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Background: 1.8% of youth identify as transgender; a growing proportion are transgender male (female sex, male gender identity). Many receive gonadotropin releasing hormone agonist (GnRHa) therapy to suppress endogenous puberty and/or will start testosterone to induce secondary sex characteristics that align with gender identity. Objective(s): To determine the effects of 12 months of testosterone on cardiometabolic health among transgender youth, including insulin sensitivity, body composition, and bone mineral density and whether changes in outcomes differ based on prior GnRHa treatment. Methods: Participants (n = 19, baseline age 15.0 ± 1.0 years) were examined prior to and 12 months after testosterone therapy in a longitudinal observational study. Fasted morning blood draw, a 2-hour 75-gram oral glucose tolerance test, body composition and bone mineral density (dual-energy X-ray absorptiometry) were assessed at baseline and 12 months. Insulin sensitivity was estimated by HOMA-IR and Matsuda index. Changes were compared with mixed linear regression models evaluating time (baseline, 12 months), group (GnRHa treatment yes/no), and their interaction. Results: In the entire cohort, fasted insulin decreased (median [25,75 %ile]: −3 [-5, 0] mIU/L, p = 0.044) and 2-hour glucose increased (mean ± standard deviation): +18.5 ± 28.9 mg/dL, p = 0.013 from baseline after 12 months of testosterone therapy. There were no significant changes in HOMA-IR (p = 0.062) or Matsuda index (p = 0.096), nor by GnRHa status. Absolute (+6.2 [4.7, 7.5] kg, p = 0.016) and percent fat-free mass increased (+7.3 [5.4, 9.1] %, p = 0.003) and percent fat mass declined (−7.4 [-9.3, 5.3]%, p = 0.005) for the entire cohort. There were time*group interactions for absolute (p = 0.0007) and percent fat-free mass (p = 0.033). There were time*group interactions for bone mineral content (p = 0.006). Conclusions: Twelve months of testosterone in transgender adolescents resulted in changes in body composition and bone mineral density, with baseline differences between the +/-GnRHa group and convergence after 12 months. There were no changes in insulin sensitivity over time or between groups.

Background Transgender and gender diverse (TGD) individuals and long‐term survivors with adult congenital heart disease (ACHD) are both growing populations with specialized needs. No studies assess temporal trends or evaluate the care of TGD individuals with ACHD. Methods and Results Meetings between congenital cardiology and gender‐affirming care specialists identified unique considerations in TGD individuals with ACHD. A retrospective chart review was then performed to describe patient factors and outpatient trends in those with an ACHD diagnosis undergoing gender‐affirming hormonal or surgical care (GAHT/S) at 1 adult and 1 pediatric tertiary care center. Thirty‐three TGD individuals with ACHD were identified, 21 with a history of GAHT/S. Fourteen (66%) had moderate or complex ACHD, 8 (38%) identified as transgender male, 9 (43%) transgender female, and 4 (19%) other gender identities. Three had undergone gender‐affirming surgery. There were zero occurrences of the composite end point of unplanned hospitalization or thrombotic event over 71.1 person‐years of gender‐affirming care. Median age at first gender‐affirming appointment was 16.8 years [interquartile range 14.8–21.5]. The most common treatment modification was changing estradiol administration from oral to transdermal to reduce thrombotic risk (n=3). An increasing trend was observed from zero TGD patients with ACHD attending a gender diversity appointment in 2012 to 14 patients in 2022. Conclusions There is a growing population of TGD patients with ACHD and unique medical and psychosocial needs. Future studies must fully evaluate the reassuring safety profile observed in this small cohort. We share 10 actionable care considerations for providers with a goal of overseeing a safe and fulfilling gender transition across all TGD patients with ACHD.

