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Objectives: To examine differences in the growth pattern and the age at adiposity rebound (AR) between children with premature adrenarche (PA) and their healthy peers (controls)., Study Design: In this cross-sectional study of 82 prepubertal children with PA and 63 controls, the main outcome measures were height and body mass index SDS progression, from birth to presentation at the clinic, baseline biochemical and hormonal evaluation, bone age determination, and age at AR., Results: Children with PA were significantly taller and more adipose than controls from the first years of life. 33% of children with PA presented the growth pattern of constitutional advancement of growth (ie, early growth acceleration) vs 19% of controls (P = .045). Children with PA had an earlier AR compared with controls; mean age at AR in girls with PA was 3.73 (1.03) years vs 4.93 (1.36) years for control girls (P = .001) and in boys with PA was 3.45 (0.73) vs 5.10 (1.50) years in control boys (P = .048). Both obese and nonobese girls with PA were taller and had earlier age at AR compared with nonobese controls., Conclusions: Early AR and constitutional advancement of growth may be triggering factors for adrenal androgen production and PA., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To assess skeletal maturity by measuring bone age (BA) in children with Cushing syndrome (CS) before and 1-year after transsphenoidal surgery or adrenalectomy, and to correlate BA with hormone levels and other measurements., Study Design: This case series conducted at the National Institutes of Health Clinical Center included 93 children with Cushing disease (CD) (43 females; mean age, 12.3 ± 2.9 years) and 31 children with adrenocorticotropic hormone-independent CS (AICS) (22 females, mean age 10.3 ± 4.5 years). BA was obtained before surgery and at follow-up. Outcome measures were comparison of BA in CD vs AICS and analysis of the effects of hypercortisolism, insulin excess, body mass index, and androgen excess on BA., Results: Twenty-six of the 124 children (21.0%) had advanced BA, compared with the expected general population prevalence of 2.5% (P < .0001). Only 4 of 124 (3.2%) had delayed BA. The majority of children (76%) had normal BA. The average BA z-score was similar in the children with CD and those with AICS (0.6 ± 1.4 vs 0.5 ± 1.8; P = .8865). Body mass index SDS and normalized values of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androsteonedione, estradiol, and testosterone were all significantly higher in the children with advanced BA vs those with normal or delayed BA. Fifty-nine children who remained in remission from CD had follow-up BA 1.2 ± 0.3 years after transsphenoidal surgery, demonstrating decreased BA z-score (1.0 ± 1.6 vs 0.3 ± 1.4; P < .0001)., Conclusion: Contrary to common belief, endogenous CS in children appears to be associated with normal or even advanced skeletal maturation. When present, BA advancement in CS is related to obesity, insulin resistance, and elevated adrenal androgen levels and aromatization. This finding may have significant implications for treatment decisions and final height predictions in these children., (Published by Mosby, Inc.)

Objectives: To examine risk factors for fracture in a racially diverse cohort of healthy children in the US., Study Design: A total of 1470 healthy children, aged 6-17 years, underwent yearly evaluations of height, weight, body mass index, skeletal age, sexual maturation, calcium intake, physical activity levels, and dual-energy x-ray absorptiometry (DXA) bone and fat measurements for up to 6 years. Fracture information was obtained at each annual visit, and risk factors for fracture were examined using the time-dependent Cox proportional hazards model., Results: The overall fracture incidence was 0.034 fracture per person-year with 212 children reporting a total of 257 fractures. Being white (hazard ratio [HR] = 2.1), being male (HR = 1.8), and having skeletal age of 10-14 years (HR = 2.2) were the strongest risk factors for fracture (all P ≤ .001). Increased sports participation (HR = 1.4), lower body fat percentage (HR = 0.97), and previous fracture in white girls (HR = 2.1) were also significant risk factors (all P ≤ .04). Overall, fracture risk decreased with higher DXA z scores, except in white boys, who had increased fracture risk with higher DXA z scores (HR = 1.7, P < .001)., Conclusions: Boys and girls of European descent had double the fracture risk of children from other backgrounds, suggesting that the genetic predisposition to fractures seen in elderly adults also manifests in children., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: To assess the interrelationship between extent of adrenarche at presentation in girls with precocious adrenarche (PA) born appropriate for gestational age and their growth pattern, pubertal course and adult height., Study Design: We reviewed clinical and laboratory data from medical charts of 85 girls with PA aged 5.0 to 8.8 years at referral, stratified in 3 subgroups according to bone age (BA) minus chronological age (CA) ≤0 years; 0 1 year., Results: Extent of pubarche and dehydroepiandrosterone-sulfate levels were greatest in the BA-CA >1 subgroup (P=.02, P=.008, respectively), who also were taller at diagnosis (P=.002) and during childhood (P=.01). In all subgroups, pubertal onset was within normal range; menarche occurred earlier than in control subjects (P<.02); all attained adult height within their mid-parental height range. Predicted adult height was overestimated in girls with BA ≤CA (P=.04) and underestimated with BA-CA >1 (P<.001)., Conclusions: Although a more pronounced adrenarche and BA advancement at diagnosis in girls with PA born appropriate for gestational age had an impact on their pre-pubertal growth pattern, it was not associated with early and rapid progression of puberty or reduced adult height. This reassuring clinical course indicates that PA is a benign condition, irrespective of the extent of adrenarche at presentation. Adult height prediction is unreliable in PA., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objectives: To investigate in an open-label randomized study, the effect of two doses of growth hormone (GH) on final height and height velocity during the first 2 years of treatment of children with idiopathic short stature (mean baseline height standard deviation score [SDS] -3.2)., Study Design: Patients were treated with GH at 0.24 mg/kg/week, 0.24 mg/kg/week for the first year and at 0.37 mg/kg/week thereafter (0.24-->0.37), or 0.37 mg/kg/week. Final height was evaluated in 50 patients at study completion (mean treatment duration, 6.5 years)., Results: Patients who received 0.37 mg/kg/week (n = 72) experienced a significantly greater increase in height velocity than those who received 0.24 mg/kg/week (n = 70) (treatment difference = 0.8 cm/year; P = .003) or 0.24-->0.37 mg/kg/week (n = 67) (treatment difference = 0.9 cm/year; P = .001). For the 50 patients for whom final height measurements were available, mean height SDS increased by 1.55, 1.52, and 1.85 SDS, respectively, for the three dose groups. For the primary comparison between the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups, the mean treatment difference (adjusted for differences in baseline predicted height SDS) was 0.57 SDS (3.6 cm; P = .025). Mean overall height gains (final height minus baseline predicted height) were 7.2 cm and 5.4 cm for the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups, respectively, without dose effects on safety parameters. Final height measurements were within the normal adult height range for 94% of patients randomized to 0.37 mg/kg/week who continued to final height., Conclusion: GH treatment dose-dependently increases height velocity and final height in children with idiopathic short stature.

