Overall, recent studies in 48,XXYY, 48,XXXY and 49,XXXXY have identified a much larger spectrum of cognitive abilities than described in the original literature, where nearly all subjects had intellectual disability.
While many authors, including our group, have emphasized the factors that distinguish 48,XXYY, 48,XXXY and 49,XXXXY from 47,XXY/Klinefelter syndrome, recognition of these three disorders as entirely distinct from 47,XXY Klinefelter syndrome has both positive and negative implications (see for comparisons). The most important reasons for distinction are related to recognition of the associated medical problems that are more common in the sex chromosome tetrasomy and pentasomy conditions and which often require additional evaluations, interventions and therapies. Also, while there is a spectrum of cognitive and behavioural symptoms in 47,XXY, those in 48,XXYY, 48,XXXY and 49,XXXXY are often more severe and require additional interventions and community supports. For example, in some states, 47,XXY is not a qualifying diagnosis for early intervention services because of the presence of normal early milestones in some 47,XXY infants and toddlers. In 48,XXYY, 48,XXXY and 49,XXXXY, early speech and motor delays are almost universal, and early intervention therapies are extremely important and warranted. Similarly, in adolescence and adulthood, the degree of disability and complexity of psychological symptoms are more significant in 48,XXYY, 48,XXXY and 49,XXXXY, and comparisons to adults with 47,XXY/Klinefelter syndrome (most of whom do not require adult disability services) hinder access to appropriate supports.
However, some factors make comparison to 47,XXY/Klinefelter syndrome important. First, 47,XXY is the most common chromosomal abnormality in males, with a prevalence of 1:650 male births. While research on 47,XXY is still extremely limited in comparison with other genetic and endocrinologic disorders with lower prevalence rates, there has been renewed interest in 47,XXY over the past 5 years, with research progressing in understanding cognitive features, (50
) neuroimaging correlates, (52
) advances in fertility research, (40
) efficient and sensitive high-volume diagnostic techniques, (6
) genotype–phenotype relationships (56
) and associated medical conditions (17
). Findings in all of these research areas are also pertinent to 48,XXYY, 48,XXXY and 49,XXXXY syndromes, and clinical treatments and additional research directions in these conditions will likely grow from findings in 47,XXY. If the syndromes are viewed as distinct conditions, they will be less likely to be included in new research projects, and research on the rarer disorders will be more difficult to fund and execute because of the lower sample sizes. Similarly, while 47,XXY/Klinefelter syndrome is the most common chromosomal abnormality in males, there is very low professional and public awareness and ongoing misperceptions of males with 47,XXY that are slowly improving with efforts of the national advocacy groups, the interesting new research in 47,XXY and increasing rates of genetic testing in medical practice. A complete distinction of 48,XXYY, 48,XXXY and 49,XXXXY would not be of benefit to these rarer conditions or to 47,XXY as it could lead to additional public confusion and duplication of advocacy efforts. Thus, education and advocacy about sex chromosome aneuploidy conditions as a group should be coordinated to be most effective.
Finally, the development of hypergonadotropic hypogonadism occurs in all aneuploidy conditions where males have one or more extra X chromosome(s), and the general evaluation and treatment protocols for testosterone replacement therapy do not currently differ based on the specific genetic diagnosis. Although more research is needed to determine whether there should be any differences in the approach to testosterone replacement therapies for 48,XXYY, 48,XXXY and 49,XXXXY compared with classic 47,XXY, currently the treatment approaches are the same as 47,XXY and classifying the conditions as entirely distinct from one another may lead to confusion or undertreatment of hypogonadism in 48,XXYY, 48,XXXY and 49,XXXXY.
The phenotype of all sex chromosome aneuploidy disorders is proposed to result from gene dosage effects, in which genes on the additional X and/or Y chromosomes that are not X-inactivated are therefore expressed at higher levels than in typical 46, XY males. For example, homologous genes in the pseudoautosomal regions of the sex chromosomes are expressed from both the X&Y chromosomes, and thus, in 48,XXYY, 48,XXXY and 49,XXXXY, these genes would be expressed twofold to threefold in comparison with a 46,XY male. Microarray studies in 47,XXY have identified genes that are differentially expressed compared with 46,XY, (59
) and differentially expressed genes were correlated with verbal cognitive skills in one study (56
). This study was small (six XY compared with 11 XXY subjects) and has yet to be replicated. While subjects with 48,XXYY, 48,XXXY and 49,XXXXY are slightly more difficult to locate in large numbers, we propose that the sex chromosome tetrasomy and pentasomy conditions may be a better comparison group for these initial genotype–phenotype studies because a 2.0-fold (for 48,XXYY and 48,XXXY) and 2.5-fold (for 49,XXXXY) increase in gene expression would be expected compared with 1.5-fold in 47,XXY. Also, the more significant cognitive and behavioural differences between 48,XXYY, 48,XXXY, and 49,XXXXY and 46,XY may prove more valuable in determining candidate genes involved in the psychological and behavioural phenotype. Studies that compare psychological features in 47,XXY to 46,XY often find inconsistent differences between groups, likely due to the significant overlap in the phenotypes, small sample sizes and confounding variables such as socioeconomic status and other environmental factors that impact cognitive outcomes. However, 48,XXYY, 48,XXXY and 49,XXXXY have much less overlap, so the differences between groups are easier to identify.
Many new techniques have been developed that can inexpensively and accurately screen large populations for sex chromosome aneuploidy (6
). While universal newborn screening for these conditions remains controversial, newborn screening studies for research purposes would help to increase ascertainment of these rarer conditions so that prospective studies in unselected samples could be conducted. Consequently, interventions to address the developmental delays and learning problems could be studied in a controlled manner to determine whether earlier identification and interventions clearly lead to improved outcome.
Now that more comprehensive descriptions of the medical and psychological features of 48,XXYY and 49,XXXXY syndromes have been published, the next steps include identifying genes and gene pathways that lead to these features, as well as developing specific treatments and interventions. The recent surge in research in 47,XXY will provide important background applicable to the 48,XXYY, 48,XXXY and 49,XXXXY and prompt researchers in 47,XXY to value the utility and clinical importance of including the tetrasomy and pentasomy aneuploidies in their studies. We anticipate that with a new interest in copy number variations as a mechanism of variation and pathology in the general population, the sex chromosome aneuploidy disorders will benefit from related strategies developed and further interest in genomic sciences.
Clinical research over the next 5 years should focus on understanding factors that lead to the most significant medical problems in 48,XXYY, 48,XXXY and 49,XXXXY and developing evidence-based clinical care guidelines that are readily available to practitioners. It will be important to determine whether there are differences in the timing and progression of hypogonadism in 48,XXYY, 48,XXXY and 49,XXXXY compared with 47,XXY and to better understand the psychological and behavioural effects of testosterone therapy so that appropriate recommendations are made for each disorder. Increasing awareness and ascertainment of all sex chromosome aneuploidy disorders are important, and burgeoning molecular screening methods will facilitate achieving these goals.