Testing the extreme male brain theory of autism spectrum disorder in a familial design.

Autism Spectrum Disorder (ASD) may be an extreme manifestation of some male-typical traits in both neuroanatomy and cognition. Using the ratio of the second to fourth digit (2D:4D) and digit length as biomarkers of (pre- and postnatal) testosterone levels, examined was whether hypermasculinized digit ratios and/or lengths were familial traits in ASD and investigated their relation to sexually dimorphic cognitive abilities. 2D:4D ratios and digit lengths of 216 children with ASD, 202 unaffected siblings, and 360 parents were compared with those of 174 control children and their 146 parents. Generalized Estimation Equations, Generalized Linear Models, and Linear Mixed Models were used to investigate parent-offspring relationships and group differences. In ASD probands and their relatives alike, digit length relative to overall height was significantly increased in comparison to controls. No significant group differences were found between affected and unaffected subjects, or between males and females. Additionally, 2D:4D ratios increased with age. No (consistent) associations were found between 2D:4D ratio or digit lengths and systemizing and empathizing skills. The findings emphasize the role of familially based elevated pre- and postnatal testosterone levels in the liability for ASD, but challenge the use of 2D:4D ratio as a proxy of prenatal testosterone exposure solely. Given that many genes influence digit length, the exact mechanisms underlying a familial predisposition toward increased digit length in ASD are as yet unknown and needs to be explored in future studies.