Objectives: To compare growth of children with type B Niemann-Pick disease (NPD) with disease variables including genotype, organomegaly, bone age, and serum insulin-like growth factor-1 (IGF-1)., Study Design: A cross-sectional analysis of growth was performed in 23 children and adolescents with enzymatically and genotypically confirmed NPD. Liver and spleen volumes were measured by quantitative computed tomography and skeletal age by a wrist radiograph., Results: The mean Z scores for height and weight were -1.24 (29th percentile) and -0.75 (34th percentile). The mean liver and spleen volumes were 2.06 and 13.46 times normal for weight, respectively. Skeletal age was delayed by an average of 2.5 years, and serum IGF-1 level was at or below the 2nd percentile in 8 of 12 patients. Short stature and low weight were significantly correlated with large organ volumes, delayed bone age, and low IGF-1 levels. In contrast to patients with other mutations, individuals homozygous for the DeltaR608 mutation had normal height and weight, markedly less hepatosplenomegaly and bone age delay, and normal IGF-1 levels., Conclusions: Abnormal linear growth and delayed skeletal maturation are common in children and adolescents with type B NPD; however, homozygosity for DeltaR608 is associated with normal growth.

Objective: To examine changes in bone and body composition of adolescent female artistic gymnasts (GYM; n = 7), level 5+, compared with nongymnast controls (CON; n = 10) over 3 years., Study Design: Areal bone mineral density (aBMD; g/cm(2)), bone mineral content (BMC; g) and bone area (cm(2)), of the total body (TB), total proximal femur (TPF), trochanter (Tr), femoral neck, lumbar spine (LS), and distal radius were measured using dual-energy X-ray absorptiometry. Fat-free soft tissue mass (FFST; g), fat mass (g), and percent body fat (%FAT) were also assessed., Results: No initial differences in height or weight between GYM and CON were observed, and both groups demonstrated parallel increases in these parameters over time (P <.05; h(2) >or=0.15). At baseline, GYM possessed significantly lower %FAT and higher aBMD at all sites (except TB; P <.05; h(2) >or=0.15). Over 3 years, GYM increased more than CON (P <.05; eta (2) >or=0.15) in TB, Tr, and TPF aBMD, TB and LS BMC, and FFST., Conclusion: Female adolescents participating in competitive artistic gymnastics training over 3 years have enhanced rates of aBMD, BMC and FFST accrual.

Objective: To obtain objective information on the relationship between adult height (AH), glucocorticoid (GC) dose, and degree of hormonal suppression in a population of patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21-OHD CAH) to optimize treatment regimes., Study Design: Multicenter retrospective chart review of patients with salt wasting 21-OHD CAH diagnosed in the first 6 months of life, and who had reached AH (n = 54). The data were compiled into a single database., Results: Mean adult height standard deviation score - midparental height standard deviation score was -1.1 for both sexes. Growth velocity was normal during childhood but compromised during infancy and puberty. Onset and tempo of puberty were normal-to-delayed. Bone age was closely correlated with chronologic age (r = 0.93). AH was negatively correlated with androstenedione in infancy (r -0.68; P =.03) and childhood (-0.66; P <.01) and with testosterone in childhood (r -0.44; P =.01), but not with dehydroepiandrosterone or 17-hydroxyprogesterone. GC dose was not associated with AH., Conclusions: Mean AH was in the lower range of genetic potential in this group of persons with 21-OHD CAH. Androgen levels should be used in conjunction with growth velocity measurements to optimize GC dosing in persons with 21-OHD CAH.

We evaluated bone mineral density, vitamin D status, and biochemical markers of bone turnover in seven children with epidermolysis bullosa (EB). Four had osteopenia (Z score, -1.5) and four 25(OH) vitamin D <34 nmol/L (14 ng/mL), two of which had hyperparathyroidism. Children with severe EB should have evaluation of bone metabolism.

Objective: African American children have earlier pubertal and skeletal maturation and a higher body mass index (BMI) than Caucasian children. We tested the hypothesis that advanced bone age in African American children is accounted for by their greater adiposity., Study Design: We studied 252 African American (n = 97) and Caucasian (n = 155) children aged 5 to 12 years. Skeletal age was determined by a radiologist blinded to clinical details. The difference between bone age (BA) and chronological age (CA) (noted as BA - CA) and the ratio of bone age to chronological age (BA/CA) were determined. Analysis of covariance was used to adjust skeletal maturation for the effects of adiposity, as measured by BMI, BMI standard deviation score (BMI SDS), and fat mass by dual energy x-ray absorptiometry (DXA)., Results: African American children were significantly heavier than Caucasians (BMI SDS 2.7 +/- 3.4 vs 1.7 +/- 2.4, P <.05). Both BA - CA (0.75 +/- 1.46 vs 0.28 +/- 1.38, P <.05) and BA/CA (1.09 +/- 0.17 vs 1.03 +/- 0.16, P <.05) were significantly greater in African Americans than Caucasians. BA - CA and BA/CA were significantly correlated with lean body mass, BMI, BMI SDS, and DXA fat mass (all r > 0.46, P <.001). Neither BA - CA nor BA/CA of African Americans and Caucasians were significantly different after correction for lean body mass and measures of adiposity, including BMI, BMI SDS, or DXA fat mass., Conclusion: Skeletal age is more advanced in African American than Caucasian children and is significantly related to body mass. In large measure, the advancement in skeletal maturation of prepubertal and early pubertal African American children can be accounted for by their greater adiposity.

Objective: To assess the long-term systemic and neurologic responses to enzyme replacement therapy (ERT) with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher's disease., Study Design: Patients with type 3 Gaucher's disease (n = 21), aged 8 months to 35 years, were enrolled in a prospective study. Enzyme dose was adjusted to control systemic manifestations. Clinical and laboratory evaluations were performed at baseline and every 6 to 12 months thereafter. Patients were followed up for 2 to 8 years., Results: Significant improvement in hemoglobin levels, platelet count, and acid phosphatase values occurred. Liver and spleen volume markedly decreased, and bone structure improved. Nineteen patients had asymptomatic interstitial lung disease unresponsive to ERT. Supranuclear gaze palsy remained stable in 19 patients, worsened in one patient, and improved in one. Cognitive function remained unchanged or improved over time in 13 patients but decreased in 8 patients, 3 of whom developed progressive myoclonic encephalopathy accompanied by cranial magnetic resonance imaging and electroencephalographic deterioration., Conclusions: At relatively high doses, ERT reverses almost all the systemic manifestations in patients with type 3 Gaucher's disease. Most treated patients do not deteriorate neurologically. Novel therapeutic strategies are required to reverse the pulmonary and neuronopathic aspects of the disease.

