David B. Allen

Long-Term Growth Hormone Therapy Changes the Natural History of Body Composition and Motor Function in Children with Prader-Willi Syndrome

BACKGROUND Children with Prader-Willi syndrome (PWS) have decreased muscle mass, hypotonia, and impaired linear growth. Recombinant human GH (hGH) treatment reportedly improves body composition and physical function in children with PWS, but these studies lack long-term control data. To assess the impact of hGH therapy begun early in life on the natural history of PWS, we compared height, body composition, and strength in similar-age children with PWS naïve to hGH with those treated with hGH for 6 yr. OBJECTIVES Forty-eight children with PWS were studied: 21 subjects (aged 6-9 yr) treated with hGH for 6 yr (beginning at 4-32 months, mean 13 +/- 6 months) were compared with 27 children of similar age (5-9 yr) prior to treatment with hGH. Percent body fat, lean body mass, carbohydrate/lipid metabolism, and motor strength were compared using analysis of covariance. RESULTS PWS children treated with hGH demonstrated lower body fat (mean, 36.1 +/- 2.1 vs. 44.6 +/- 1.8%, P < 0.01), greater height (131 +/- 2 vs. 114 +/- 2 cm; P < 0.001), greater motor strength [increased standing broad jump 22.9 +/- 2.1 vs. 14.6 +/- 1.9 in. (P < 0.001) and sit-ups 12.4 +/- 0.9 vs. 7.1 +/- 0.7 in 30 sec (P < 0.001)], increased high-density lipoprotein cholesterol (58.9 +/- 2.6 vs. 44.9 +/- 2.3 mg/dl, P < 0.001), decreased low-density lipoprotein (100 +/- 8 vs. 131 +/- 7 mg/dl, P < 0.01), and no difference in fasting glucose or insulin. CONCLUSIONS hGH treatment in children with PWS, begun prior to 2 yr of age, improves body composition, motor function, height, and lipid profiles. The magnitude of these effects suggests that long-term hGH therapy favorably alters the natural history of PWS to an extent that exceeds risks and justifies consideration for initiation during infancy.

Effect of conjugated linoleic acid on body fat accretion in overweight or obese children

BACKGROUND Conjugated linoleic acid (CLA) is a supplemental dietary fatty acid that decreases fat mass accretion in young animals. OBJECTIVE The aim of this study was to determine CLAs efficacy with regard to change in fat and body mass index (BMI; in kg/m(2)) in children. DESIGN We conducted a 7 +/- 0.5-mo randomized, double-blind, placebo-controlled trial of CLA in 62 prepubertal children aged 6-10 y who were overweight or obese but otherwise healthy. The subjects were randomly assigned to receive 3 g/d of 80% CLA (50:50 cis-9,trans-11 and trans-10,cis-12 isomers) or placebo in chocolate milk. RESULTS Fifty-three subjects completed the trial (n = 28 in the CLA group, n = 25 in the placebo group). CLA attenuated the increase in BMI (0.5 +/- 0.8) compared with placebo (1.1 +/- 1.1) (P = 0.05). The percentage change in body fat measured by dual-energy X-ray absorptiometry was smaller (P = 0.001) in the CLA group (-0.5 +/- 2.1%) than in the placebo group (1.3 +/- 1.8%). The change in abdominal body fat as a percentage of total body weight was smaller (P = 0.02) in the CLA group (-0.09 +/- 0.9%) than in the placebo group (0.43 +/- 0.6%). There were no significant changes in plasma glucose, insulin, or LDL cholesterol between groups. Plasma HDL cholesterol decreased significantly more (P = 0.05) in the CLA group (-5.1 +/- 7.3 mg/dL) than in the placebo group (-0.7 +/- 8 mg/dL). Bone mineral accretion was lower (P = 0.04) in the CLA group (0.05 +/- 0.03 kg) than in the placebo group (0.07 +/- 0.03 kg). Reported gastrointestinal symptoms did not differ significantly between groups. CONCLUSIONS CLA supplementation for 7 +/- 0.5 mo decreased body fatness in 6-10-y-old children who were overweight or obese but did not improve plasma lipids or glucose and decreased HDL more than in the placebo group. Long-term investigation of the safety and efficacy of CLA supplementation in children is recommended.

Childhood Obesity and Medical Neglect

The incidence of childhood obesity has increased dramatically, including severe childhood obesity and obesity-related comorbid conditions. Cases of severe childhood obesity have prompted the following question: does childhood obesity ever constitute medical neglect? In our opinion, removal of a child from the home is justified when all 3 of the following conditions are present: (1) a high likelihood that serious imminent harm will occur; (2) a reasonable likelihood that coercive state intervention will result in effective treatment; and (3) the absence of alternative options for addressing the problem. It is not the mere presence or degree of obesity but rather the presence of comorbid conditions that is critical for the determination of serious imminent harm. All 3 criteria are met in very limited cases, that is, the subset of obese children who have serious comorbid conditions and for whom all alternative options have been exhausted. In these limited cases, a trial of enforced treatment outside the home may be indicated, to protect the child from irreversible harm.

