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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.

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.