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Last updated: March 24, 2022
Years published: 2022
NORD gratefully acknowledges Nicole Tartaglia, MD, Developmental-Behavioral Pediatrician, Director, Denver Fragile X Clinic; Founder & Director, eXtraordinarY Kids Clinic, Professor of Pediatrics, University of Colorado School of Medicine, Kelly Wigglesworth, MD, University of Colorado School of Medicine, and The XXYY Project of AXYS for the preparation of this report.
48, XXYY is a genetic disorder that occurs in males and is characterized by additional sex chromosomes compared to the typical male karyotype of 46, XY. 48, XXYY syndrome has previously been described as a variant of Klinefelter syndrome because affected males have similar physical characteristics (tall stature and small, dysfunctional testes), however the medical and neurodevelopmental features are more complex than typically seen in 47, XXY/Klinefelter syndrome.
In infancy and early childhood, delayed milestones in speech and motor skills are common, as are medical features including low muscle tone (hypotonia), feeding disorders, delayed appearance of teeth, crossed eyes (strabismus) and a twisted neck (torticollis) with flattening on one side of the head. Other physical features can include a skin fold of the upper eyelid covering the inner corner of the eye (epicanthal fold), an abnormally large distance between the eyes (hypertelorism) and an abnormally bend or curved 5th finger (clinodactyly). There are also increased risks for congenital heart defects, kidney malformations and skeletal abnormalities including pes planus, club foot, radioulnar synostosis, cubitus varus (with prominent elbows), scoliosis and kyphosis.
Other medical conditions that are more frequent in 48, XXYY syndrome include epilepsy (~15%), tremor (~60% of adults), asthma/allergies (~60%), significant dental problems (~90%), gastrointestinal problems (feeding intolerance, reflux, constipation, eosinophilic esophagitis), joint laxity, sleep apnea, thrombosis (~18%) and type 2 diabetes (~20% in adulthood). Tall stature is another common physical feature that can be more noticeable in adolescence.
Small testes (microorchidism) and resulting testicular dysfunction leads to hypergonadotropic hypogonadism (low testosterone levels) that is nearly universal which starts in adolescence and persists throughout the lifetime. Low testosterone levels can be associated with incomplete pubertal development (decreased development of facial and body hair), decreased muscle bulk and strength, fatigue, low endurance and mental health effects such as depression. Testicular dysfunction is also associated with impaired fertility. Undescended testes (cryptorchidism), inguinal hernias, micropenis, and enlargement of breast tissue (gynecomastia) can also be associated, however gynecomastia can be prevented or minimized with appropriate testosterone management starting in adolescence.
48, XXYY syndrome presents with more significant cognitive impairments and behavior challenges compared to 47, XXY. Developmental delays are often present in the first 3 years of life in the areas of speech and motor development. Overall cognitive abilities tend to be in the borderline range (IQ of 70 โ 80) with approximately 1/3 of males with 48, XXYY with full scale IQ in the intellectual disability range (<70). Cognitive profiles often show significantly lower verbal reasoning skills compared to nonverbal and visual-spatial skills (which are often areas of strength). Language disorders and learning disabilities (especially with reading) are very common. Adaptive functioning (life skills) also commonly show deficits in communication, social skills, self-care and self-direction. Motor coordination deficits are also common.
Behavioral characteristics can include executive function impairments, difficulties with attention, impulsivity and hyperactivity. Attention-deficit/hyperactivity disorder (ADHD) is often diagnosed. Mood instability, short frustration tolerance, anxiety, compulsive behaviors and emotional immaturity are also characteristic of 48, XXYY. Additional features can include nail biting, sugar cravings and intense interests. There is increased risk for social difficulties, including difficulties in social skills, reciprocal social interactions and insight into social relationships. As a result, there is an increased risk for an autism spectrum disorder (ASD) diagnosis, and approximately half of males with 48, XXYY met DSM-5 criteria for ASD in a research study. Common strengths include artistic skills, computer skills and navigation skills.
48, XXYY syndrome is not inherited, Males with 48, XXYY have an extra X and Y chromosome because of a nondisjunction error that randomly occurs during the division of the sex chromosomes in the egg or sperm cells. There are no commonly known factors predisposing to the specific occurrence of these nondisjunction events resulting in 48, XXYY.
There is an estimated incidence of 48, XXYY in 1/18,000 to 1/50,000 male births.
48, XXYY is usually identified by a standard karyotype or chromosomal microarray (CMA) performed on peripheral blood, amniotic fluid or buccal swab. Fluorescence In Situ Hybridization (FISH) is another approach to investigate the presence of extra copies of chromosomes X and Y on a larger sample of cells. Prenatal diagnosis is possible, but 48, XXYY is usually diagnosed during childhood during evaluation of physical and/or developmental concerns that warrant genetic testing. A 2008 study looking at 95 males with 48, XXYY syndrome reported the mean age of diagnosis to be 7.7 years of age.
Treatment
Comprehensive interdisciplinary care is important to evaluate and manage developmental, medical, and psychological conditions that may be associated with 48, XXYY syndrome. At diagnosis, a thorough physical exam, renal ultrasound and echocardiography should be performed to evaluate for congenital defects. Vision and hearing screening and routine dental care are important throughout the lifespan. Physical examination should focus on common physical features and medical findings described above. Starting around age 10, pubertal examinations and serum hormone profiles should be monitored by endocrinology and testosterone supplementation should be considered when evidence of hypogonadism is present. Routine screening for hyperlipidemia, diabetes and thyroid disease is recommended starting in adolescence. Eosinophilic esophagitis should be considered in males with XXYY who have feeding problems, dysphagia (pain with swallowing), reflux, choking or other feeding problems, especially in patients with food allergies. Symptoms suggestive of any other associated medical conditions should be promptly evaluated and treated as appropriate.