Background: Delays in bone age, the onset of puberty, and skeletal growth in gymnasts could be, in part, the reason for an interest in gymnastics, rather than being the result of vigorous exercise. We hypothesized that short stature and delayed bone age are present at the start of gymnastics, and training delays growth, producing short stature, even after retirement., Methods: Sitting height and leg length were measured in 83 active female gymnasts, 42 retired gymnasts, and 154 healthy control subjects. Results were expressed as age-specific SD scores (mean +/- SEM)., Results: In the cross-sectional data, active gymnasts had delayed bone age (1.3 +/- 0.1 years), reduced height -1.32 +/- 0.08 SD, sitting height -1.24 +/- 0.09 SD, and leg length, -1.25 +/- 0.08 SD (all P <.001). However, in those training for less than 2 years, the deficit was confined to leg length (-0.8 +/- 0.2 SD). During 2 years of follow-up of 21 gymnasts, only the deficit in sitting height worsened (by 0.4 +/- 0.1 SD). In 13 gymnasts followed up in the immediate 12 months after retirement, sitting height accelerated, resulting in a lessening of the deficit in sitting height by 0.46 +/- 0.14 SD (P <.01). Adult gymnasts who had been retired for 8 years had no deficit in sitting height, leg length, or menstrual dysfunction., Conclusions: Short stature in active gymnasts is partly due to selection of individuals with reduced leg length. Reduced sitting height is likely to be acquired but is reversible with cessation of gymnastics. A history of gymnastic training does not appear to result in reduced stature or menstrual dysfunction in adulthood.

A male pseudohermaphrodite with 17alpha-hydroxylase deficiency and complete nonvirilization was monitored for excessive weight from the age of 3.5 to 11.5 years before the absence of sex steroids was detected. The retrospective analysis of growth data showed retarded bone age development despite adequate growth, which led to a remarkable increase in final height prognosis.

Objective: The objective of this study was to determine the relation of plasma zinc (Zn) status to growth and maturation in children with SS genotype sickle cell disease., Study Design: A cross-sectional study of 104 subjects who were 50% female and ranged in age from 0.4 to 18 years was performed. Measures included plasma Zn concentration (Znp), height, weight, skinfold thicknesses, elbow breadth, upper arm muscle area, and fat-free mass and fat mass by total body electrical conductivity. Skeletal maturation was assessed by hand-wrist x-ray evaluation and sexual maturation by Tanner stage., Results: A total of 44% of the patients had low Znp (<10.7 micromol/L [70 microg/dl]); those with low Znp had significantly lower SD scores for height (p = 0.003), weight (p = 0.003), upper arm muscle area (p = 0.045), fat-free mass (p = 0.025), and elbow breadth (p = 0.017) and greater skeletal maturation delay (p = 0.04). In older children (>9 years) low Znp was associated with decreased Tanner scores for pubic hair (p = 0.001) and breast and genital maturation (p = 0.009). No significant differences were seen in age, sex, or fat stores according to Zn status., Conclusions: Decreased plasma Zn is common in children with SS genotype sickle cell disease and is associated with decreased linear growth, skeletal growth, muscle mass, and sexual and skeletal maturation.

Poor longitudinal growth and low body weight affect many persons with cystic fibrosis (CF). The Cystic Fibrosis Foundation reports that 28% of all persons with CF are below the 10th percentile for height and that 34% are below the 10th percentile for weight. Intensive nutritional supplementation has not resulted in sustained improvement in the poor linear growth and low weight in CF. Because of the significant impact of nutrition in CF, the anabolic effects of growth hormone (GH) may make the agent useful as adjunctive treatment for malnutrition and poor linear growth. To date, 24 patients with CF (16 boys; 87% Tanner stage 1) have been enrolled in the National Cooperative Growth Study. The average age at enrollment was 10.3 years, and there was significant delay in height in all patients (mean height age, 7.1 years). Bone age was also significantly delayed (mean delay, 3.0 years). The mean maximum stimulated GH level was 12.3 micrograms/L and the mean GH dose given was 0.291 +/- 0.038 mg/kg per week. After 1 and 2 years of treatment with GH the growth rate increased in all patients with available growth rate data. The growth rates in these children were slightly lower than in children who were treated with GH for idiopathic GH deficiency. The weight-for-height standard deviation scores improved significantly after 2 years of GH treatment. There were adverse reactions (glucose intolerance) to GH in only two patients; treatment was suspended in one of these patients but was continued in the other. National Cooperative Growth Study data indicate that treatment with GH increases linear growth and weight in prepubertal patients with CF. These data suggest that GH may be useful for treating malnutrition in CF.

Real-time ultrasonography was performed in 142 patients with Turner syndrome, aged 0.57 to 21 years, with different karyotypes (45,X [4896], X mosaicism [17%], and X structural abnormalities [35%]). Ovarian and uterine volumes were calculated and the data collected in a mixed longitudinal and cross-sectional mode. Thirty-eight patients were followed longitudinally during pubertal age (10 to 18 years bone age) for ovarian data. Patients with Turner syndrome were divided into two groups according to the presence or absence of detectable ovaries. Patients with Turner syndrome with detectable ovaries showed the first increase in ovarian volume at about 9 years of bone age; this increase was continuous and more evident only after 14 years of age and appeared later than in control subjects. When followed longitudinally during puberty, the ovaries showed a hormonal function in some cases. Girls with X mosaicism had the highest percentage of bilateral detectable ovaries and the greatest total ovarian volume; about 50% of them had spontaneous breast appearance and 38.5% had spontaneous menarche. They showed also the lowest gonadotropin levels, when bilateral ovaries were present during puberty. On the contrary, patients with the 45,X karyotype had the lowest percentage of detectable ovaries, ovarian volume, and spontaneous breast appearance. In our patients with Turner syndrome, uterine measures increased significantly with age and this was more evident in subjects with detectable ovaries after 13 years of bone age. Compared with control subjects, they showed significantly lower uterine measures, and patients with X mosaicism had greater and more progressive increments. In conclusion, pelvic ultrasonography in Turner syndrome is particularly useful in detecting ovaries and their possible increase in volume. These data, linked with karyotype pattern and gonadotropin levels, have prognostic value in predicting the future sexual development of these patients.

A group of 18 boys with non-growth hormone (GH)-deficient short stature without GH therapy (group A) and another group of 9 boys with non-GH-deficient short stature with GH therapy in doses of 0.5 IU (0.17 mg)/kg per week administered 5 to 6 times weekly (group B) were observed until they reached their final height. The mean duration of GH therapy was 4.2 years (range 3.2 to 5.0 years). These two groups were matched with respect to their standard deviation score (SDS) for bone age at the start of observation. Mean +/- SD of the final height for group A and group B was 162.0 +/- 5.4 cm and 154.2 +/- 4.2 cm, respectively. During the prepubertal period, height SDS for bone age of these two groups was not affected by GH therapy. During the pubertal period, however, height SDS for bone age remained constant for group A but decreased gradually for group B. Our observation indicates that for boys with non-GH-deficient short stature GH therapy does not improve height SDS for bone age during the prepubertal period, and in fact reduces it during the pubertal period, possibly resulting in a shorter final height than might have been attained naturally.

