Syndrome-Specific Neuroanatomical Phenotypes in Girls With Turner and Noonan Syndromes.

Background: Turner syndrome (TS) and Noonan syndrome (NS) are distinct genetic conditions with highly similar physical and neurodevelopmental phenotypes. TS is caused by X chromosome absence, whereas NS results from genetic mutations activating the Ras-mitogen-activated protein kinase signaling pathway. Previous neuroimaging studies in individuals with TS and NS have shown neuroanatomical variations relative to typically developing individuals, a standard comparison group when initially examining a clinical group of interest. However, none of these studies included a second clinical comparison group, limiting their ability to identify syndrome-specific neuroanatomical phenotypes.

Methods: In this study, we compared the behavioral and brain phenotypes of 37 girls with TS, 26 girls with NS, and 37 typically developing girls, all ages 5 to 12 years, using univariate and multivariate data-driven analyses.

Results: We found divergent neuroanatomical phenotypes between groups, despite high behavioral similarities. Relative to the typically developing group, TS was associated with smaller whole-brain cortical surface area (p ≤ .0001), whereas NS was associated with smaller whole-brain cortical thickness (p = .013). TS was associated with larger subcortical volumes (left amygdala, p = .002; right hippocampus, p = .002), whereas NS was associated with smaller subcortical volumes (bilateral caudate, p ≤ .003; putamen, p < .001; pallidum, p < .001; right hippocampus, p = .015). Multivariate analyses also showed diverging brain phenotypes in terms of surface area and cortical thickness, with surface area outperforming cortical thickness at group separation.

Conclusions: TS and NS have syndrome-specific brain phenotypes, despite their behavioral similarities. Our observations suggest that neuroanatomical phenotypes better reflect the different genetic etiologies of TS and NS and may be superior biomarkers relative to behavioral phenotypes.