The underlying mechanisms of neurobehavioral risks in sex chromosome trisomies
SOPHIE VAN RIJN
Clinical Child and Adolescent Studies, Leiden University, Leiden, the Netherlands.
doi: 10.1111/dmcn.13983
This commentary is on the original article by Wilson and Bishop on pages 1132–1139 of this issue.
Considering the exceptionally high density of genes on the sex chromosomes that are essential for the development of the brain, it is not surprising that children with sex chro- mosome trisomies ([SCT]; i.e. 47,XXY, 47,XXX, and 47, XYY) are at increased risk for neurodevelopmental prob- lems. Over the last decade there has been an increasing interest in SCT, driven by an increasing awareness that we can gain important knowledge about mechanisms of devel- opmental risk by studying such genetically defined popula- tions. Also, there have been recent technological advances that allow for safe and early screening for genetic syn- dromes. As the number of children prenatally diagnosed with SCT is expected to increase,1 this calls for more knowledge about the phenotype of SCT.
This need for knowledge may be most pressing for the neurobehavioral domain: so far, most studies (about 75%) have focused on the somatic/medical phenotype, with only 25% studying the neurobehavioral phenotype. Traditionally, most studies in this field are of a descriptive nature and many focus on the behavioral aspects. What is also needed, is a better understanding of the mechanisms underlying the behavioral phenotype. Similar behavioral problems may arise from different underlying information processing dys- functions in the brain. Knowledge about these building blocks of behavior has consequences for diagnostic assess- ment and treatment, as it helps in identifying the exact type of vulnerability, as well as specific targets for intervention, enabling more tailored mental health care.
One of the major domains of vulnerability in SCT is language development. To illustrate, a robust finding is that 70% to 80% of children with 47,XXY have language
difficulties, already from a young age.2 The study of Wilson and Bishop,3 showing typical language lateraliza- tion in 75 children with SCT using functional transcranial Doppler ultrasonography, is an excellent example of a research study providing the need to better understand the underlying mechanisms. It is a great addition to the field because of the large sample size, the various SCT sub- groups and the sensitive and objective techniques used.
What we need in addition to this, is the study of language from a longitudinal, developmental perspective. Brain development is thought to continue into (at least) the mid- twenties– in part until the thirties. It would be interesting to better understand the developmental course of language deficits in SCT from infancy onwards, especially as this might help explain potential differences between findings in childhood, adolescence, and adulthood. For example, a functional magnetic resonance imaging study on language lateralization in adults with SCT4 showed increased involvement of the right hemisphere during language, lead- ing to reduced lateralization. We cannot exclude that this increased activation is a compensatory neural mechanism that develops over time. Although the adult study had a much smaller sample size, the findings remained significant at p=0.038 after removing outliers. Although very specula- tive, only longitudinal studies will help to gain insight into how the brain (both structurally and functionally) develops over time in SCT, not only in the language domain but in other cognitive domains as well.
One of the next steps in the field of SCT is to not only take a more longitudinal perspective, but also to study the phenotype of SCT from an early age onwards. This genetic condition can already be diagnosed prenatally, which provides the responsibility and unique opportunity to identify early markers of ‘at-risk’ development and the evaluation of effectiveness of early interventions. This is especially relevant for language difficulties, as these are present in most children with SCT from an early age, pre- senting a window of opportunity to positively influence the development of language areas in the brain.
REFERENCES
1. Samango-Sprouse C, Keen C, Sadeghin T, Gropman A.
The benefits and limitations of cell-free DNA screening for 47, XXY (Klinefelter syndrome). Prenat Diagn 2017;
37: 497–501.
2. Boada R, Janusz J, Hutaff-Lee C, Tartaglia N. The cog- nitive phenotype in Klinefelter syndrome: a review of the
literature including genetic and hormonal factors. Dev Disabil Res Rev 2009;15: 284–94.
3. Wilson AC, Bishop DVM. Sex chromosome trisomies are not associated with atypical lateralization for language.
Dev Med Child Neurol 2018;60: 1132–39.
4. van Rijn S, Aleman A, Swaab H, Vink M, Sommer I, Kahn RS. Effects of an extra X chromosome on language lateralization: an fMRI study with Klinefelter men (47, XXY). Schizophr Res 2008;101: 17–25.
Commentaries 1071 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