Objective: Patients with neural tube defects (myelomeningocele) have severe growth retardation, and treatment with recombinant human growth hormone (rHGH) for 6 months accelerates growth velocity. We examined patients treated for longer periods to determine whether accelerated growth persists, and whether patients demonstrated to be growth hormone deficient have a greater response to rHGH therapy., Methods: We retrospectively evaluated the growth rate and length standard deviation score (SDS) of 22 patients in response to treatment with 0.3 mg/kg per week of rHGH for 7 to 72 months. Nine of 22 patients were growth hormone deficient (nocturnal and provocative growth hormone responses < 7 ng/ml). Treatment success was defined as an increase of length SDS of > 0.2 SD per year., Results: Fourteen patients (64%) had treatment successes, and eight had treatment failures. Length SDS improved from a pretreatment value of -2.9 (+/- 1.2) to the most recent length SDS of -1.9 (+/- 1.4) (p < 0.001). The growth rate was significantly increased through year 4 of treatment. The annualized growth rate after 6 months of rHGH treatment was significantly different for the success and failure groups (11.0 +/- 2.6 cm/yr vs 5.1 +/- 3 cm/yr, p < 0.001). The annualized 6-month growth rate during treatment was related to the probability of treatment success., Conclusion: Treatment with rHGH significantly improves the growth rate and length SDS of children with neural tube defects. The 6-month annualized growth velocity during treatment was predictive of long-term treatment response. The effect on adult stature is unknown.

Treatment of adults with gonadotropin releasing hormone analogs has resulted in rapid loss in bone mineral density (BMD). We measured lumbar and femoral neck BMD by dual-energy x-ray absorptiometry during 2 years of depot leuprolide therapy in 13 girls (mean age, 7.5 years; mean bone age, 10.9 years). At baseline, BMD was elevated for age and concordant with the advanced skeletal age. During therapy with gonadotropin releasing hormone analog, BMD values increased and BMD standard deviation scores for age and skeletal age did not change.

To evaluate whether girls with premature thelarche progress to central precocious puberty (CPP) and to analyze their clinical and hormonal characteristics, we retrospectively examined 100 girls with premature thelarche who were followed for several years. Fourteen of the patients with characteristics diagnostic of premature thelarche (isolated breast development before age 8 years, bone age advancement within 2 SD of normal, normal growth velocity, follicle-stimulating hormone-predominant response to luteinizing hormone-releasing hormone) progressed during follow-up to precocious or early central puberty (progressive breast size increase, bone age acceleration, and significant decrease in predicted adult height). The chronologic age of this group of 14 girls was 5.1 +/- 2.0 years at the onset of premature thelarche and 7.8 +/- 0.6 years (mean +/- SD) after progression to central early or precocious puberty. Pelvic ultrasonography showed significant differences in measurements between the time of diagnosis of premature thelarche and progression to CPP. Nine of these patients required treatment, three with cyproterone acetate and six with luteinizing hormone-releasing hormone analogs, and all responded as expected for classic CPP. At baseline evaluation, no clinical or hormonal characteristics could be established that separated the 14 children who progressed to precocious or early puberty from the 86 girls who did not. We conclude that premature thelarche is not always a self-limited condition and may sometimes accelerate the timing of puberty.

Children with cerebral palsy have been reported to have poor growth and delayed skeletal maturation, but it is unclear whether these effects are related to the underlying brain injury or to concomitant malnutrition. This study was designed to evaluate the effects of hemiplegic cerebral palsy on skeletal maturation and growth, with the unaffected side used as each subject's control. Bilateral hand-wrist radiographs were obtained for 19 children with spastic hemiplegia. Skeletal maturation was determined in a blinded fashion with the Fels method. The skeletal age of the affected (hemiplegic) side was less than that of the unaffected (control) side in all 19 subjects; the mean difference in skeletal age was 7.3 months (p < 0.001). The delay in skeletal maturation of the affected side correlated linearly with age and upper extremity function. These findings show that brain injury results in delayed skeletal maturation independent of malnutrition. This effect on skeletal maturation may explain, in part, the reason that some children with cerebral palsy grow poorly.

We evaluated the effect of growth hormone (GH) therapy on bone age, pubertal maturation and predicted adult height in two groups of boys treated for 4 years: 40 growth hormone-deficient boys who had growth hormone response to provocative stimulation < 10 micrograms/L (GHD group) and 43 boys whose stimulated growth hormone > or = 10 micrograms/L (group with neurosecretory dysfunction (NSD)). All patients had a subnormal integrated concentration of growth hormone < or = 3.2 micrograms/L, height < -2 SD, growth velocity < 4.5 cm/yr, and bone age < or = -2 SD for chronologic age. Patients were treated with recombinant growth hormone, 0.1 mg/kg per dose given three times a week. The pretreatment height SD of the GHD group (-3.6 +/- 1.0) was less than that of the NSD group (-2.7 +/- 0.7; p < 0.001). After 4 years of therapy, both groups had catch-up growth (GHD group to -2.0 +/- 1.3 height SD (n = 35), and NSD group to -1.4 +/- 0.7 height SD (n = 32)); the rate of height SD gain was better in patients with GHD (p < 0.01). The response to growth hormone was inversely related to pretreatment chronologic age (p < 0.001). The Tanner-Whitehouse II predicted adult height improved for both groups: +9.3 +/- 7.7 cm in the GHD group, giving an adult height SD of -0.9 +/- 1.0, and +5.4 +/- 5.5 cm in patients with NSD, for an adult height SD if -0.8 +/- 0.7. Testosterone levels became higher in the NSD group after 2 years and remained higher at year 4. We conclude that patients respond favorably to growth hormone therapy and in a manner similar to patients with GHD. Initiation of therapy at a younger age gives a greater improvement in gained height and predicted adult height.

Short-term administration of human growth hormone to children with idiopathic short stature can improve mean growth rate and predicted adult height. It is yet unknown whether therapy would alter pubertal development or affect final height. Three-year treatment results in a group of children with idiopathic short stature are reported. For year 1 of the study, 121 prepubertal children were randomly selected to receive somatotropin, 0.3 mg/kg per week, administered subcutaneously three times weekly (n = 63), or to be nontreatment control subjects (n = 58). After 1 year, all subjects were again randomly selected to receive either three-times-weekly or daily dosing at the same total dose. For the 92 subjects who completed 36 months of treatment, mean growth rate increased from a mean of 4.6 cm/yr before treatment to a mean of 8.0 cm/yr in the first year of treatment. Daily dosing resulted in a significantly faster mean growth rate (9.0 cm/yr) than three-times-weekly dosing (7.8 cm/yr) (p = 0.0005). Mean growth rates were 7.6 and 7.2 cm/yr during years 2 and 3, respectively, and did not differ by dosing group. Mean standardized height for all subjects improved from -2.7 to -1.6 after 3 years. When the growth rate was standardized for bone age, however, subjects who remained prepubertal had a significantly greater gain in mean height SD score than subjects who became pubertal during that 3-year period (p < 0.02). Mean standardized Bayley-Pinneau predicted adult height SD score increased from -2.7 to -1.6 and was independent of the timing of pubertal onset, but for individuals this score was more variable. Year-1 growth response, expressed as growth rate or change in height SD score, was the best predictor of growth in subsequent years. Responses to therapy could not be reliably predicted from baseline anthropometric variables, plasma insulin-like growth factor I SD score, growth hormone levels. Final height assessment will be needed to determine the ultimate benefit of therapy.

