ESPE Abstracts

Background: Loss of function variants in Steroidogenic Factor 1 (NR5A1/SF-1) lead to a broad spectrum of phenotypes, but data on the whole picture of phenotypes are currently lacking. We aimed to investigate the phenotype of individuals with SF-1 variants in a large international cohort.

Methods: We identified the individuals through the international I-DSD network and through contacting researchers from previous publications on SF-1 variation. Collaborators from 27 centres retrospectively entered phenotypic data on 107 individuals, according to the I-DSD registry and the Human Phenotype Ontology project in a REDCap database. Collaborators of SF1next study group are listed here: https://www.dropbox.com/s/wza2bud5naw2ftd/SF1next%20study%20group.pdf?dl=0.

Results: Of 107 individuals, 96 (89.7%) were 46,XY, nine were 46,XX (8.4%), and two were 47,XYY and 47,XXY respectively (0.9% each). Median age at follow-up was 12 years (range 0-54 years). Sex assignment at last follow-up was male in 62/107 (57.9%) and female in 45/107 (42%) individuals. Ten individuals had sex reassignment during the follow-up period (eight from female to male, one from male to female, one from other to male). Most (101/107, 94.3%) had differences of sex development (DSD), including 84/101 (83.1%) with disorders of gonadal development, 12/101 (11.8%) with non-specific XY DSD, and 1/101 (0.9%) with disorders of androgen action or other types of DSD (4/101, 3.9%). In 95 individuals, we had sufficient data on overall health problems. Thirty-six of 95 individuals (38%) had health problems which were not DSD-related in the following organ systems: urinary (10/95, 11%), blood and spleen (each 9/95, 9.4%), skeletal and central nervous system (each 7/95, 7.3%), head/neck (3/95, 3.1%), adrenal, metabolism/homeostasis and psychosocial (each 4/95, 4%), integument and muscle (each 3/95, 3.1%), immune and endocrine (each 2/95, 2.1%), cardiovascular, connective tissue and peripheral nervous system (each 1/95, 1%). There were no abnormalities in abdomen, breast, vasculature or respiratory system.

Conclusion: More than one third of individuals with SF-1 variants had multiple organ abnormalities, with a broad spectrum of phenotypes. Blood and spleen abnormalities were as frequent as urinary tract problems. Comprehensive gene profiling will allow to assess genotype-phenotype correlation and identify likely disease-causing variants in additional genes that might impact the phenotype. Genotype-phenotype patterns may help to identify individuals at risk for additional health problems.