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Context: Premature pubarche (PP) is reported in children with Prader-Willi Syndrome (PWS). Pubarche is preceded by adrenarche - an increase in serum levels of adrenal androgens, most specifically dehydroepiandrosterone sulphate (DHEAS)., Objectives: To assess DHEAS levels, the age at and progression of pubarche and the prevalence of PP in children with PWS., Design/patients: In the Dutch PWS Cohort Study, 120 children (6 months-17 years) are prospectively followed. Their age at onset of pubarche and various pubic hair stages and prevalence of PP were determined. Serum DHEAS levels were assessed in 97 children., Results: Median serum DHEAS levels were significantly higher in children with PWS than in healthy age-matched controls at ages 3-6 years (girls: P = 0·004 and boys: P = 0·010) and 6-10 years (girls: P = 0·045 and boys: P = 0·001). Age and gender significantly influenced DHEAS levels in children with PWS. The median [P10-P90] age at onset of pubarche in children with PWS was significantly younger than in healthy peers, 9·04[6·75-11·84] years in PWS girls (P < 0·0001) and 10·31 [8·65-12·29] years in PWS boys (P = 0·003). The prevalence of PP in children with PWS was 30·0% in girls and 16·1% in boys., Conclusions: Compared to healthy children, children with PWS have significantly higher DHEAS levels from 3 to 10 years of age. They are younger at onset of pubarche and have a higher prevalence of premature pubarche. DHEAS levels in PWS are influenced by age and gender. Our findings indicate earlier maturation of the zona reticularis of the adrenal glands in children with PWS., (© 2011 Blackwell Publishing Ltd.)

Objective: Untreated girls with Turner syndrome (TS) have short stature, relatively broad shoulders, a broad pelvis, short legs, a high fat mass and low muscle mass. Our objective was to assess the effect of the weak androgen oxandrolone (Ox) on body proportions and composition in growth hormone (GH)-treated girls with TS., Design/patients: 133 patients were included in a randomized, placebo-controlled, double-blind study., Methods: Patients were treated with GH (1.33 mg/m(2) per day) from baseline, combined with placebo (Pl) or Ox in a low (0.03 mg/kg per day) or previously conventional (0.06 mg/kg per day) dose from the age of eight, and oestrogens from the age of twelve. Sitting height, biacromial and biiliacal distances compared with height (i.e. shape values), BMI, waist circumference, sum of 4 skinfolds (sum4skin) and upper arm muscle area (UAMA) SD scores (SDS) were assessed half-yearly., Results: Compared with GH + Pl, adult shape values on GH + Ox tended to be higher for sitting height (Ox 0.03, P = 0.2; Ox 0.06, P = 0.02) and biacromial distance (Ox 0.03, P = 0.2; Ox 0.06, P = 0.07) and lower for biiliacal distance (Ox 0.03, P = 0.004; Ox 0.06, P = 0.08). Sum4skin SDS tended to decrease more (Ox 0.03, P = 0.2; Ox 0.06, P = 0.005) while UAMA SDS increased more (Ox 0.03, P < 0.001; Ox 0.06, P < 0.001) than on GH + Pl. The increase in BMI and waist circumference SDS was comparable between the dosage groups., Conclusions: In GH-treated girls with TS, Ox 0.06 increases sitting height and tends to increase biacromial distance and decrease biiliacal distance, while Ox 0.03 significantly decreases biiliacal distance compared with height. Furthermore, Ox 0.06 reduces subcutaneous fat mass, and both Ox dosages increase muscle mass.

Background: Prader-Willi syndrome (PWS) children have impaired growth, and abnormal body composition. Previous 1-year controlled studies showed improvement of height and body composition during GH-treatment., Objective: To evaluate growth, body composition and body proportions during GH-treatment in a large group of PWS children., Design/patients: We performed a randomized controlled GH trial in 91 prepubertal PWS children (42 infants, 49 children, aged 3-14 years). After stratification for age, infants were randomized to GH-treatment (GH-group; 1 mg/m(2)/day; n = 20), or no treatment (control group; n = 22) for 1 year. In the second year all infants were treated with GH. After stratification for BMI, children > 3 years of age were randomized to GH-treatment (GH-group; 1 mg/m(2)/day; n = 27) or no treatment (control group; n = 22) for 2 years. Anthropometric parameters were assessed once in every 3 months. Body composition was measured by Dual Energy X-ray Absorptiometry., Results: Median (interquartile range, iqr) height SDS increased during 2 years of GH in infants from -2.3 (-2.8 to -0.7) to -0.4 (-1.1-0.0) and in prepubertal children from -2.0 (-3.1 to -1.7) to -0.6 (-1.1 to -0.1). In non-GH-treated children height SDS did not increase. Head circumference completely normalized during 1 and 2 years of GH in infants and children, respectively. Body fat percentage and body proportions improved in GH-treated children, but did not completely normalize. Lean body mass SDS improved compared to the control group. Serum IGF-I increased to levels above the normal range in most GH-treated children., Conclusions: Our randomized study shows that GH-treatment in PWS children significantly improves height, BMI, head circumference, body composition and body proportions. PWS children are highly sensitive to GH, suggesting that monitoring of serum IGF-I is indicated.