The goal of this prospective study was to assess whether intensive physical training during puberty could alter the growth potential of adolescent female athletes. Height, sitting height, leg length, weight, body fat, and pubertal stage of 22 gymnasts aged 12.3 +/- 0.2 years (mean +/- SEM), with an average training period of 22 hr/wk, and of 21 swimmers aged 12.3 +/- 0.3 years (average training period 8 hr/wk) were recorded half-yearly for a mean period of 2.35 years (range 2.0 to 3.7 years). Adult height predictions were performed with the methods of Bayley and Pinneau; Roche, Wainer, and Thissen, and Tanner et al. Growth velocity of gymnasts was significantly lower than that of swimmers from 11 to 13 years of bone age (p < 0.05), with a mean peak height velocity of 5.48 +/- 0.32 cm/yr versus 8.0 +/- 0.50 cm/yr for swimmers. Height standard deviation score decreased significantly in gymnasts with time (r = -0.747; p < 0.001). This observation was not associated with a significant alteration of chronologic age/bone age ratio. By contrast, height standard deviation score remained unchanged in swimmers (r = -0.165; p = 0.1). A marked stunting of leg-length growth was observed in gymnasts from 12 years of bone age, resulting in a marked difference in overall sitting-height/leg-length ratio (gymnasts 1.054 +/- 0.005 vs swimmers 1.100 +/- 0.005; p < 0.001). Concomitantly, predicted height of gymnasts decreased significantly with time (Tanner et al.: r = 0.63, p < 0.001; Bayley-Pinneau: r = 0.44, p < 0.001), whereas those of swimmers did not change. We conclude that heavy training in gymnastics (> 18 hr/wk), starting before puberty and maintained throughout puberty, can alter growth rate to such an extent that full adult height will not be reached. The mechanisms underlying these observations are not settled; we suggest that prolonged inhibition of the hypothalamic-pituitary-gonadal axis by exercise, together with or because of the metabolic effects of dieting, is responsible for them.

Children with short stature, slowed linear growth velocity, and delayed skeletal maturation may secrete growth hormone (GH) normally in response to provocative stimuli but may also have spontaneous undersecretion of GH. Orally administered clonidine, an alpha 2-adrenergic agonist, is a potent acute stimulator of growth hormone releasing hormone-mediated pituitary GH release. We performed a double-blind, placebo-controlled crossover study of nightly oral clonidine therapy (0.1 mg/m2) in 10 short, slowly growing, non-GH-deficient (stimulated GH level > 15 micrograms/L) prepubertal boys (range, 6.1 to 12.2 years; mean height standard deviation score, -2.3 +/- 0.4). Results of 6 months of clonidine therapy were compared with the results of 6 months of placebo therapy; GH responsiveness was subsequently assessed in 7 of 10 patients. Growth velocity (4.9 +/- 0.6 cm/yr baseline) was not improved by clonidine (4.6 +/- 1.2 cm/yr) or placebo (5.2 +/- 1.2 cm/yr), but it increased (p < 0.001) with GH therapy (8.2 +/- 1.3 cm/yr). Clonidine therapy similarly did not significantly affect plasma levels of insulin-like growth factor I or bone age maturation. Diminution in clonidine-stimulated peak GH levels was not observed after long-term oral clonidine therapy. Thus, in contrast to previous non-placebo-controlled studies, nightly clonidine therapy did not increase growth velocity or plasma insulin-like growth factor I levels. Subsequent acceleration in growth velocity during GH therapy suggests that a proposed increase in clonidine-induced endogenous GH secretion does not result in an effective growth-promoting stimulus.

Seventy girls with Turner syndrome, verified by karyotype, were randomly assigned to observation or treatment with human growth hormone (hGH), oxandrolone, or a combination of hGH plus oxandrolone for a period of 12 to 24 months, to assess the effect of treatment on growth velocity and adult height. Subsequently, all subjects received either hGH alone or hGH plus oxandrolone. Data are presented for 62 subjects treated for a period of 3 to 6 years. When compared with the anticipated growth rate in untreated patients, the growth rate after treatment with hGH, both alone and in combination with oxandrolone, showed a sustained increase for at least 6 years. Treatment is continuing in over half of the subjects; at present, 14 (82%) of 17 girls receiving hGH alone and 41 (91%) of 45 girls receiving combination therapy exceeded their expected adult heights. Thirty girls have completed treatment; mean height for these 30 patients is 151.9 cm, compared with their mean original projected adult height of 143.8 cm. We conclude that therapy with hGH, alone and in combination with oxandrolone, can result in a sustained increase in growth rate and a significant increase in adult height for most prepubertal girls with Turner syndrome.

Sixty prepubertal short children (39 boys) with heights less than 2 SD for age and gender were treated daily for 1 year with recombinant human growth hormone (GH), either 0.1 IU/kg (group 0.1, n = 32) or 0.05 IU/kg (group 0.05, n = 28). Reserve of GH was determined by at least one GH provocative stimulus and 24-hour continuous blood withdrawal to determine the integrated concentration of GH (IC-GH). All participants had a GH response to provocative tests greater than 10 micrograms/L. The height velocity (mean +/- SD) of the group as a whole increased from 4.46 +/- 1.02 to 7.59 +/- 1.65 cm/yr (p less than 0.001). The growth velocity of group 0.1 was significantly greater than that of group 0.05 (8.1 +/- 1.5 vs 7.0 +/- 1.65 cm/yr; p less than 0.01). Bone age did not advance more than 1 year during the treatment period. Growth velocity after 1 year of GH therapy was inversely correlated with the IC-GH in both groups, as was the pretreatment height velocity. We found no correlation of growth velocity during GH therapy with other measures such as parental heights, bone age/chronologic age ratio, maximal GH response to provocative tests, chronologic age, or pretreatment insulin-like growth factor I levels. We conclude that the best predictors for the 1-year growth outcome of short children with a normal GH response to provocative tests are the pretreatment growth velocity and the IC-GH. The short-term benefit from GH therapy in children with a normal growth velocity and a normal IC-GH is poor, whereas marked growth acceleration is noted in children with a low growth velocity and a low 24-hour IC-GH.

A controlled study of growth in children receiving alternate-day versus daily corticosteroid regimens was performed with 60 children and adolescents with kidney grafts. The study started 14 to 27 months after transplantation in patients with normal graft function, after a graft biopsy. Thirty-five patients were available for the growth study; 17 were randomly allocated to receive alternate-day therapy and 18 remained on a daily regimen. The cumulative dose was similar in the two groups, as were bone age and renal function. After 1 year of follow-up, the mean statural growth, expressed as change in SD score, was significantly better in those on the alternate-day regimen (+0.49 +/- 0.42 SD/yr) than in those on the daily regimen (-0.12 +/- 0.53 SD/yr; p less than 0.005). The difference was also significant when prepubertal and pubertal children were analyzed separately. During the second year of the study most children who were receiving daily treatment were given alternate-day therapy; their mean growth velocity increased to +0.29 +/- 0.35 SD/yr (p less than 0.05 vs the first year); children who had been on the alternate-day regimen since the outset of the study continued to have similar positive SD scores (0.52 +/- 0.37 SD/yr). Renal function remained stable throughout the study regardless of corticosteroid regimen, except in the case of one patient undergoing daily therapy who had a rejection crisis. We conclude that in children with a kidney graft a given cumulative dose of corticosteroid has a significantly lesser inhibitory effect on growth velocity when given on alternate days.

