ESPE Yearbook of Paediatric Endocrinology

Brief Summary: The SF1next study describes a cohort of 197 individuals with NR5A1 / SF-1 variants, identified through the I-DSD registry and a research network involving 55 centers across 18 countries. NR5A1/SF-1 plays a crucial role in the development and function of human sex and steroid producing organs, and variants in this gene can significantly affect early sex determination and differentiation. This can lead to a wide spectrum of differences in sex development (DSD), from healthy carriers to severe forms of DSD. Despite extensive research, a comprehensive understanding of the diverse clinical presentations of NR5A1/SF-1 variants is still lacking.

SF1next is a global collaborative effort aimed at collecting data on the largest cohort to date, to address the variability of rare DSD associated with NR5A1/SF-1 variants. The study used a standardized dataset consisting of data collected during care delivered according to international recommendations for the optimal clinical care of individuals with DSD. The findings confirmed a broad range of phenotypes, from severe DSD (defined as >2 of the genital features degree of labioscrotal fusion, length of the genital tubercle, position of the urethral meatus, and locations of the right and left gonads being atypical for karyotype prior to any surgery) in over 70% of 46,XY individuals to healthy carriers in 90% of 46,XX females. Phenotypic variability was observed even among families with the same genetic variants, indicating no clear genotype–phenotype correlation. The study concludes that phenotypic variability in NR5A1/SF-1 variants may involve additional genetic factors, suggesting a possible oligogenic cause for some individuals with DSD.

The authors acknowledge the limitations of relying on data not originally collected for the specific purpose of this study and sometimes partially incomplete or inaccurate data due to problems inherent to the study design and use of registry data in this multicenter retrospective study.

Beyond genetics and DSD phenotype, information on birth weight, anthropometric measurements at the last visit, involvement of other organ systems, surgical procedures performed on patients, germ cell tumor development, and pubertal developmental course were included. Collectively, these results expand our knowledge of individuals with NR5A1/SF-1 variants.