Objective To describe auxologic, physical, and behavioral features in a large cohort of males with 47,XYY (XYY), ages newborn to young adult. Study design This is a cross-sectional descriptive study of male subjects with XYY who were evaluated at 1 of 2 specialized academic sites. Subjects underwent a history, physical examination, laboratory testing, and cognitive/behavioral evaluation. Results In 90 males with XYY (mean age 9.6 ± 5.3 years [range 0.5-36.5]), mean height SD was above average (1.0 ± 1.2 SD). Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly in 47/90 (52%), and hypertelorism in 53/90 (59%). There was testicular enlargement for age (>2 SD) in 41/82 (50%), but no increase in genital anomalies. No physical phenotypic differences were seen in boys diagnosed prenatally vs postnatally. Testosterone, luteinizing hormone, and follicle stimulating hormone levels were in the normal range in most boys. There was an increased incidence of asthma, seizures, tremor, and autistic spectrum disorder (ASD) compared with the general population rates. Prenatally diagnosed boys scored significantly better on cognitive testing and were less likely to be diagnosed with ASD (P < .01). Conclusions The XYY phenotype commonly includes tall stature, macrocephaly, macroorchidism, hypotonia, hypertelorism, and tremor. Physical phenotypic features were similar in boys diagnosed prenatally vs postnatally. Prenatal diagnosis was associated with higher cognitive function and less likelihood of an ASD diagnosis.

A subset of the XYY and KS groups had behavioral difficulties that were more severe in the XYY group. These findings could guide clinical practice and inform patients and parents. Boys diagnosed with XYY or KS should receive a comprehensive psychoeducational evaluation and be screened for learning disabilities, attention-deficit/hyperactivity disorder, and autism spectrum disorders.

Aims To investigate risk factors for metabolic syndrome in prepubertal boys with Klinefelter syndrome. Methods Eighty-nine boys with Klinefelter syndrome, ages 4–12.9 years, and 34 age-matched control boys had height, weight, waist circumference and blood pressure measured and their parents completed a questionnaire about physical activity. The boys with Klinefelter syndrome also had measurement of lipids, fasting glucose and insulin. Insulin-glucose homeostasis model assessment was calculated, and the boys were evaluated for childhood metabolic syndrome. Results The Klinefelter syndrome and control groups were similar ages (7.5 ± 2.4 vs. 8.1 ± 2.3 years). Body mass index measurements were similar, but waist circumference was >90‰ in 30% of boys with Klinefelter syndrome versus 21% of controls. The mean daily time spent running was 42 min less in the Klinefelter syndrome versus control groups (p < 0.01). About 37% of the boys with Klinefelter syndrome had elevated LDL cholesterol, 24% had insulin resistance, and 7% met the three criteria for diagnosis of metabolic syndrome. Conclusions Truncal obesity, insulin resistance and metabolic syndrome are present in boys as young as 4–12 years with Klinefelter syndrome, and these occur in association with reduced running-type activity.

Context Daily growth hormone (GH) injections can be burdensome for patients and carers. Somapacitan is a long-acting, reversible albumin-binding GH derivative in development for once-weekly administration in patients with growth hormone deficiency (GHD). Objective The objective of this study is to evaluate the efficacy, safety, and tolerability of once-weekly somapacitan vs once-daily GH. Design REAL 3 is a multicenter, randomized, controlled, double-blind (somapacitan doses), phase 2 study with a 26-week main and 26-week extension phase (NCT02616562). Setting This study took place at 29 sites in 11 countries. Patients Fifty-nine GH treatment-naive prepubertal children with GHD were randomly assigned; 58 completed the trial. Interventions Interventions comprised 3 somapacitan doses (0.04 [n = 16], 0.08 [n = 15], or 0.16 mg/kg/wk [n = 14]) and daily GH (0.034 mg/kg/d [n = 14]), administered subcutaneously. Main Outcome Measures The primary end point was height velocity (HV) at week 26. Secondary efficacy end points included HV SD score (SDS) and insulin-like growth factor-I (IGF-I) SDS. Results At week 26, mean (SD) annualized HV for the somapacitan groups was 8.0 (2.0), 10.9 (1.9), and 12.9 (3.5) cm/year, respectively, vs 11.4 (3.3) cm/year for daily GH; estimated treatment difference (somapacitan 0.16 mg/kg/week—daily GH): 1.7 [95% CI –0.2 to 3.6] cm/year. HV was sustained at week 52, and significantly greater with somapacitan 0.16 mg/kg/week vs daily GH. Mean (SD) change from baseline in HV SDS at week 52 was 4.72 (2.79), 6.14 (3.36), and 8.60 (3.15) for the somapacitan groups, respectively, vs 7.41 (4.08) for daily GH. Model-derived mean (SD) IGF-I SDS for the somapacitan groups was −1.62 (0.86), −1.09 (0.78), and 0.31 (1.06), respectively, vs −0.40 (1.50) observed for daily GH. Safety and tolerability were consistent with the profile of daily GH. Conclusions In children with GHD, once-weekly somapacitan 0.16 mg/kg/week provided the closest efficacy match with similar safety and tolerability to daily GH after 26 and 52 weeks of treatment. A short visual summary of our work is available (1).

ClinicalTrials.gov: NCT00348946.

The most common sex chromosome aneuploidy, Klinefelter syndrome (KS), is associated with primary gonadal failure and increased morbidity and mortality from cardiometabolic disorders in adulthood. Children with KS also have a high prevalence of metabolic syndrome (MetS). To assess the relationship of gonadal and cardiometabolic function in children with KS, we evaluated serum hormones (gonadotropins, inhibin B (INHB), anti-mullerian hormone (AMH), total testosterone (TT)), and features of MetS (waist circumference, fasting lipid panel, fasting blood glucose (FBG), and blood pressure) in 93 prepubertal boys with KS age 4–12 years (mean 7.7 ± 2.5 years). The cohort was grouped by age and tanner stage, and biomarkers were compared to normal ranges. 80% of this prepubertal cohort had ≥1 feature of metabolic syndrome (MetS) and 11% had ≥3 features of MetS. Risk of MetS was independent of age and body mass index. Sertoli cell dysfunction was common with 18% having an INHB below the normal range. A low INHB was associated with higher FBG, triglycerides, and LDL and lower HDL (p<0.05). An INHB <50 ng/dl yielded a sensitivity of 83% and a specificity of 79% for having ≥3 features of MetS. INHB and AMH positively correlated with each other (p<0.001), and high AMH was protective of MetS. TT was below the lower limit of normal in 49% of subjects, with mean values significantly lower than expected (3.3 ng/dl versus 4.9 ng/dl, p<0.0001), however no convincing relationship between TT and MetS was seen. In conclusion, gonadal and cardiometabolic dysfunction are prevalent in prepubertal boys with KS. Although the relationship of testosterone deficiency and MetS is well known, this study is the first to report an association between impaired sertoli cell function and cardiometabolic risk.

Ox has positive effects on measures of cardiometabolic health in prepubertal boys with KS; however, it does lower HDL cholesterol and advance bone age.

There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3-4.6 cm. If Ox dosages <0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization (including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated, or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03-0.05 mg/kg/day starting from the age of 8-10 years onwards can be considered.