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Context Boys with XXY have greater adiposity and a higher risk of cardiovascular disease. Infants with XXY have lower testosterone concentrations than typical boys, but no studies have evaluated adiposity in infants with XXY or the physiologic effects of giving testosterone replacement. Objective To determine the effect of testosterone on body composition in infants with XXY. Design Prospective, randomized trial. Setting Tertiary care pediatric referral center. Participants 20 infants 6 to 15 weeks of age with 47,XXY. Intervention Testosterone cypionate 25 mg intramuscularly monthly for three doses vs no treatment. Main Outcome Measures Difference in change in adiposity (percent fat mass z scores); other body composition measures, penile length, and safety outcomes between treated and untreated infants; and comparison with typical infants. Results The increase in percent fat mass (%FM) z scores was greater in the untreated group than in the treated group (+0.92 ± 0.62 vs −0.12 ± 0.65, P = 0.004). Increases in secondary outcomes were greater in the testosterone-treated group for total mass, fat-free mass, length z score, stretched penile length, and growth velocity (P < 0.002 for all). At 5 months of age, adiposity in untreated infants with XXY was 26.7% compared with 23.2% in healthy male infants of the same age (P = 0.0037); there was no difference in %FM between the treated XXY boys and controls. Reported side effects were minimal and self-limited; no serious adverse events occurred. Conclusions Adiposity of untreated infants was 15% greater than that of male controls by 5 months of age. Testosterone treatment for infants with XXY resulted in positive changes in body composition.

Context Klinefelter syndrome (KS) is the most common sex aneuploidy in men. Affected males have hypogonadism, and, as a result, face an increased risk for osteoporosis and fractures. Androgen therapy is standard in adolescents and adults with KS but has not been used earlier in childhood. Objective To determine the effects of androgen treatment on bone mass in children with KS. Methods Randomized, double-blind, placebo-controlled clinical trial of oxandrolone (OX; 0.06 mg/kg daily; n = 38) versus placebo (PL; n = 40) for 2 years in boys with KS (ages 4-12 years). Changes in bone mass were examined by digital x-ray radiogrammetry, which determines the Bone Health Index (BHI) and standard deviation score (SDS). Results BHI SDS was similar between groups at baseline (–0.46 ± 1.1 vs –0.34 ± 1.0 OX vs PL, P > .05) and higher in the OX group at 2 years (–0.1 ± 1.3 vs –0.53 ± 0.9, OX vs PL, P Conclusion Bone mass using BHI SDS is reduced in some children with KS and improves with OX. Since these individuals are at risk for osteoporosis, age-appropriate androgen replacement and future studies on bone health in children with KS should be further explored.

Background: Studies of transgender adults on gender affirming hormone therapy have shown increased rates of cardiovascular events (myocardial infarction and stroke) and features of metabolic syndrome including increased body mass index (BMI, transgender males) and dyslipidemia (transgender males and females). Studies in youth are limited by mostly small, single-center studies. With 1.8% of adolescents identifying as transgender, and increasing referral rates to gender clinics for care, more information is needed to better inform clinicians, patients and families about potential health risks in this cohort. PEDSnet, a pediatric Learning Health System, captures data from some of the largest pediatric care institutions in the U.S. We aimed to evaluate differences in diagnoses related to metabolic syndrome or cardiometabolic risk among youth with a diagnosis of gender dysphoria compared to matched cisgender controls. Methods: All youth with a diagnosis of gender dysphoria (n=4,177) and at least one outpatient encounter were extracted from the PEDSnet database (6 sites, years 2009-2019) and propensity-score matched on 7 variables (year of birth, age at last visit, site, race, ethnicity, insurance status, duration in database) to 4 controls without gender dysphoria (n=16,664). The odds of having a diagnosis of overweight/obesity, hypertension, dyslipidemia, dysglycemia, liver dysfunction, polycystic ovary syndrome (PCOS) or metabolic syndrome, was examined using generalized estimating equations with an interaction term for sex (as listed in the chart). Results: Of the transgender youth, 66% were female sex, 73% were white race, 9% were of Hispanic ethnicity, and 61% had private insurance. The control group was similar: 67% female sex, 72% white, 9% Hispanic, and 61% had private insurance. Transgender youth and controls both had on average 7 years duration in the database and were 16.2 years old at last visit. Transgender youth had higher odds of dyslipidemia (OR: 1.6 [95% CI: 1.3, 1.8], p