We evaluated height prognosis and therapeutic efficacy of long-term, combination therapy with gonadotropin releasing-hormone agonist and growth hormone (GH) in five children (three girls) with coexistent precocious puberty and GH deficiency. Their clinical characteristics and growth response were compared with those of 12 girls with idiopathic true precocious puberty and eight prepubertal GH-deficient children (one girl). Precocious GH-deficient subjects were older than the precocious GH-sufficient children (9.5 +/- 1.8 years vs 6.5 +/- 1.3 years; mean +/- SD), but bone ages were comparable (12 +/- 3.7 years vs 10 +/- 0.9 years); their chronologic age was similar to that of the prepubertal GH-deficient children (9.6 +/- 2.1 years), but bone age was significantly more advanced (6.9 +/- 2.3 years). The mean height velocity of the prepubertal GH-deficient children (3.8 +/- 1.5 cm/yr) was lower than that of the precocious GH-deficient subjects (6.7 +/- 1.6 cm/yr) and the precocious GH-sufficient children (9.5 +/- 2.9 cm/yr). Baseline adult height prediction z scores were significantly lower in the precocious GH-deficient children (-3.7 +/- 1.0) than in either the precocious GH-sufficient children (-2.2 +/- 1.0) or the prepubertal GH-deficient subjects (-1.5 +/- 0.8). During therapy with gonadotropin releasing-hormone agonist, growth rates slowed to an average of 3.7 cm/yr in the precocious GH-deficient children but increased after the addition of GH to 7.4 cm during the first year of combination therapy. After 2 to 3 years of combination therapy, height predictions increased an average of 10 cm, compared with an increase of 2.8 cm in the precocious GH-sufficient group treated with gonadotropin releasing-hormone agonist alone. We conclude that combination treatment with gonadotropin releasing-hormone agonist and GH improves the height prognosis of children with coexistent true precocious puberty and GH deficiency, but falls short of achieving normal adult height potential.

Children with short stature but normal growth rate and/or normal growth hormone response to sleep and secretagogues were treated with recombinant methionyl human growth hormone, 0.3 mg/kg per week. In each year of treatment, about 80% of the subjects maintained an increase in growth rate greater than the defined limit (greater than 1 cm/yr above pretreatment growth rate) for continuation of human growth hormone treatment. Comparison of the group that continued to respond to human growth hormone with the group that did not maintain an accelerated growth rate did not reveal differences in bone age delay, sleep or secretagogue-stimulated human growth hormone secretion, degree of short stature either absolute or relative to target height, and somatomedin C concentration before or after initiation of therapy. The group that failed to respond to the human growth hormone treatment in the first year of treatment was younger and had a higher pretreatment growth rate. Review of the longitudinal growth curves revealed five patterns of response to human growth hormone treatment: (1) failure to increase growth rate in two subjects with height SD scores within 1 SD of target height, (2) failure to increase growth rate in five subjects with height SD scores greater than 1 SD less than the target height, (3) acceleration in growth rate in three subjects that was not maintained until achievement of a height within 1 SD of the target height, (4) acceleration of growth rate in five subjects that was maintained until achievement of a height within 1 SD of the target height, and (5) acceleration in growth rate that was maintained during the 3 years of treatment in 15 subjects who had not attained a height within 1 SD of the target height. We conclude that human growth hormone treatment of some but not all short children with "normal" growth hormone secretion will result in sustained acceleration of growth rate and attainment of prepubertal heights that are closer to but do not exceed their genetic height potential. A clinical trial of human growth hormone may be necessary to determine which subjects will benefit from the treatment.

The effect of recombinant human growth hormone on children with Down syndrome who had growth retardation and microcephaly was examined. Thirteen children with trisomy 21 without congenital heart disease who were short for age (-1.19 to -3.5 standard deviation score) and microcephalic (-1.58 to -6.60 standard deviation score) were given recombinant human growth hormone, 0.1 mg/kg subcutaneously, 3 days a week for 1 year. Before treatment, peak serum growth hormone concentrations were less than 10 micrograms/L after levodopa and clonidine stimulation tests in five patients, after clonidine in three patients, and after levodopa in three patients. Three patients had nocturnal integrated growth hormone concentrations of 0.5, 1.5 and 0.65 micrograms/L, respectively. The mean growth rate before treatment was 5.4 +/- 1.6 cm/yr and increased to 12.2 +/- 3.2 cm/yr (p less than 0.001) after 12 months of recombinant human growth hormone treatment. The mean head circumference standard deviation score before treatment was -3.1 +/- 1.3 and increased to -2.3 +/- 1.2 (p less than 0.001) at 12 months. Bone age before and 1 year after treatment increased in correspondence with chronologic age. Plasma hemoglobin A1c concentration was normal during treatment with recombinant human growth hormone. The mean plasma concentrations of insulin-like growth factor I at baseline and at 12 months were 0.54 +/- 0.19 U/ml and 1.25 +/- 0.97 U/ml, respectively (p less than 0.02). We conclude that recombinant human growth hormone therapy can result in a significant increase in annual growth rate and head circumference in children with Down syndrome, without significant side effects.

To determine how accurately several methods of height prediction estimate adult height, we compared height predictions calculated by the Bayley-Pinneau, Roche-Wainer-Thissen (RWT), target height, and Tanner-Whitehouse Mark I (TW-MI), and Mark II (TW-MII) methods with final adult height in 37 boys and 32 girls with short stature and constitutional delay of growth and puberty. They were first seen at a chronologic age (mean +/- SD) of 14.80 +/- 1.70 years (boys) and 12.87 +/- 2.56 years (girls). Adult height at 23.14 +/- 1.95 years and 21.05 +/- 2.02 years was 170.4 +/- 5.4 cm (boys) and 157.8 +/- 4.2 cm (girls), respectively, and thus within the lower range of normal. Height predictions were calculated for the total group and for patients with parents of normal (group 1) as well as short stature (group 2). For boys, the RWT method gave very accurate results, underestimating adult height by -0.6 cm for the total group. The prediction errors for the other methods were -7.3 cm (TW-MI), -4.2 cm (TW-MII), and +3.1 cm (Bayley-Pinneau method) or +1.7 cm (target height). For girls, no method was superior in estimating adult height. The mean prediction error was -0.8 cm, -2.1 cm, and -1.8 cm with the Bayley-Pinneau, TW-MI, and TW-MII methods, respectively. In contrast, adult height was overpredicted by +2.3 cm and +1.2 cm with the RWT and target height methods. We conclude that patients with short stature and constitutional delay of growth and puberty reach an adult height in the lower range of normal. Height prediction methods differ with respect to their accuracy and their tendency to overestimate or underestimate adult height.