Background: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, feeding difficulties and failure to thrive in infancy. GH treatment improves growth velocity and body composition. Research on the effects of GH on psychomotor development in infants with PWS is limited., Objective: To evaluate psychomotor development in PWS infants and toddlers during GH treatment compared to randomized controls., Design/patients: Forty-three PWS infants were evaluated at baseline. Twenty-nine of them were randomized into a GH group (n = 15) receiving 1 mg/m(2)/day GH or a non-GH-treated control group (n = 14). At baseline and after 12 months of follow-up, analysis with Bayley Scales of Infant Development II (BSID-II) was performed. Data were converted to percentage of expected development for age (%ed), and changes during follow-up were calculated., Results: Infants in the GH group had a median age of 2.3 years [interquartile range (IQR) 1.7-3.0] and in the control group of 1.5 years (IQR 1.2-2.7) (P = 0.17). Both mental and motor development improved significantly during the first year of study in the GH group vs. the control group: median (IQR) change was +9.3% (-5.3 to 13.3) vs.-2.9% (-8.1 to 4.9) (P < 0.05) in mental development and +11.2% (-4.9 to 22.5) vs.-18.5% (-27.9 to 1.8) (P < 0.05) in motor development, respectively., Conclusion: One year of GH treatment significantly improved mental and motor development in PWS infants compared to randomized controls.

Background: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, obesity and short stature. Several endocrine abnormalities have been described, including GH deficiency and hypogonadotrophic hypogonadism. Published data on thyroid hormone levels in PWS children are very limited., Objective: To evaluate thyroid function in children with PWS, before and during GH treatment., Design/patients: At baseline, serum levels of T4, free T4 (fT4), T3, reverse T3 (rT3) and TSH were assessed in 75 PWS children. After 1 year, assessments were repeated in 57 of the them. These children participated in a randomized study with two groups: group A (n = 34) treated with 1 mg GH/m(2)/day and group B (n = 23) as controls., Results: Median age (interquartile range, IQR) of the total group at baseline was 4.7 (2.7-7.6) years. Median (IQR) TSH level was -0.1 SDS (-0.5 to 0.5), T4 level -0.6 SDS (-1.7 to 0.0) and fT4 level -0.8 SDS (-1.3 to -0.3), the latter two being significantly lower than 0 SDS. T3 level, at 0.3 SDS (-0.3 to 0.9), was significantly higher than 0 SDS. After 1 year of GH treatment, fT4 decreased significantly from -0.8 SDS (-1.5 to -0.2) to -1.4 SDS (-1.6 to -0.7), compared to no change in untreated PWS children. However, T3 did not change, at 0.3 SDS (-0.1 to 0.8)., Conclusions: We found normal fT4 levels in most PWS children. During GH treatment, fT4 decreased significantly to low-normal levels. TSH levels remained normal. T3 levels were relatively high or normal, both before and during GH treatment, indicating that PWS children have increased T4 to T3 conversion.

The role of GH insufficiency in the pathogenesis of short stature in Noonan syndrome is unclear. Cross-sectional study. Seventeen patients with Noonan syndrome (13 boys, 4 girls; aged 4.8-13.3 (mean 9.2) years) and short stature before start of GH treatment. Spontaneous 12-h overnight GH secretion by continuous sampling analysed using Pulsar, plasma IGF-I and IGFBP-3 levels, and 24-h urinary GH excretion were measured at start of GH treatment. A glucagon stimulation test was performed. Height and height velocity were monitored before and after 1 year of GH treatment. IGF-I and IGFBP-3 were remeasured after 1 year of GH treatment. Nine of the 17 children had a mean overnight GH concentration below the lower limit of the normal range. In six of the 17 patients, overnight GH profiles showed high trough GH concentrations. Glucagon stimulation tests were normal in 16 of the 17 patients. Mean IGF-I level was below normal (-0.4 SD). None of the parameters regarding GH secretion obtained from the overnight profile or provocative test was related to height or height velocity, nor to first year response to GH treatment. IGF-I and IGFBP-3 did not correlate with any of the GH secretion data. IGF-I and IGFBP-3 were related to height and height velocity at the start of GH treatment (r = 0.53 (P < 0.01) and r = 0.61 (P < 0.03) respectively). Rises in IGF-I and IGFBP-3 under GH treatment were related to the increment in height velocity (r = 0.70 (P < 0.01) and r = 0.71 (P < 0.02) respectively). Abnormalities in GH secretion are frequent in patients with Noonan syndrome and short stature. These abnormalities were not related to auxology at start of or response to GH treatment. Clinically GH insufficiency is not important in Noonan syndrome and monitoring spontaneous GH secretion is not necessary before the start of GH treatment.

Background and Objective: Growth hormone treatment in children with idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long-term effect of GH therapy in children with idiopathic short stature., Design: We have treated 27 prepubertal children with ISS with recombinant human GH (rhGH) in an initial dosage of 2 IU/m2 body surface/day subcutaneously, which was doubled either after the first year if the height velocity increment was less than 2 cm/year, or thereafter if height velocity fell below the P50 for bone age. Growth and bone maturation of the treatment group (ISS group, n = 21) were compared to those of an untreated control group with ISS (ISS controls, n = 27) and of a group of rhGH treated children with isolated GH deficiency (GHD group, n = 7)., Results: In 9 patients of the ISS group still on treatment, height standard deviation score (HSDS) for chronological age increased from -3.8 +/- 0.7 to -2.3 +/- 0.9 (mean +/- standard deviation) over 6 years, while in matched ISS controls HSDS for age did not change. HSDS for age in the GHD group increased from -3.9 +/- 0.6 to -1.8 +/- 0.7 after 4 years, significantly more than the ISS group. Bone maturation was accelerated in the ISS and GHD groups. HSDS for bone age and predicted adult height did not change in either group. Final height in 12 children of the ISS group was -2.6 +/- 1.0 SDS. In the untreated controls final height was similar. A low integrated GH concentration over 24 hours, a low GH peak to provocative stimuli, and minimal initial BA delay predicted a favourable outcome., Conclusion: rhGH treatment in this group of children with idiopathic short stature did not increase average final height. Part of the heterogeneity of the response can be attributed to the variation in endogenous GH secretion and initial bone age delay.