Background: While cardiac complications, short stature, and infertility are often discussed in the context of Turner Syndrome (TS), abnormalities of liver function are less well described. In order to address this gap in knowledge, we sought to better characterize hepatic abnormalities in youth with TS. Methods: PEDSnet is a collaboration across 7 major US pediatric institutions that unifies electronic medical data including diagnoses, prescriptions, and laboratory measurements for over 6 million children. 2,145 females with a diagnosis of TS were matched to 8,580 females without TS (1:4 ratio) on site, race (68% White), ethnicity (15% Hispanic), payer source, year of birth, age at most recent visit (median 14 years), and duration of care (mean 8 years). Outcomes of interest included highest recorded liver enzyme values (AST and ALT) categorized as normal or above the upper limit of normal (ULN) defined as >95th percentile for their age, and specific liver diagnoses. Proportions were compared between the cohorts using odds ratios (OR) and 95% confidence intervals (CI) from a generalized estimating equations approach. Multinomial logistic regression was conducted to investigate potential risk factors for liver abnormalities within the TS cohort. Results: Out of 1,159 girls with TS who had liver enzymes recorded in PEDSnet, 58% had at least one AST or ALT above the ULN. TS patients were more likely to have enzymes 1-2 times ULN (OR: 1.7, 95% CI: 1.4-1.9), more likely to be in the 2-3 times ULN category (OR: 2.7, 95% CI: 1.7-3.3), and more likely to be in the >3 times ULN category (OR: 1.7, 95% CI: 1.3-2.2) compared to girls without TS. TS patients were also more likely to have any liver diagnosis (OR: 2.4, 95% CI: 1.7-3.3), including significantly higher risk of fatty liver disease (OR: 1.9, 95% CI: 1.1-3.2), hepatitis (OR: 3.7, 95% CI: 1.9-7.1), cirrhosis/fibrosis (OR: 5.8, 95% CI: 1.3-25.0), and liver tumor/malignancy (OR: 4.8, 95% CI: 1.4-17.0). In the multinomial model, age, BMI, and the presence of a thyroid condition, cardiovascular diagnosis, or diabetes significantly (p < 0.05) increased the risk for elevated liver enzymes in girls with TS, while mosaicism, estrogen prescription, and celiac disease did not. Stratifying by age groups, over 40% of girls with TS had ALT elevations (24% > 2 times ULN, some with diagnosed liver conditions) under age 10, when liver screening is officially recommended per TS guidelines. Conclusions: Prevalence of elevated liver enzymes and diagnoses of liver disease are significantly higher in youth with TS vs. controls, emphasizing the need for clinical monitoring and additional research. Given the high percentage of girls

Background: The Megalencephaly Capillary Malformation syndrome (MCAP) is a genetic overgrowth disorder characterized by brain overgrowth, polymicrogyria, vascular malformations, and segmental somatic overgrowth secondary to activating mutations in the PI3K-AKT-mTOR pathway (PIK3CA). Congenital macrosomia and postnatal asymmetric overgrowth is typical in this condition, however both growth failure and hypoglycemia have been reported in a significant fraction of affected children raising the concern for growth hormone deficiency (GHD). Methods: We performed an observational multi-institution study of children with MCAP and GHD. Medical records were abstracted including growth trajectories, laboratory data, and treatment response to growth hormone (GH), if applicable. Results: Eight participants (4 female, 4 male) were diagnosed with GHD at mean age of 3.2 years. All had very low or undetectable insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGF-BP3) concentrations. Four underwent GH stimulation testing and all had insufficient responses with a median peak GH of 3.1 ng/ml (range 1.1-7.3). Growth patterns revealed a drastic decline in height z-scores within the first year of life from greater than 2.0 at birth to less than -2.0 z-score by 12 months of age. Growth velocity was in the low-normal range between 1-4 years of age therefore height z-scores were stable but remained low. Four of the 8 had hypoglycemia with fasting. Central hypothyroidism was diagnosed in one and adrenal insufficiency in another. Brain MRI reports were available in 7 children and all had a structurally normal pituitary gland. Three children were treated with GH; one became inconsolable after one week of treatment and it was discontinued. The other two children have continued on GH with excellent responses in linear growth velocity. Conclusion: Profound GHD is a notable feature of MCAP, a condition with gain-of-function mutations promoting cell growth and proliferation. Therefore, children with MCAP and either hypoglycemia and/or postnatal growth failure should be evaluated for GHD. The universally low IGF-BP3 levels in this cohort were striking given this is an unusual finding even in GHD. Additional research is needed into the mechanisms underlying this phenomenon as well as whether treatment with GH is effective and safe in this condition.