We designed a prospective study of height potential in girls with idiopathic precocious puberty, comparing the presenting features of girls with and without evidence of reduced adult height potential. The 14 girls with impaired adult height prognoses (group 1) were reexamined after treatment with a gonadotropin releasing hormone agonist, nafarelin. The seven girls with the prognosis of unimpaired height (group 2) were followed without therapy. We found that the group could be distinguished at initial examination by the greater bone age/height age ratio of group 1 (mean +/- SEM: 1.4 +/- 0.06 vs 1.0 +/- 0.05; p less than 0.005) and by the greater difference between predicted height and target height in group 1. The mean predicted height in group 1 was significantly less than the mean target height (150.7 +/- 2.1 vs 165.4 +/- 3.0 cm; p less than 0.005), whereas the mean predicted and target heights in group 2 were similar (165.4 +/- 3.0 vs 164.3 +/- 2.1 cm). Initial estradiol levels were also greater in group 1 than in group 2 (21.6 vs 10.6 pg/ml; p less than 0.05), although this difference was not sustained during follow-up. In group 1, nafarelin therapy suppressed the pituitary-gonadal axis, and although there was a transient reduction in height potential in girls with the youngest bone ages during the first 6 months of therapy, 2 years of treatment slightly improved predicted heights from 150.7 +/- 2.1 to 152.7 +/- 2.0 cm (p less than 0.05). Height predictions also increased without therapy during the 2-year observation period in group 2, from 165.4 +/- 3.0 to 168.7 +/- 4.1 cm (p less than 0.05). Our data indicate that gonadotropin releasing hormone agonist therapy preserves height potential in girls with an initially impaired height prognosis, and that height potential is preserved without therapy in those with a good initial height prognosis.

Because patients with uremia have evidence for growth hormone resistance, we investigated whether this resistance can be overcome by administration of recombinant human growth hormone in supraphysiologic doses in children with severe uremia. Nine stunted children with end-stage renal disease (median age 5.8 years, median bone age 2.7 years) were treated with recombinant human growth hormone, 4 IU/m2/day subcutaneously, for a period of 1 year. Median height velocity was increased from 4.4 cm/yr before therapy to 8.0 cm/yr during treatment. Negative values for height velocity standard deviation scores for chronologic age were improved from a median of -2.6 to +1.5 without advancing bone age more than chronologic age. The growth hormone-insulin-like growth factor I resistance may be explained in part by the increased serum concentration of the high molecular weight insulin-like growth factor binding protein despite normal insulin-like growth factor I serum concentration. Treatment with recombinant human growth hormone improved the ratio between the serum concentrations of insulin-like growth factor I and its binding protein, and normalized the somatomedin bioactivity in the growth cartilage bioassay.

During the control period of the Growth Failure in Children With Renal Diseases Study, investigators at 23 centers were able to observe and characterize growth and to make anthropometric and nutritional measurements in 82 children with mild to moderate renal insufficiency. As a multicenter, controlled clinical trial designed to study the relative efficacy of 1,25-dihydroxyvitamin D3 and dihydrotachysterol in the treatment of renal osteodystrophy, no prior vitamin D exposure and a creatinine clearance of 25 to 75 ml/min/1.73 m2 were criteria for entrance into the clinical trial. Ages ranged from 18 months to 11 years (mean 5.6 +/- 3.1 years), and distribution by age category was as follows: 38%, 1 to 3 years; 28%, 4 to 6 years; and 34%, 7 to 10 years. There was a 3:1 male/female ratio; 72% of the patients had congenital disease by the International Classification of Diseases (ninth revision). Mean creatinine clearance was 49.5 +/- 20 ml/min/1.73 m2. The C-terminal parathyroid hormone values (1121 +/- 1562 pg/ml) were well above 2 SD of the mean of a normal growing population of similar age. Parathyroid hormone values correlated with degree of renal insufficiency (r = -0.57) and with height by bone age but not with chronologic height or growth velocity. The bone age/height age ratio, a predictor of growth potential in normal children, was low for the entire series of patients (0.88 +/- 0.35) but failed to correlate with growth velocity and was negatively correlated with rising parathyroid hormone levels. Average values for height, weight, triceps skin fold, mid-arm muscle circumference, and body mass index were within 2 SD of the mean of the normal population, although measurements for the 1- to 3-year age group were significantly less than those of the older patients. Total energy intake averaged less than 86% of the recommended dietary allowances; total protein intake was more than 161% of the allowance. Nitrogen balance in 23 patients was positive and correlated most significantly with increasing energy intake (r = 0.6). Growth velocity, calculated from the interval gain during the month control period, averaged +0.3 SD, with the highest growth velocity z scores recorded for those with acquired disease. A growth velocity index, expressed as the slope of the regression between change in height SD and growth velocity z score, was used to describe the growth accomplished in the control period by age category.(ABSTRACT TRUNCATED AT 400 WORDS)

A prospective analysis of physical growth in 56 children with congenital hypothyroidism compared the children's height, weight, and head circumference with population percentiles. Two measures of skeletal maturation and predictions of adult height were also compared with population standards. The mean percentiles for the children's height and head circumference were higher than population means. Although mean bone age scores were slightly higher, predictions of adult height did not differ significantly from midparental height (arithmetic mean of sum of parental heights) and population means. The duration of intrauterine hypothyroidism as measured by gestational bone age and the duration of postnatal hypothyroidism were inversely correlated with heights attained up to 9 years. This association suggests a possible long-term influence of early hypothyroidism on growth. In children with congenital hypothyroidism, maintenance of serum thyroxine levels in the upper half of the normal range results in normal growth patterns.

Sixteen prepubertal children with constitutional growth delay (10 boys and six girls, mean age 7.2 +/- 2.1 years) were administered a daily dose of clonidine (0.15 mg/m2) for a period of 1 year. Growth hormone levels, plasma somatomedin C, and linear growth rate were significantly increased at the end of the treatment. Six of the children maintained the higher growth rate even 6 months after treatment. These and other studies suggest that prolonged stimulation of the hypothalamus by clonidine may ameliorate the impairment of growth hormone release seen in some children with constitutional growth delay. Because of the low cost and the convenience of the oral route, administration of clonidine could be a mode of treatment in some children with poor growth.

