Identification and clinical phenotypes of sex chromosome aneuploidies in children with a predominant male phenotype: a single center study

This study aims to provide a comprehensive description of clinical phenotypes in a large clinical cohort of children with sex chromosome aneuploidies (SCAs), presenting predominantly with a male phenotype. We hereby particularly focused on the relationship between the sex chromosome composition and clinical phenotypes. Patients with SCAs were identified from a clinical cohort of 20,226 children who presented with one or more of the following clinical phenotypes: external genital anomalies, intellectual/developmental disabilities, speech delay, seizures, growth failure, or gynecomastia. All individuals underwent diagnostic evaluation via fluorescence in situ hybridization (FISH) or karyotyping. We conducted statistical analysis of demographic characteristics and clinical phenotypes. Correlation between clinical phenotypes and genetic findings was explored and visualized using Locally Weighted Scatterplot Smoothing (LOESS) fitted curves and Negative Binomial Regression model (NBR). 153 individuals (0.76%, 153/20,226) were identified with SCAs (median age = 3.6 years, range: birth to 16 years). 124 SCAs individuals were identified by FISH (median age = 3.4 years, range: birth to 16 years), 29 by karyotyping (median age = 5.2 years, range: 25 days to 15 years). 108 (70.59%) had a 47,XXY karyotype and its other variants (Klinefelter syndrome, KS) (median age = 4.3 years, range: birth to 16 years); 23 (15.03%) with a 47,XYY karyotype (47,XYY syndrome) (median age = 3.1 years, range: 25 days to 11 years) and 22 (14.38%) showed sex chromosome of 45,X/46,XY mosaicism (median age = 1.6 years, range: birth to 13.8 years). Cryptorchidism was most common anomaly in the entire clinical cohort, as well as in KS and 47,XYY groups, whereas hypospadias was more commonly observed in the 45,X/46,XY mosaicism group. LOESS fitting curve analysis suggests that patients with high-grade of X and Y sex chromosomes aneuploidies (HGAs, e.g., 48,XXXY, 49,XXXXY) in KS and non-mosaic 47,XYY had a higher burden of comorbidities. Significant correlations between the extra X chromosome proportion and clinical phenotypes were observed exclusively in the KS group under the NBR ( P = 0.006). In contrast, significant correlation was observed between the extra Y chromosomes proportion and clinical phenotype in the 47,XYY group ( P = 0.99), nor between the XY cells proportion and clinical phenotype in the 45,X/46,XY mosaicism ( P = 0.94). Children with SCAs diagnosed early due to severe developmental disorders, primarily exhibit clinical phenotypes including external genitalia anomalies (e.g., cryptorchidism, concealed penis, and hypospadias) and central nervous system (CNS) disorders in our clinical cohort. The severity of clinical phenotypes in KS may show a positive correlation with the extra X chromosome proportion. In contrast, in 47,XYY and 45,X/46,XY mosaicism groups, sex chromosome composition may not correlate with clinical phenotypes.