Background: An additional X chromosome occurs in 1 in 1,000 females resulting in a 47,XXX karyotype also known as Trisomy X. Abnormal ovarian function was suggested from a cohort of 10 females with Trisomy X followed from birth through young adulthood who had later age of menarche and one girl who developed secondary amenorrhea with elevated gonadotropin levels (1). There have since been several case reports of premature menopause in women with Trisomy X, and 3.8% of women with premature ovarian insufficiency (POI) have been reported to have Trisomy X (2). Ovarian reserve can be estimated by serum anti-mullerian hormone (AMH) concentrations, with low AMH concentrations concerning for diminished ovarian reserve and poor fertility prospects. Ovarian function in youth with Trisomy X has not been evaluated. The purpose of this study was to evaluate AMH as a marker of ovarian reserve in girls with Trisomy X. Methods: Parents and youth with Trisomy X seen at a tertiary care referral center were counselled on the risk for POI and AMH was offered as a screen for ovarian reserve. All participants provided informed consent to use their clinical data for research purposes. A total of 11 girls with a non-mosaic 47,XXX karyotype had AMH measured by chemiluminescent assay (Esoterix Laboratory Services) between December 2015 and October 2018. Results: The median age of participants was 13.3 years (IQR 12.4 – 17.9) and 9 of 11 girls had experienced menarche at a median age of 12.5 years (IQR 11.5-12.6); none had primary or secondary amenorrhea. The median AMH concentration was 0.7 ng/ml (IQR 0.2-1.7), significantly lower than the laboratory provided median of 5.23 ng/ml (one sample Wilcoxin Signed Rank Test p=0.001). 72% had an AMH below 1.05 ng/ml, the lower limit of normal for age. Discussion: Despite normal menarchal timing and ongoing menses, the majority of youth with Trisomy X had a low AMH concerning for diminished ovarian reserve and potentially impaired fertility. Although there is great interest in fertility preservation for girls with oncological diagnoses and Turner syndrome, there is limited awareness of ovarian dysfunction in Trisomy X. Research on ovarian function and fertility in Trisomy X is needed across the lifespan, as well as investigation into the mechanisms of the additional X chromosome leading to the diminished ovarian reserve observed in this adolescent sample. (1) Ratcliffe et al, 1990, Birth Defects: Original Article Series, 26(4): 1-44. (2) Goswami et al, 2003, Fertil Steril, 80(4): 1052-4.

Background: Congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) causes cortisol insufficiency and androgen excess. A phase 2 trial of crinecerfont, a CRF1 receptor antagonist, in 18 adults with 21OHD showed prominent decreases in ACTH, 17-hydroxyprogesterone, and androstenedione (A4), and in women, testosterone (T), after 14 days of treatment. In men with 21OHD, T derives from both adrenals and testes; in poor disease control, A4/T ratio is elevated due to disproportionately increased adrenal A4 production and decreased testicular T production. We sought to determine the impact of crinecerfont on both adrenal and gonadal androgen production in men with 21OHD in this phase 2 trial. Methods: A4 and T data were analyzed for 7 men who completed 1 or more of 4 oral dosing regimens: Cohort 1, 50 mg QHS, n=4; Cohort 2, 100 mg QHS, n=2; Cohort 3, 100 mg QPM, n=5; and Cohort 4, 100 mg BID, n=3 (14 total treatment periods). Mean 0600-1000 4-hour morning window (M4hMW) and mean 24-hour (M24h) A4, T, and A4/T ratios were analyzed from serial serum samples at baseline and on day 15. Results: Dose-dependent reductions in M4hMW A4 were observed [median (range)] in men, consistent with previously presented data in all subjects:Cohort 1: -21% (-84 to -12%);Cohort 2: -37% (-51% to -23%);Cohort 3: -43% (-85% to +140%);Cohort 4: -62% (-90% to -33%). In contrast, M4hMW T showed inconsistent changes [median (range)]: Cohort 1: +18% (-40% to +82%);Cohort 2: -4% (-4.3% to -3.8%);Cohort 3: +9% (-11 to +24%);Cohort 4: +9% (-3% to +27%). Thus, M4hMW A4/T ratios decreased with dose. Values at baseline, on day 15, and percent changes [median (range)] were, respectively:Cohort 1: 0.9 (0.3–2.6), 0.6 (0.1–2.1), -26% (-91% to +23%);Cohort 2: 5.0 (4.8–5.2), 3.3 (2.5–4.2), -35% (-49% to -20%);Cohort 3: 0.6 (0.1–6.9), 0.3 (0.1–2.7), -54% (-85% to +178%);Cohort 4: 3.9 (0.6–5.9), 0.4 (0.3–2.1), -65% (-92% to -31%). M24h A4/T ratios similarly declined in all cohorts. Values at baseline, on day 15, and percent changes [median (range)] were, respectively:Cohort 1: 1.0 (0.3–2.3), 0.4 (0.1–1.9), -33% (-92% to +2%);Cohort 2: 4.3 (3.8–4.9), 2.7 (2.4–3.0), -36% (-51% to -22%);Cohort 3: 0.5 (0.1–4.7), 0.4 (0.1–2.4), -59% (-78% to +310%);Cohort 4: 3.2 (0.4–4.1), 0.4 (0.3–1.7), -58% (-89% to -31%). Conclusions: Following crinecerfont therapy, A4 and A4/T decreased in a dose-dependent manner in men with 21OHD. In contrast to reductions in T observed in women with 21OHD, T did not change consistently and rose in some men. Preserved T values despite marked A4 reductions suggests testicular T production increased during crinecerfont therapy, perhaps due to release of gonadotropin suppression from adrenal-derived androgens. Long term studies are needed to determine if crinecerfont treatment improves additional measures of testicular function in men with 21OHD. Reference: RJ Auchus, et al. J Endocr Soc 2020;4(Suppl 1):OR25-03.