Clinical, Cognitive and Neurodevelopmental Profile in Tetrasomies and Pentasomies: A Systematic Review

Abstract

Background: Sex chromosome aneuploidies (SCAs) are a group of disorders characterised by an abnormal number of sex chromosomes. Collective prevalence rate of SCAs is estimated to be around 1 in 400–500 live births; sex chromosome trisomies (e.g., XXX, XXY, XYY) are most frequent, while tetra- and pentasomies (e.g., XXXX, XXXXX, XXXY, XXXXY) are rarer, and the most common is 48, XXYY syndrome. The presence of additional X and/or Y chromosomes is believed to cause neurodevelopmental differences, with increased risk for developmental delays, language-based learning disabilities, cognitive impairments, executive dysfunction, and behavioural and psychological disorders. Aim of the Study: Our review has the purpose of analysing the neurocognitive, linguistical and behavioural profile of patients affected by sex chromosomes supernumerary aneuploidies (tetrasomy and pentasomy) to better understand the specific areas of weakness, in order to provide specific rehabilitation therapy. Methods: The literature search was performed by two authors independently. We used MEDLINE, PubMed, and PsycINFO search engines to identify sources of interest, without year or language restrictions. At the end of an accurate selection, 16 articles fulfilled the inclusion and exclusion criteria. Results and Conclusions: International literature has described single aspects of the neuropsychological profile of 48, XXYY and 49, XXXXY patients. In 48, XXYY patients, various degrees of psychosocial/executive functioning issues have been reported and there is an increased frequency of behavioural problems in childhood. Developmental delay and behavioural problems are the most common presenting problems, even if anxiety, depression and oppositional defiant disorder are also reported. They also show generalized difficulties with socialization and communication. Cognitive abilities are lower in measures of verbal IQ than in measures of performance IQ. Visuospatial skills are a relative strength compared to verbal skills. In patients with 49, XXXXY, both intellectual and adaptive functioning skills fall into the disability range, with better non-verbal cognitive performance. Speech and language testing reveals more deficits in expressive language than receptive language and comprehension. Anxiety, thought problems, internalizing and externalizing problems, and deficits in social cognition and communication are reported. Behavioural symptoms lessen from school age to adolescence, with the exception of thought problems and anxiety. Individuals affected by sex chromosome aneuploidies show testosterone deficiency, microorchidism, lack of pubertal progression and infertility. Hormone replacement therapy (HRT) is usually recommended for these patients: different studies have found that testosterone-based HRT benefit a wide range of areas initiated in these disorders, affecting not only neuromotor, cognitive and behavioural profile but also structural anomalies of the brain (i.e., increase of volume of grey temporal lobe matter). In conclusion, further studies are needed to better understand the neuropsychological profile with a complete evaluation, including neurocognitive and psychosocial aspects and to establish the real impact of HRT on improving the cognitive and behavioural profile of these patients.

Case report: Bipolar disorder in 48,XXYY syndrome

“…48,XXYY syndrome is considered a variant of 47,XXY Klinefelter syndrome due to a shared endocrinologic and physical phenotype. It was first described in 1964 and is associated with additional medical problems and more apparent psychological and neurodevelopmental features ( 5 ). The most common physiologic findings associated with 48,XXYY syndrome include an eunuchoid body habitus, small testes, azoospermia, gynecomastia, increased height, testicular atrophy following puberty, and increased follicular stimulating hormone ( 1 ).…”

“…In addition, individuals with 48,XXYY syndrome were found to have significant developmental delays, problems with adaptive functions, and language-based cognitive deficits. Neurodevelopmental disorders are also common with the rates of ADHD reported at 72.2%, autism spectrum disorder at 18.9%, mood disorder at 26.3%, and tic disorders at 18.9%, with 55.9% of them on psychopharmacologic medications ( 5 ). Intellectual disturbances and behavioral issues among these patients are attributed to their sex-chromosomal abnormalities ( 5 ).…”

“…Neurodevelopmental disorders are also common with the rates of ADHD reported at 72.2%, autism spectrum disorder at 18.9%, mood disorder at 26.3%, and tic disorders at 18.9%, with 55.9% of them on psychopharmacologic medications (5). Intellectual disturbances and behavioral issues among these patients are attributed to their sex-chromosomal abnormalities (5).…”

“…For cognitive abilities among patients with 48, XXYY, their measures of verbal IQ are lower than in their measures of performance IQ. Their verbal skills are relatively stronger compared to the visuospatial skills ( 5 ). Testosterone-based hormonal replacement therapy (HRT) has been proposed to improve the cognitive and behavioral profile including aggression ( 5 ).…”

“…Their verbal skills are relatively stronger compared to the visuospatial skills ( 5 ). Testosterone-based hormonal replacement therapy (HRT) has been proposed to improve the cognitive and behavioral profile including aggression ( 5 ). However, recent review ( 5 ) has suggested the need of further studies to establish the real impact of HRT on improving the cognitive and behavioral profile of these patients.…”