Orphanet Journal of Rare Diseases | Neurocognitive Function Analysis in Males with 46,XX T-DSD

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This study systematically evaluated the neurocognitive differences between males with 46,XX T-DSD and controls for the first time, revealing a significant reduction in working memory index in 46,XX T-DSD males. It provides important evidence for cognitive research related to rare disorders of sex development.

 

Literature Overview
This article, titled 'Neurocognitive function in males with 46,XX testicular difference of sex development', published in the Orphanet Journal of Rare Diseases, reviews and summarizes comparative studies between males with 46,XX T-DSD and 46,XY controls in terms of neurocognitive function. The WAIS-IV scale was used for assessment, and the results showed that 46,XX T-DSD males scored significantly lower on the working memory index. Moreover, 56% of patients fell into the low-average or below range in overall FSIQ, suggesting they may face certain cognitive challenges.

Background Knowledge
46,XX T-DSD (46,XX testicular disorder of sex development) is a rare condition where individuals have a 46,XX karyotype but present with a male phenotype. The molecular mechanism primarily involves translocation of the SRY gene or variations in other genes such as SOX3, SOX9, NR5A1, and WT1 in SRY-negative individuals. Although most patients maintain sexual function through testosterone replacement therapy, their neurocognitive profiles have not been systematically studied. Patients with Klinefelter syndrome (KS) exhibit a wide range of neurocognitive deficits, but the neurocognitive characteristics of 46,XX T-DSD males remain unclear. This study aims to fill this gap by conducting a detailed comparison using the standardized neurocognitive assessment tool WAIS-IV. Both 46,XX T-DSD and KS present with hypergonadotropic hypogonadism, but differ in chromosomal composition. Studying their neurocognitive features can help elucidate the potential impact of testosterone deficiency on brain development and the role of specific gene variations in cognitive function. Additionally, working memory is a crucial component of learning and daily cognitive processing, and deficits may significantly affect educational and occupational performance. Therefore, this study contributes to a better understanding of the neurocognitive phenotype in 46,XX T-DSD males and helps optimize clinical management.

 

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Research Methods and Procedures
The study included 25 genetically confirmed 46,XX T-DSD males and 22 age- and education-matched 46,XY controls. All participants underwent the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) assessment to determine their Full-Scale IQ (FSIQ) and four indices: Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI). Statistical analyses were conducted using independent-sample t-tests and Wilcoxon rank-sum tests to assess group differences.

Key Findings and Observations

• Working Memory Index (WMI) in 46,XX T-DSD males was significantly lower than controls (p = 0.017), especially in the Arithmetic and Letter-Number Sequencing subtests (p < 0.05).
• Although no significant difference in Full-Scale IQ (FSIQ) was found between groups (p = 0.086), 56% of 46,XX T-DSD males (n=14) scored in the low-average or below range, compared to only 13.6% (n=3) of controls.
• Two 46,XX T-DSD males (both SRY-positive) scored below 69 in FSIQ, which is considered extremely low, while no such individuals were found in the control group.
• In the Verbal Comprehension Index (VCI), 46,XX T-DSD males scored significantly lower in the Similarities and Information subtests (p=0.047 and p=0.005).
• In the Processing Speed Index (PSI), 46,XX T-DSD males performed worse in the Symbol Search subtest (p=0.037), though no significant differences were observed in other subtests.
• All test scores remained within the normal range, but the 46,XX T-DSD group exhibited a more scattered score distribution, indicating cognitive heterogeneity.

Significance and Future Directions
This study represents the first systematic evaluation of neurocognitive function in 46,XX T-DSD males, revealing specific deficits in working memory and suggesting clinicians should pay attention to cognitive characteristics when managing such patients. The findings provide guidance for educational, occupational, and clinical interventions. Future studies should expand the sample size and incorporate more comprehensive neuropsychological assessments, including non-cognitive factors (e.g., motivation, personality traits), to further elucidate the mechanisms underlying cognitive impairments. Genetic variation analysis will also help clarify the influence of different genetic backgrounds on cognitive function.

 

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Conclusion
This study systematically assessed the neurocognitive function of males with 46,XX testicular difference of sex development (T-DSD) compared to 46,XY controls. It found that T-DSD males scored significantly lower on the Working Memory Index (WMI) and had a higher proportion in the low-average or below range in Full-Scale IQ (FSIQ). Although overall IQ remains within the normal range, the findings suggest a tendency toward lower cognitive performance, which may affect educational and occupational achievements. This study offers preliminary evidence for clinical evaluation and intervention and lays the foundation for future genotype-phenotype correlation studies and investigations into the role of testosterone in neurodevelopment. Further research integrating large cohorts, multi-omics analysis, and comprehensive neuropsychological assessments will provide a more complete understanding of the neurocognitive features and clinical needs of 46,XX T-DSD males.

 

Etki Albayrak Rasborg Hartogsohn, Mirkka Hiort, Julia Rohayem, Agnethe Berglund, and Claus Højbjerg Gravholt. Neurocognitive function in males with 46,XX testicular difference of sex development. Orphanet Journal of Rare Diseases.