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A rare sex chromosome number anomaly disorder characterized, genetically, by the presence of an extra X and Y chromosome in males and, clinically, by tall stature, dysfunctional testes associated with infertility and insufficient testosterone production, cognitive, affective and social functioning impairments, global developmental delay, and an increased risk of congenital malformations.
ORPHA:10Classification level: Disorder
- Synonym(s): -
- Prevalence: Unknown
- Inheritance: Not applicable or Unknown
- Age of onset: Infancy, Neonatal, Childhood, Adolescent
- ICD-10: Q98.8
- OMIM: -
- UMLS: C2936741
- MeSH: D007713
- GARD: 5677
- MedDRA: 10048230
The estimated prevalence is between 1/18,000 to 1/50,000 male births.
Presentation is often in infancy or early childhood with hypotonia and global development delay, sometimes accompanied by mild dysmorphic facies, plagiocephaly, and flat feet. Testicular hypogonadism, starting in adolescence and persisting throughout adulthood, is nearly universal. Cryptorchidism, micropenis, and gynecomastia have been occasionally reported. Overall, cognitive abilities tend to be in the borderline range (70-80) with about 1/3 of males with full scale IQ in the intellectually disabled range. Significantly lower verbal reasoning skills are often present. Relative to IQ, adaptive functioning is significantly impaired, with common deficits in communication, social skills, self-care, and self-direction. Many medical conditions are frequently associated, including significant dental problems (~90%), tremor (~60% of adults), asthma/allergies (~60%), skeletal anomalies (club foot, radioulnar synostosis, prominent elbows with cubitus varus, scoliosis, and kyphosis), type 2 diabetes (~20% in adulthood), thrombosis (~18%), epilepsy (~15%), strabismus (~15%), gastrointestinal problems (feeding intolerance, reflux, constipation), congenital heart defects, and renal abnormalities. Non-specific dysmorphic features may include epicanthal folds, hypertelorism, and clinodactyly. Behavioral patterns can include characteristics of attention-deficit/hyperactivity disorder and autism spectrum disorder, in addition to mood instability, anxiety, obsessive-compulsive behaviors, and emotional immaturity.
48,XXYY syndrome results from a nondisjunction event of sex chromosomes during spermatogenesis or, less often, from post-zygotic mitotic nondisjunction during cell division. There are no known predisposing factors.
Diagnosis is often made during childhood evaluation of physical and/or developmental concerns. Diagnosis is confirmed with standard karyotype or chromosomal microarray.
Main differential diagnoses include 47,XXY syndrome; 48,XXXY syndrome; 49,XXXXY syndrome; 45,X/46,XY mosaicism and 46,XX males. Other possible overlapping conditions include Fragile X, Jacob, Prader-Willi, Soto, Börjeson-Forssman Lehman, Weaver, and Cohen syndromes.
Non-invasive prenatal screening through cell-free fetal DNA can identify a fetus with 48,XXYY but this test is not diagnostic. Antenatal diagnosis is possible by amniocentesis or chorionic villus sampling.
48,XXYY is typically due to a sporadic aneuploidy event with an estimated recurrence risk of <1%. Genetic counseling should include a review of the potential physical, medical, developmental and psychological features.
Management and treatment
Comprehensive interdisciplinary care is important to evaluate and manage the associated developmental, medical, and psychological conditions. A thorough physical exam, renal ultrasound and echocardiography should be performed to evaluate for congenital defects. Vision/hearing screenings and routine dental care are important throughout life. Comorbidities, such as asthma and epilepsy, should be diagnosed and managed as they would be in individuals without 48,XXYY. Pubertal examinations and serum hormone profiles should be monitored beginning around age 10, and testosterone supplementation should be considered for hypogonadism. Annual screening for hyperlipidemia, diabetes, and autoimmune thyroid disease is recommended starting in adolescence. Comprehensive, interdisciplinary neurodevelopmental and behavioral evaluation is warranted throughout childhood. Interventions targeting psychological functioning (including emotional and behavioral disorders) and speech/language, motor, and self-care skills should be evidence-based and individualized. School- and community-based supports and services frequently form part of the treatment plan.
While there is no cure, with appropriate treatment for associated medical and psychiatric conditions, life expectancy is typically normal. Health-related quality of life and degree of independence varies depending on the severity of symptoms and access to appropriate health care and support services.
A summary on this disease is available in Deutsch (2019) Español (2019) Italiano (2019) Nederlands (2019) Français (2011) Português (2011) Hebrew (2021, pdf) Greek (2011, pdf) Polski (2011, pdf)
- Article for general public
- English (2005, pdf) - Unique
- Français (2011, pdf) - Unique
- Clinical practice guidelines
- English (2018) - Nat Rev Endocrinol
- Français (2022)
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