Introduction: Here we report an infant with a 46,XY karyotype and novel de novo PPP1R12A stop-loss variant with a concomitant anorectal malformation (ARM) and difference in sex development (DSD). Case report: This is an infant born with ambiguous genitalia and rectoperineal fistula. Genetic testing confirmed a 46,XY chromosomal complement and whole exome sequencing demonstrated a novel de novo heterozygous PPP1R12A stop-loss variant. The infant underwent tapering jejunoplasty, proximal jejunostomy and mucous fistula creation for jejunal atresia and posterior sagittal anorectoplasty for the ARM. The gonad will be addressed with a biopsy and orchiopexy when the infant reaches six months of age. Conclusion: Although Müllerian anomalies and hypospadias may be common with ARM, a true DSD of this nature is exceedingly rare. Multidisciplinary care with urology, endocrinology, genetics, and colorectal surgery is paramount to providing optimal care for this patient.

Objective: While the field of pediatric endocrinology, and the American Board of Pediatrics, continues expanding training to include gender-affirming care, many pediatric endocrinology fellowship programs do not have formal curriculum for this patient population. Members of the Pediatric Endocrine Society (PES) that have a special interest in transgender health designed a curriculum based on Endocrine Society practice guidelines to expand the knowledge of gender affirming care for medical trainees' and faculty. Methods: PES members designed a 5-part self-guided educational module series with embedded knowledge questions. Uniquely, medical ethical reflections were included within each module. Participants completed baseline demographic and baseline and follow-up knowledge surveys. Results: Most participants were pediatric endocrinology fellows and 44 % percent (n = 21) completed all study components, including the follow up knowledge survey. Knowledge question data analysis demonstrated knowledge gained in medical management of pubertal youth and surgical interventions. Conclusion: This is the first medical education curriculum in gender-affirming care created by pediatric endocrinologists grounded in the Endocrine Society practice guidelines. This study demonstrates medical knowledge gained in caring for gender diverse youth and is the first to incorporate ethical considerations for this patient population. While initially designed for pediatric endocrinology trainees and faculty, this curriculum may be of great utility for any provider interested in caring for gender diverse youth.

Lipoid congenital adrenal hyperplasia (LCAH) is typically inherited as an autosomal recessive condition. There are 3 reports of individuals with a dominantly acting heterozygous variant leading to a clinically significant phenotype. We report a 46,XY child with a novel heterozygous intronic variant in STAR resulting in LCAH with an attenuated genital phenotype. The patient presented with neonatal hypoglycemia and had descended testes with a fused scrotum and small phallus. Evaluation revealed primary adrenal insufficiency with deficiencies of cortisol, aldosterone, and androgens. He was found to have a de novo heterozygous novel variant in STAR : c.65-2A>C. We report a case of a novel variant and review of other dominant mutations at the same position in the literature. Clinicians should be aware of the possibility of attenuated genital phenotypes of LCAH and the contribution of de novo variants in STAR at c.65-2 to the pathogenesis of that phenotype.

Androgen insensitivity syndrome (AIS) is caused by mutations in the gene encoding the androgen receptor (AR). The incidence of AIS is estimated to be 1 in 99,000. Complete androgen insensitivity syndrome (CAIS) is characterized by a 46,XY karyotype with external genitalia that appear typically female and results from mutations that render the androgen receptor non-functional. Partial androgen insensitivity syndrome (PAIS) results from partial loss of function mutations in AR. Rarely, PAIS results from somatic mosaicism for an AR mutation and not from a hypomorphic variant. We present two cases of PAIS due to somatic mosaicism, one caused by a novel nonsense mutation and one caused by a missense mutation previously reported in CAIS. Two patients with atypical genitalia presented to our multidisciplinary clinic for disorders of sex development and sequencing of AR was performed as part of the diagnostic evaluation. In case one, AR sequencing revealed mosaicism for a nonsense mutation, c.1331T > A; p.Leu444Ter. This mutation has not previously been reported, but is presumed to be pathogenic. In case two, AR sequencing revealed a mosaic missense mutation, c.2279 C > A; p.Ser760Tyr, which has previously been reported in CAIS but not in PAIS. Similar phenotypes may result from AR mutations that are present in a mosaic state with full loss of function or hypomorphic mutations that partially impair the function of the protein in either all tissues or in a mosaic state.