Height, expressed as standard deviation scores for chronological age and for bone age, was studied in relation to glomerular filtration rate, bone age delay, and bone histology in 47 children with chronic renal disease and GFR less than 80 ml/min/1.73 m2. In multiple regression in all 47 patients, only GFR and bone age delay significantly affected height; 40% of children were short (height standard deviation score less than -2) for chronological age, and 9% were short for bone age. Renal osteodystrophy, which only occurred at GFR less than 30 ml/min/1.73 m2, significantly affected height only in children with congenital renal disease and GFR less than 20 ml/min/1.73 m2. Although radiological and biochemical changes of renal osteodystrophy were seen more often in short children, histological bone disease occurred just as frequently in tall children as in short children. Thus much of the observed height retardation in chronic renal failure is associated with delayed skeletal maturation. In addition, although severe renal osteodystrophy may contribute to growth retardation in advanced renal failure, our data suggest that milder degrees of bone disease evident only on histological study cannot be implicated in the etiology of growth failure in chronic renal impairment.

We studied the effect of recombinant human growth hormone treatment on five boys, aged 4.6 +/- 1.8 years, who had chronic renal failure secondary to congenital renal diseases (mean creatinine clearance (+/- SD): 18.3 +/- 6.3 ml/min/1.73 m2 (0.32 +/- 0.11 ml/sec/1.73 m2]. Patients received 0.125 mg/kg of growth hormone three times per week for 1 year. Before beginning treatment, the children had a mean annual growth velocity of 4.9 +/- 1.4 cm/yr (range 3.0 to 6.3 cm/yr), with a mean standard deviation score for a height of -2.98 +/- 0.73 (range -2.16 to -3.59). At the end of therapy, the mean growth velocity had increased to 8.9 +/- 1.2 cm/yr (range 7.5 to 10.7 cm/yr), and the mean height standard deviation score improved to -2.36 +/- 0.83 (range -1.15 to -3.18). Bone age advancement was consistent with the period of growth. Routine laboratory determinations, including results of glucose tolerance testing, did not vary significantly from pretreatment levels. These preliminary data indicate that growth-retarded children with chronic renal failure can respond to exogenous growth hormone therapy with a marked acceleration in growth velocity.

Cranial vault suture opacification (apparent closure) and bone age were evaluated roentgenographically in ten children with thyrotoxicosis. The bone age was advanced greater than 2 SD in only one. In comparison to 96 control children of similar age, craniosynostosis was present in each of the patients with thyrotoxicosis. Children with advanced bone age, nine due to virilizing adrenal hyperplasia and three with precocious puberty, had normal radiographic patterns of cranial suture closure. Thyrotoxic premature craniosynostosis did not interfere with continued head circumference growth nor did it result in clinical or radiographic evidence of increased intracranial pressure. We conclude that premature craniosynostosis appears to be a common feature of juvenile thyrotoxicosis. Investigation of the possible long-term adverse effects of this entity on central nervous system function is advocated.

Seventy-eight children with idiopathic growth hormone deficiency treated with human growth hormone continuously for up to 5 years were studied; 58 were prepubertal at the start of treatment, and remained so throughout the treatment period, and 20 were showing pubertal signs at the start of treatment. Height velocity increased markedly in the prepubertal group over the first year of therapy, with a gradual decrease in the following years. The increased growth rate of the first treatment year continued in the pubertal group. Height standard deviation score for chronologic age increased significantly throughout all treatment years, but for bone age did not change in either group. The more frequent the treatment regimen, the better was the growth response; a dose effect independent of frequency was identified. Thus human growth hormone treatment cannot make up a deficit in height prognosis already present at diagnosis, but prevents further loss of stature, which is why early diagnosis is important.

Forty-eight children with short stature, growth rate less than 4 cm/yr, and normal growth hormone response to secretagogues were given exogenous human growth hormone (hGH) for 6 months to determine its effect on the short-term growth rate in these children. All except three had an increase in growth rate with hGH therapy. The mean +/- SD pretreatment growth rate (3.4 +/- 0.8 cm/yr) was significantly less than either the growth rate during 6 months of hGH therapy (6.9 +/- 2.6 cm/yr) or after therapy (4.1 +/- 1.8 cm/yr). Several patterns of response were observed after treatment was stopped: the mean growth rate in 22 children decreased after treatment but remained above basal rates, the mean growth rate in seven children was similar to the rates during treatment, and the mean growth rate in 16 children was less than basal rates. Twenty children received therapy for an additional 6 months and had a mean increase in growth rate from 3.6 +/- 1.3 to 6.7 +/- 2.4 cm/yr. The decreased growth rate after discontinuation of treatment and increased rate with resumption of therapy indicates that maintenance of the increased growth rate might be dependent on continuation of hGH therapy.

We determined the effect of pituitary human growth hormone treatment on the growth rate of 52 children with Turner syndrome. The pretreatment growth rate was 3.2 +/- 0.8 cm/yr. Growth hormone treatment (0.2 IU/kg three times per week) resulted in enhancement of the growth rate to 5.9 +/- 1.4 cm/yr for the first year of therapy. The bone age advanced approximately 1 year during the year of therapy. The growth hormone therapy was discontinued at 12 months, and the mean growth rate decreased to pretreatment levels, 3.1 +/- 1.9 cm/yr; 26 of 41 patients actually had post-treatment growth rates that were less than the pretreatment rate. Glucose tolerance tests at 6-month intervals did not indicate an effect of hGH treatment on glucose intolerance. Several patients had glucose intolerance that preceded hGH treatment, but this remained stable during treatment; glucose intolerance likely was related to obesity in this group of patients. Basal and hGH-stimulated somatomedin C levels (32 patients) correlated with age of the patient but not with growth rate during therapy. We conclude that hGH therapy can accelerate the growth rate of patients with Turner syndrome. The growth rate increased to "normal" levels and was dependent on continued treatment with hGH. If the response continues, long-term treatment of Turner syndrome may result in increased adult height.

Thirty short, slowly growing children with normal plasma growth hormone response to standard provocation tests were randomly assigned to a group (n = 20) undergoing therapy with methionyl growth hormone, 2 IU/m2 subcutaneously once daily, (group 1) or a control group (n = 10, group 2). The mean (+/- SD) height velocity increment in group 1 was 3.0 +/- 1.9 cm/yr in the first year, compared with -0.2 +/- 0.7 cm/yr in group 2. Of the 18 children who completed the first year of treatment, 12 had a height velocity increment of more than 2 cm/yr and 11 of them continued treatment for a second year (group 1A). The remaining six children also reached height velocities greater than the mean for bone age, but because of a low height velocity increment they were termed nonresponders and their growth hormone dosage was increased to 4 IU/m2/day (group 1B). Of the 10 children in the control group, seven received authentic biosynthetic growth hormone in the second year of the study (group 2); the remaining three received no therapy (group 3). The mean height velocities (measured in centimeters per year) before and during the first and second years of therapy were 3.6, 7.6, and 6.1 in group 1A; 5.7, 6.9, and 7.3 in group 1B; 4.2, 4.0, and 6.7 in group 2; and 5.0, 4.9, and 5.2 in group 3. The effect of doubling the dosage was a further increase of 1.9 cm/yr. Bone age advance paralleled growth acceleration, resulting in an unchanged height standard deviation score for bone age and ambiguous results on final height prediction. Growth hormone therapy in such short children appears to be safe and efficacious in increasing growth velocity for 2 years, but its efficacy in terms of increasing final height is uncertain.