Article| Volume 25, ISSUE 7, 100847, July 2023

The behavioral profile of 49,XXXXY and the potential impact of testosterone replacement therapy

Published:April 12, 2023DOI:



      49,XXXXY (1:85,000-100,000) is a rare sex chromosome aneuploidy that often presents with complex musculoskeletal abnormalities, decreased cognitive capabilities, speech and language dysfunction, and behavioral complications. Hormonal replacement therapy, or testosterone replacement therapy, is associated with improved neurodevelopmental and behavioral outcomes in males with 49,XXXXY. Two forms of testosterone replacement therapy, early hormonal treatment (EHT) and hormonal booster therapy (HBT), are associated with improved neurodevelopmental and behavioral outcomes in these boys. This study investigates the impact of EHT and HBT on behavioral symptoms in males with 49,XXXXY.


      A total of 59 individuals were divided into 4 groups: 19 no testosterone (no-T), 23 EHT, 6 HBT, and 11 EHT and HBT. An analysis of variance examined group differences on the Child Behavior Checklist and the Behavior Rating Inventory of Executive Function ranging from 5 to 18 years.


      Although no differences were identified on the Behavior Rating Inventory of Executive Function, the 3 hormonal replacement therapy groups presented with decreased complications on numerous variables on the Child Behavior Checklist; these include somatic complaints (P = .0095), somatic problems (P = .041), internalizing problems (P = .034), externalizing problems (P = .0001), and withdrawn/depression (P = .025).


      This study presents evidence that HBT may be a beneficial treatment for individuals with 49,XXXXY.


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        • Kleczkowska A.
        • Fryns J.P.
        • Van den Berghe H.
        X-chromosome polysomy in the male. The Leuven experience 1966-1987.
        Hum Genet. 1988; 80: 16-22
        • Linden M.G.
        • Bender B.G.
        • Robinson A.
        Sex chromosome tetrasomy and pentasomy.
        Pediatrics. 1995; 96: 672-682
        • Samango-Sprouse C.A.
        • Lasutschinkow P.C.
        • McLeod M.
        • et al.
        Speech and language development in children with 49,XXXXY syndrome.
        Am J Med Genet A. 2020; 185: 3567-3575
        • Visootsak J.
        • Graham Jr., J.M.
        Klinefelter syndrome and other sex chromosomal aneuploidies.
        Orphanet J Rare Dis. 2006; 1: 42
        • Gropman A.L.
        • Porter G.F.
        • Lasutschinkow P.C.
        • et al.
        Neurocognitive development and capabilities in boys with 49,XXXXY syndrome.
        Am J Med Genet A. 2021; 185: 3541-3546
        • Lomelino C.A.
        • Reiss A.L.
        49,XXXXY syndrome: behavioural and developmental profiles.
        J Med Genet. 1991; 28: 609-612
        • Galasso C.
        • Arpino C.
        • Fabbri F.
        • Curatolo P.
        Neurologic aspects of 49,XXXXY syndrome.
        J Child Neurol. 2003; 18: 501-504
        • Tosi L.
        • Mitchell F.
        • Porter G.F.
        • et al.
        Musculoskeletal abnormalities in a large international cohort of boys with 49,XXXXY.
        Am J Med Genet A. 2021; 185: 3531-3540
        • Borghgraef M.
        • Fryns J.P.
        • Smeets E.
        • Marien J.
        • van den Berghe H.
        The 49,XXXXY syndrome. Clinical and psychological follow-up data.
        Clin Genet. 1988; 33: 429-434
        • Curfs L.M.
        • Schreppers-Tijdink G.
        • Wiegers A.
        • Borghgraef M.
        • Fryns J.P.
        The 49,XXXXY syndrome: clinical and psychological findings in five patients.
        J Ment Defic Res. 1990; 34: 277-282
        • Sheridan M.K.
        • Radlinski S.S.
        • Kennedy M.D.
        Developmental outcome in 49,XXXXY Klinefelter syndrome.
        Dev Med Child Neurol. 1990; 32: 532-539
        • Lasutschinkow P.C.
        • Gropman A.L.
        • Porter G.F.
        • Sadeghin T.
        • Samango-Sprouse C.A.
        Behavioral phenotype of 49,XXXXY syndrome: presence of anxiety-related symptoms and intact social awareness.
        Am J Med Genet A. 2020; 182: 974-986
        • Samango-Sprouse C.A.
        • Gropman A.L.
        • Sadeghin T.
        • Kingery M.
        • Lutz-Armstrong M.
        • Rogol A.D.
        Effects of short-course androgen therapy on the neurodevelopmental profile of infants and children with 49,XXXXY syndrome.
        Acta Paediatr. 2011; 100: 861-865
        • Mazzilli R.
        • Delfino M.
        • Elia J.
        • et al.
        Testosterone replacement in 49,XXXXY syndrome: andrological, metabolic and neurological aspects.
        Endocrinol Diabetes Metab Case Rep. 2016; 2016150114
        • Kabilan A.
        • Skakkebæk A.
        • Chang S.
        • Gravholt C.H.
        Evaluation of the efficacy of transdermal and injection testosterone therapy in Klinefelter syndrome: a real-life study.
        J Endocr Soc. 2021; 5: bvab062
        • Samango-Sprouse C.A.
        • Tran S.L.
        • Lasutschinkow P.C.
        • et al.
        Neurodevelopmental outcome of prenatally diagnosed boys with 47,XXY (Klinefelter syndrome) and the potential influence of early hormonal therapy.
        Am J Med Genet A. 2020; 182: 1881-1889
        • Salman H.
        • Abanamy A.
        • Khan N.
        • Basset G.
        • Choudhury A.H.
        • El-Ruby M.O.
        Klinefelter syndrome, rare variant 49, XXXXY.
        Ann Saudi Med. 1991; 11: 352-354
        • Flannigan R.
        • Patel P.
        • Paduch D.A.
        Klinefelter syndrome. The effects of early androgen therapy on competence and behavioral phenotype.
        Sex Med Rev. 2018; 6: 595-606
        • Mehta A.
        • Clearman T.
        • Paduch D.A.
        Safety and efficacy of testosterone replacement therapy in adolescents with Klinefelter syndrome.
        J Urol. 2014; 191: 1527-1531
        • Achenbach T.M.
        The Child Behavior Checklist and related instruments.
        in: Maruish M.E. The Use of Psychological Testing for Treatment Planning and Outcomes Assessment. Lawrence Erlbaum Associates Publishers, 1999: 429-466
        • Baron I.S.
        Behavior Rating Inventory of Executive Function.
        Child Neuropsychol. 2000; 6: 235-238