Neurocognitive function in males with 46,XX testicular difference of sex development

46,XX testicular difference of sex development (46,XX T-DSD) is a rare condition, in which individuals with a typical female chromosomal pattern (46,XX) present with a male phenotype. Although neurocognitive function has previously been reported as normal in males with 46,XX T-DSD, studies indicate potential neurocognitive challenges, including lower educational attainment.

We aimed to assess neurocognitive function in males with 46,XX T-DSD compared to 46,XY male controls using the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV).

47 participants were included in the study, comprising 25 males with 46,XX T-DSD and 22 46,XY male controls matched on age and educational level. Of the 25 46,XX T-DSD males, 23 had an SRY translocation, while the remaining two were SRY-negative; one of these showed a SOX9 duplication, and no genetic cause was identified for the other despite extensive testing. All participants completed the WAIS-IV. We calculated each participant's Full-Scale Intelligence Quotient (FSIQ) and four index scores: Verbal Comprehension Index, Perceptual Reasoning Index, Working Memory Index, and Processing Speed Index.

Males with 46,XX T-DSD scored significantly lower on the Working Memory Index (mean ± SD: 93.3 ± 15.7 vs. 104.3 ± 14.6, p = 0.017) compared to controls, with two of three subtests showing lower scores (p < 0.05). In the 46,XX T-DSD group, mean scores on the Verbal Comprehension Index and overall FSIQ were 91.6 ± 16.7 and 93.8 ± 15.6, respectively, compared with 98.9 ± 11.4 and 100.7 ± 10.3 in controls. Neither difference reached statistical significance (VCI: p = 0.092, FSIQ: p = 0.086). All mean scores for both groups remained within the normal range. Among males with 46,XX T-DSD, 56% (n = 14) scored in the low average range (80-89) or below on the FSIQ, compared to only 13.6% (n = 3) in the control group. Additionally, two males in the 46,XX T-DSD group scored in the extremely low range (≤ 69), whereas none in the control group did.

Our findings indicate that 46,XX T-DSD males score significantly lower on the Working Memory Index compared to controls. No other statistically significant differences in index scores were observed, and all mean scores for both groups remained within the normal range. Larger-scale research and more comprehensive assessments of non-cognitive factors will be essential for gaining deeper insight into these findings and assessing their clinical significance.