ESPE Abstracts

Background: NR5A1/SF-1 variants result in a wide range of phenotypes including DSD, male infertility, and primary ovarian insufficiency (POI). Little is known of how NR5A1/SF-1 variants affect puberty in individuals with or without DSD. This study aimed to assess the impact of NR5A1/SF-1 variants on pubertal development and investigate whether abnormal puberty is linked to the severity of DSD in an international cohort with NR5A1/SF-1 variants.

Methods & Patients: Collaborators from 55 centres (I-DSD registry and beyond) provided retrospective data on pubertal development and on DSD phenotype of individuals with NR5A1/SF-1 variants. We classified individuals into four DSD phenotype groups to define the degree of DSD based on the deviation of the external genitalia at birth from the typical phenotype for karyotype. We categorized pubertal development as: normal, abnormal, or unknown. Individuals without spontaneous start of puberty, receiving sex hormones, having Tanner stage outside expected range for the given age, or without having menarche by the age of 15, were classified as having abnormal puberty. For family members, we requested clinicians to indicate pubertal development status directly. (SF1next study group: https://www.dropbox.com/s/wza2bud5naw2ftd/SF1next%20study%20group.pdf?dl=0)

Results: Data on pubertal development were available for 112 individuals. Among them, 68% had a 46,XY karyotype, 30% had a 46,XX karyotype, and 2% had a 47,XXY or 47,XYY karyotype. Out of the 112 individuals, 57 (51%) had a DSD and five had POI. Sixty-two individuals (38 46,XY and 24 46,XX) had normal puberty, out of which 81% did not have a DSD (26 46,XY and 24 46,XX), 11% (7 46,XY) had a mild DSD phenotype and 8% (5 46,XY) had a severe DSD phenotype. Abnormal puberty was observed in 50 individuals, of which 45 had a DSD, with 60% had an opposite sex DSD phenotype (25 46,XY and 2 47,XYY or 47,XYY), 36% had a severe DSD phenotype (13 46,XY and 3 46,XX), and 4% had a typical phenotype (2 46,XX). 71 individuals of the SF1next study cohort were too young to assess puberty.

Conclusion: Individuals with NR5A1/SF-1 variants and a DSD are likely to manifest with an abnormal pubertal development compared to those without a DSD. Individuals with opposite sex DSD phenotype have abnormal puberty, while individuals with a mild DSD phenotype have normal pubertal development. Further studies in individuals with NR5A1/SF-1 variants without DSD are required to investigate whether NR5A1/SF-1 variants contribute to (minor) anomalies of pubertal development or fertility and reproduction in the general population.