Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series.

study questionWhat is the long-term outcome of individuals born with bilateral testicular regression (BTR) in relation to its underlying etiology? SUMMARY ANSWER: Statural growth and pubertal development are adequate with incremental doses of testosterone replacement therapy (TRT); however, penile growth is often suboptimal, especially in those with a suspected genetic etiology (i.e. heterozygous WHAT IS KNOWN ALREADY: BTR is a rare and poorly understood condition. Although a vascular origin has been postulated, heterozygous missense variants in STUDY DESIGN SIZE DURATION: For this cross-sectional study, individuals with BTR were recruited in eight Belgian pediatric endocrinology departments, between December 2019 and December 2022. A physical exam was performed cross-sectionally in all 17 end-pubertal participants and a quality of care questionnaire was completed by 11 of them. Exome-based panel testing of 241 genes involved in gonadal development and spermatogenesis was performed along with a retrospective analysis of presentation and management. A centralized histological review of gonadal rests was done for 10 participants. PARTICIPANTS/MATERIALS SETTING

methodsA total of 35 participants (33 with male, 1 with female, and 1 with non-binary gender identity) were recruited at a mean age of 15.0 ± 5.7 years. MAIN RESULTS AND THE ROLE OF CHANCE: The median age at presentation was 1.2 years [0-14 years]. Maternal gestational complications were common (38.2%), with a notably high incidence of monozygotic twin pregnancies (8.8%). Heterozygous (likely) pathogenic missense variants in LIMITATIONS REASONS FOR CAUTION: The limitations of this study include the relatively small sample size (n = 35) and the few individuals with WIDER IMPLICATIONS OF THE

findingsTRT provides adequate statural growth, even when initiated in late adolescence, thus providing time for physicians to explore the patients' gender identity if needed. However, sufficient and understandable information regarding the effects and side effects of TRT is required throughout the management of these patients. SPL remains suboptimal in many individuals and could be improved by TRT during infancy to mimic the physiological mini-puberty. An environmental origin in some participants is supported by the high incidence of gestational complications (38.2%) and by the three monozygotic twin pregnancies discordant for the BTR phenotype. Individuals with a heterozygous STUDY FUNDING/COMPETING INTERESTS: Funding was provided by the Belgian Society for Pediatric Endocrinology and Diabetology (BESPEED) and by Ghent University Hospital under the NucleUZ Grant (E.D.B.). M.C. and E.D.B. are supported by an FWO senior clinical investigator grant (1801018N and 1802220N, respectively). The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.