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

Rasborg Hartogsohn Etki Albayrak; Mirkka Hiort; Julia Rohayem; Jens Fedder; Sandra Laurentino; Jorg Gromoll; Lukas Ridder; Anne Skakkebaek; Cecilie Buskbjerg; Agnethe Berglund; Gravholt Claus H.

doi:10.1530/endoabs.110.P1068

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Endocrine Abstracts (2025) 110 P1068 | DOI: 10.1530/endoabs.110.P1068

ECEESPE2025 Poster Presentations Reproductive and Developmental Endocrinology (93 abstracts)

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

Etki Albayrak Rasborg Hartogsohn ^1,2 , Mirkka Hiort ³ , Julia Rohayem ^4,5 , Jens Fedder ^6,7 , Sandra Laurentino ⁵ , Jörg Gromoll ⁵ , Lukas Ridder ^1,2 , Anne Skakkebæk ^8,9 , Cecilie Buskbjerg ¹⁰ , Agnethe Berglund ^2,8 & Claus H. Gravholt ^1,2,9

Author affiliations

¹Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark; ²Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; ³Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany, Münster, Germany; ⁴Children’s Hospital of Eastern Switzerland, St. Gallen, Switzerland; ⁵Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany; ⁶Centre of Andrology & Fertility Clinic, Odense University Hospital, Odense, Denmark; ⁷Research Unit of Gynaecology and Obstetrics, University of Southern Denmark, Odense, Denmark; ⁸Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark; ⁹Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; ¹⁰Psychology and Behavioral Sciences - Unit for Psychooncology and Health Psychology, Aarhus University, Aarhus, Denmark

JOINT113

Background: 46,XX testicular disorder of sex development (46,XX T-DSD) is a rare condition, in which individuals with a typical female chromosome pattern (46,XX) present with a male phenotype. Although previously considered to have minimal influence on neurocognitive function, recent research indicates an association with neurocognitive challenges, including lower educational attainment.

Objective: The aim of this study was to assess neurocognitive function in males with 46,XX T-DSD compared to 46,XY male controls, utilizing the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV). Cases and controls were matched on educational level.

Methods: A total of 47 participants were included in the study, comprising 25 males with 46,XX T-DSD and 22 46,XY male controls. All participants completed the WAIS-IV. Based on subtest scores, we calculated Full-Scale IQ and the four index scores: Verbal Comprehension Index, Perceptual Reasoning Index, Working Memory Index, and Processing Speed Index. T-tests or Wilcoxon rank-sum tests were used to compare Full-Scale IQ, index scores, and subtest scores, depending on data normality.

Results: Males with 46,XX T-DSD demonstrated significantly lower performance on the Working Memory Index (93.3 ± 15.7 vs. 104.3 ± 14.6, P = 0.017) compared to controls, with significantly lower scores on two out of three subtests. A trend towards lower performance was also observed in the Verbal Comprehension Index (91.6 ± 16.7 vs. 98.9 ± 11.4, P = 0.092), with significantly lower scores on two out of three subtests. Similarly, a trend towards lower Full-Scale IQ was observed (93.8 ±15.6 vs. 100.7 ± 10.3, P = 0.086). Among males with 46,XX T-DSD, 56% scored in the low average range or below on the Full-Scale IQ, compared to only 13.6% in the control group. Additionally, two males in the 46,XX T-DSD group fell within the extremely low range, whereas none in the control group did.

Conclusion: These results indicate that males with 46,XX T-DSD exhibit certain neurocognitive challenges compared to 46,XY males. Significantly lower scores were found in the Working Memory Index and on two of three subtests in the Verbal Comprehension Index. In addition, a trend towards lower Full-Scale IQ suggests potential global cognitive weaknesses, warranting further investigation. These results emphasize the importance of early identification of neurocognitive challenges and the development of tailored interventions to support both educational and functional outcomes in this population. Future studies should focus on identifying strategies to minimize diagnostic delay, enabling timely intervention.