Exploring the Association between Prenatal Growth and Differences in Sexual Development in Newborns

Associated conditions, especially being born small for gestational age (SGA), have been reported with a higher prevalence in patients with differences in sexual development (DSD) compared to the general population. Our objective was to analyze the prevalence of SGA in a cohort of DSD patients evaluated at a single tertiary pediatric center, and to examine its association with sex chromosome constitution, molecular diagnosis, and clinical phenotype.

Gestational age, birth weight, and birth length were evaluated to assess prenatal growth and the prevalence of SGA. DSD patients were classified according to karyotype. Among 46,XY DSD patients, perinatal data were further analyzed based on molecular diagnosis and the presence or absence of gonadal dysgenesis.

Overall, 642 DSD patients were included: 202 (31.5%) with chromosomal DSD, 218 (33.9%) with 46,XX DSD, and 222 (34.6%) with 46,XY DSD. SGA prevalence was 30.2%, 7%, and 27.5%, respectively. In the 46,XY DSD group, a molecular diagnosis was achieved in 35% of patients. SGA was more frequent in 46,XY DSD subjects without molecular diagnosis and without gonadal dysgenesis.

A high prevalence of SGA was observed among individuals with sex chromosome DSD, consistent with the literature, whereas a lower prevalence was found among those with 46,XX DSD, as expected in the Latin American population. The frequency of SGA in the 46,XY DSD group reinforces the association between SGA and DSD in the 46,XY DSD, particularly in patients without a clear molecular diagnosis and without specific disorders of undervirilization. Factors involved in early embryonic growth, development, and gonadal differentiation may mediate the association between being born SGA and DSD in humans. Further studies are needed to clarify the etiological diagnosis.