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Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.

Background: Treatment exposures for childhood cancer reduce ovarian reserve. However, the success of assisted reproductive technology (ART) among female survivors is not well established. Methods: Five‐year survivors of childhood cancer in the Childhood Cancer Survivor Study were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, which captures national ART outcomes. The authors assessed the live birth rate, the relative risk (RR) with 95% confidence intervals (95% CIs), and associations with treatment exposure using generalized estimating equations to account for multiple ovarian stimulations per individual. Siblings from a random sample of survivors were recruited to serve as a comparison group. Results: Among 9885 female survivors, 137 (1.4%; median age at diagnosis, 10 years [range, 0–20 years]; median years of follow‐up after age 18 years, 11 years [range, 2–11 years]) underwent 224 ovarian stimulations using autologous or donor eggs and/or gestational carriers (157 autologous ovarian stimulation cycles, 67 donor ovarian stimulation cycles). In siblings, 33 (1.4%) underwent 51 autologous or donor ovarian stimulations. Of those who used embryos from autologous eggs without using gestational carriers, 97 survivors underwent 155 stimulations, resulting in 49 live births, for a 31.6% chance of live birth per ovarian stimulation (vs. 38.3% for siblings; p =.39) and a 43.9% chance of live birth per transfer (vs. 50.0%; p =.33). Prior treatment with cranial radiation therapy (RR, 0.44; 95% CI, 0.20–0.97) and pelvic radiation therapy (RR, 0.33; 95% CI, 0.15–0.73) resulted in a reduced chance of live birth compared with siblings. The likelihood of live birth after ART treatment in survivors was not affected by alkylator exposure (cyclophosphamide‐equivalent dose, ≥8000 mg/m2 vs. none; RR, 1.04; 95% CI, 0.52–2.05). Conclusions: Childhood cancer survivors are as likely to undergo treatment using ART as sibling controls. The success of ART treatment was not reduced after alkylator exposure. The results from the current study provide needed guidance on the use of ART in this population. Linking the Childhood Cancer Survivor Study database to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System revealed that childhood cancer survivors are as likely to undergo treatment with assisted reproductive technology as their siblings. The success of assisted reproductive technology was not reduced after alkylator exposure. [ABSTRACT FROM AUTHOR]