145.","DOI":"10.1016\/j.neubiorev.2022.105015"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2174\/1871530322666220704101310","article-title":"Neuroimmune Dysregulation in Prepubertal and Adolescent Individuals Affected by Klinefelter Syndrome","volume":"23","author":"Tarani","year":"2023","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Hovnik, T., Zitnik, E., Avbelj Stefanija, M., Bertok, S., Sedej, K., Bancic Silva, V., Battelino, T., and Groselj, U. (2022). An Adolescent Boy with Klinefelter Syndrome and 47,XXY\/46,XX Mosaicism: Case Report and Review of Literature. Genes, 13.","DOI":"10.3390\/genes13050744"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e476","DOI":"10.1097\/DBP.0000000000001201","article-title":"Cognition, Academic Achievement, Adaptive Behavior, and Quality of Life in Child and Adolescent Boys with Klinefelter Syndrome","volume":"44","author":"Jordan","year":"2023","journal-title":"J. Dev. Behav. Pediatr."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1111\/j.1651-2227.2011.02184.x","article-title":"Testosterone and the child (0\u201312 years) with Klinefelter syndrome (47XXY): A review: Testosterone and prepubertal Klinefelter syndrome","volume":"100","author":"Fennoy","year":"2011","journal-title":"Acta Paediatr."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"bnaa003","DOI":"10.1210\/endrev\/bnaa003","article-title":"Androgens During Infancy, Childhood, and Adolescence: Physiology and Use in Clinical Practice","volume":"41","author":"Mason","year":"2020","journal-title":"Endocr. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1210\/js.2019-00119","article-title":"Testosterone Supplementation and Cognitive Functioning in Men\u2014A Systematic Review and Meta-Analysis","volume":"3","author":"Buskbjerg","year":"2019","journal-title":"J. Endocr. Soc."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1002\/ajmg.a.61038","article-title":"The incidence of anxiety symptoms in boys with 47,XXY (Klinefelter syndrome) and the possible impact of timing of diagnosis and hormonal replacement therapy","volume":"179","author":"Lasutschinkow","year":"2019","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/gim.2017.110","article-title":"Quality of life in men with Klinefelter syndrome: The impact of genotype, health, socioeconomics, and sexual function","volume":"20","author":"Moore","year":"2018","journal-title":"Genet. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e00645","DOI":"10.1002\/brb3.645","article-title":"The role of genes, intelligence, personality, and social engagement in cognitive performance in Klinefelter syndrome","volume":"7","author":"Moore","year":"2017","journal-title":"Brain Behav."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Skakkeb\u00e6k, A., Moore, P.J., Pedersen, A.D., Bojesen, A., Kristensen, M.K., Fedder, J., Hertz, J.M., \u00d8stergaard, J.R., Wallentin, M., and Gravholt, C.H. (2018). Anxiety and depression in Klinefelter syndrome: The impact of personality and social engagement. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0206932"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s12020-023-03387-7","article-title":"Increased prevalence of nodular thyroid disease in patients with Klinefelter syndrome","volume":"81","author":"Esposito","year":"2023","journal-title":"Endocrine"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1007\/s40618-019-01037-2","article-title":"Thyroid function in Klinefelter syndrome: A multicentre study from KING group","volume":"42","author":"Balercia","year":"2019","journal-title":"J. Endocrinol. Investig."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"111777","DOI":"10.1016\/j.mrfmmm.2022.111777","article-title":"Aneuploidy, inflammation and diseases","volume":"824","author":"Fenech","year":"2022","journal-title":"Mutat. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1210\/jc.2007-1426","article-title":"Abnormal Sex Chromosome Constitution and Longitudinal Growth: Serum Levels of Insulin-like Growth Factor (IGF)-I, IGF Binding Protein-3, Luteinizing Hormone, and Testosterone in 109 Males with 47,XXY, 47,XYY, or Sex-Determining Region of the Y Chromosome (SRY)-Positive 46,XX Karyotypes","volume":"93","author":"Aksglaede","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1093\/molehr\/gaq019","article-title":"Novel genetic aspects of Klinefelter\u2019s syndrome","volume":"16","author":"Tuttelmann","year":"2010","journal-title":"Mol. Human Reprod."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1159\/000530171","article-title":"SHOX Whole Gene Duplications Are Overrepresented in SHOX Haploinsufficiency Phenotype Cohorts","volume":"162","author":"Bunyan","year":"2022","journal-title":"Cytogenet. Genome Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1136\/jmedgenet-2015-103621","article-title":"Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions","volume":"53","author":"Tropeano","year":"2016","journal-title":"J. Med. Genet."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1001\/archinte.158.12.1309","article-title":"Klinefelter Syndrome","volume":"158","author":"Smyth","year":"1998","journal-title":"Arch. Intern. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1530\/EJE-17-0902","article-title":"Endocrine and metabolic evaluation of classic Klinefelter syndrome and high-grade aneuploidies of sexual chromosomes with male phenotype: Are they different clinical conditions?","volume":"178","author":"Spaziani","year":"2018","journal-title":"Eur. J. Endocrinol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/j.1743-6109.2012.02735.x","article-title":"Hormonal Causes of Male Sexual Dysfunctions and Their Management (Hyperprolactinemia, Thyroid Disorders, GH Disorders, and DHEA)","volume":"10","author":"Maggi","year":"2013","journal-title":"J. Sex. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/nrn2639","article-title":"Effects of stress throughout the lifespan on the brain, behaviour and cognition","volume":"10","author":"Lupien","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.neuron.2013.06.028","article-title":"The Brain on Stress: Vulnerability and Plasticity of the Prefrontal Cortex over the Life Course","volume":"79","author":"McEwen","year":"2013","journal-title":"Neuron"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/cen.14553","article-title":"Klinefelter syndrome\u2014Considerations in management during the SARS-CoV-2 pandemic","volume":"98","author":"Qian","year":"2023","journal-title":"Clin. Endocrinol."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/11\/5\/509\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:33:24Z","timestamp":1760106804000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/11\/5\/509"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,24]]},"references-count":99,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["children11050509"],"URL":"https:\/\/doi.org\/10.3390\/children11050509","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,24]]}}}