The neurodevelopmental and behavioral phenotype in 48, XXYY warrants a comprehensive interdisciplinary evaluation to include psychological functioning (cognitive, learning, executive, social, emotional, and behavioral functioning), speech/language skills, motor skills and self-care skills. For infants and young children, close developmental screening is important to identify delays and the need for early intervention therapies. Further, speech-language therapy to target developmentally appropriate goals around oral-motor planning deficits, apraxia of speech, expressive and receptive language skills and pragmatic language may be necessary through early adulthood. Occupational and/or physical therapies to target decreased motor skills, dyspraxia, coordination, sensory sensitivities and overall self-care are also often warranted.
Documentation of psychological diagnoses (such as learning or intellectual disability, ADHD, anxiety and/or autism spectrum disorder) is important for qualification and access to community-based services. Interventions are recommended when psychological diagnoses are present, and treatments for emotional and behavioral disorders should be evidence-based, individualized, and chosen with consideration of language deficits, learning disabilities and other associated diagnoses. Social skills therapy can also address difficulties with social understanding, relationships and communication. Services that are tailored to the developmental disability or ASD population and delivered by providers who specialize in developmental disabilities and/or ASD are often a good fit for 48, XXYY. School-based supports including services outlined by an individualized education plan (IEP) are most often a part of the treatment plan, and evidence-based interventions for learning disabilities do not differ from those used with the general population. Through adolescence and early adulthood, adaptive skills, transition services and community-based supports are important areas of focus.
In addition to endocrinology, consultation with other medical specialists including developmental pediatrics, psychiatry and/or neurology may also help to develop treatment plans and provide medication management. Psychopharmacologic medications, in conjunction with behavioral therapy, may be warranted for behavioral and emotional symptoms and are commonly part of the treatment plan. Positive response to standard medication treatments for ADHD, anxiety and externalizing behaviors has been seen in males with 48, XXYY. There are specialized clinics primarily in the US that have experience supporting individuals with 48, XXYY. For a list of clinics, please go to the AXYS website: https://genetic.org/im-adult-looking-answers/clinics/acrc-clinics-list/
AXYS, an organization for X and Y Chromosome Variations, is dedicated to promoting research to improve treatment options and access and includes a specialized support and advocacy group for XXYY syndrome called The XXYY Project. The AXYS website is an excellent source to find information on research projects & clinical trials. https://genetic.org/about/research/
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Blumling AA, Martyn K, Talboy A, Close S. Rare sex chromosome variation 48, XXYY: An integrative review. Am J Med Genet C Semin Med Genet. 2020 Jun;184(2):386-403. doi: 10.1002/ajmg.c.31789. Epub 2020 Jun 5. PMID: 32501621.
Martin S, Cordeiro L, Richardson P, Davis S, Tartaglia N. The Association of Motor Skills and Adaptive Functioning in XXY/Klinefelter and XXYY Syndromes. Phys Occup Ther Pediatr. 2019;39(4):446-459. doi: 10.1080/01942638.2018.1541040. Epub 2018 Dec 28. PMID: 30592247; PMCID: PMC7425033.
Tartaglia NR, Wilson R, Miller JS, Rafalko J, Cordeiro L, Davis S, Hessl D, Ross J. Autism Spectrum Disorder in Males with Sex Chromosome Aneuploidy: XXY/Klinefelter Syndrome, XYY, and XXYY. J Dev Behav Pediatr. 2017 Apr;38(3):197-207. doi: 10.1097/DBP.0000000000000429. PMID: 28333849; PMCID: PMC5423728.
Hanley AP, Blumenthal JD, Lee NR, Baker EH, Clasen LS, Giedd JN. Brain and behavior in 48, XXYY syndrome. Neuroimage Clin. 2015 Apr 15;8:133-9. doi: 10.1016/j.nicl.2015.04.009. PMID: 26106537; PMCID: PMC4473812.
Tartaglia N, Ayari N, Howell S, DโEpagnier C, Zeitler P. 48, XXYY, 48, XXXY and 49, XXXXY syndromes: not just variants of Klinefelter syndrome. Acta Paediatr. 2011 Jun;100(6):851-60. doi: 10.1111/j.1651-2227.2011.02235.x. Epub 2011 Apr 8. PMID: 21342258; PMCID: PMC3314712.
Tartaglia N, Borodyanskaya M, Hall DA. Tremor in 48, XXYY syndrome. Mov Disord. 2009 Oct 15;24(13):2001-7. doi: 10.1002/mds.22700. Erratum in: Mov Disord. 2010 Aug 15;25(11):1764. Borodyanskya, Mariya [corrected to Borodyanskaya, Mariya]. PMID: 19705466; PMCID: PMC3056502.
Visootsak J, Graham JM Jr. Social function in multiple X and Y chromosome disorders: XXY, XYY, XXYY, XXXY. Dev Disabil Res Rev. 2009;15(4):328-32. doi: 10.1002/ddrr.76. PMID: 20014367; PMCID: PMC3909519.
Tartaglia N, Davis S, Hench A, Nimishakavi S, Beauregard R, Reynolds A, et al. A new look at XXYY syndrome: medical and psychological features. Am J Med Genet A. 2007; 146A:15091522. {Pubmed:18481271}
Visootsak J, Rosner B, Dykens E, Tartaglia N, Graham JM Jr. Behavioral phenotype of sex chromosome aneuploidies: 48, XXYY, 48, XXXY, and 49, XXXXY. Am J Med Genet A. 2007 Jun 1;143A(11):1198-203. doi: 10.1002/ajmg.a.31746. PMID: 17497714.
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