Characteristics of Adolescents Presenting to a Multidisciplinary Clinic for Polycystic Ovarian Syndrome

OBJECTIVE To characterize patients referred to the adolescent polycystic ovarian syndrome (PCOS) clinic at the American Family Childrens Hospital, University of Wisconsin, Madison, Wisconsin. DESIGN Chart review of patients seen in the first 33 months for details of initial presentation, age, body mass index (BMI), menstrual pattern, clinical and laboratory features of androgen excess, insulin resistance, and dyslipidemia. SETTING Multidisciplinary clinic for adolescents with PCOS at the American Family Childrens Hospital, Madison, Wisconsin. PARTICIPANTS Adolescent girls with PCOS. RESULTS Seventy patients (84% Caucasian) presented with an average age at referral of 16.2 years (range 11-22 y). Eighty four percent had a BMI > the 85(th) percentile and 70% had a BMI > 95(th) percentile. Menstrual pattern was quite varied, with some patients having primary amenorrhea, and over 50% experiencing hirsutism. There were 3 cases of type 2 diabetes, and over half of the patients had elevated fasting insulin levels and low HDL levels. CONCLUSION Polycystic ovarian syndrome is a complex and heterogeneous disorder that requires multidisciplinary expertise. Knowing the unique features of the adolescent with PCOS and metabolic risks should permit earlier intervention with intensive counseling and medical therapy to address current health concerns and prevent future co-morbidities.

Fitness Level and Body Composition are Associated with Inflammation in Non-obese Children

Childhood obesity and poor fitness are associated with insulin resistance (IR), risk for coronary heart disease (CHD), and type 2 diabetes mellitus. Elevated markers of inflammation (e.g., C-reactive protein [CRP]) are independent predictors of CHD. Whether higher percent body fat and poor fitness in non-obese children are associated with evidence of inflammation and IR is unclear. We evaluated 75 children with non-obese body mass index (BMI) for age (<95th percentile), ages 11-14 years for fasting insulin, glucose, adiponectin, CRP, body composition, and maximum oxygen-consumption (VO2max). CRP correlated positively with body composition (BMI z-score, p = 0.00062; percent body fat, p = 0.00007; and total body fat in grams, p = 0.00006) and negatively with VO2max, p = 0.036. Using multivariate analysis, VO2max and percent body fat were both independent predictors of CRP. Fasting insulin and insulin resistance as assessed by QUICKI did not correlate with CRP, fitness, or fatness in these non-obese children. Adiponectin showed no significant correlations, and gender did not influence correlation analyses. We conclude that in non-obese children, low fitness and higher body fat are both associated with inflammation (i.e., higher levels of CRP). This observation strengthens the importance of promoting both fitness and healthy body composition in all children.

Growth hormone post-marketing surveillance: safety, sales, and the unfinished task ahead.

Twenty-five years ago, the pediatric endocrinology community was stunned by news of Creutzfeldt-Jakob disease transmitted by treatment with pituitary-derived GH (pit-GH). With remarkable serendipity, recombinant DNA-derived human GH (rhGH) became available within months. In an environment fertile with concerns about unexpected adverse effects, postmarketing surveillance studies (PMSSs) were established, managed, and supported by manufacturers of rhGH, of which the Genentech National Cooperative Growth Study (NCGS) has been the largest and most comprehensive in scope. This action appeared prescient when, in the late 1980s, a possible link between GH therapy and new-onset leukemia waspublished(1).Thisassociationwaslaterdisproved(2,3), but a number of possible rhGH-associated adverse effects were subsequently identified, systematically tracked, analyzed,andreported. Inthis issueofJCEM,Belletal. (4)report more than 20 yr of NCGS safety data covering approximately 55,000 patients and nearly 200,000 patient-years of rhGH exposure. The gathering and analysis of this vast amount of drug experience information will likely not be accomplished again, making its value, in some respects, inestimable. It validates for the sponsoring company and participatingphysicians therationale,commitmentofresources, and hopes for the NCGS that marked its inception. The data confirm and extend prior NCGS reports (5, 6), summarized by these general clinical implications for rhGH therapy: 1) certain adverse effects associated with rapid growth (scoliosis progression, slipped epiphyses) and others of unknown mechanism (intracranial hypertension, pancreatitis) occur rarely and merit anticipatory guidance and close monitoring; 2) overt hyperglycemia is rare, but insulin sensitivity is reduced, and a possible increase in risk for type 2 diabetes mellitus (T2DM) may be obscured by its rising general pediatric population incidence; 3) in the rare occurrence when a child already at higher risk for sudden death dies during rhGH therapy, a possible contributing role of rhGH (e.g. reduced cortisol availability in hypopituitary children or airway compromise in children with Prader-Willi syndrome) cannot be excluded; and 4) rhGH does not increase risk for new malignancy in children without risk factors, but may slightly increase or hasten the onset of second malignancies in patients previously treated for cancer. Although the data on the whole are reassuring, caution is warranted when extrapolating these findings to future safety of rhGH. Like any drug, rhGH could cause adverse events that otherwise occur rarely in the reference population (e.g. malignancy) and/or increase the frequency of relatively common events (e.g. T2DM). In addition, adverse events can occur shortlyafter initiationofdruguse,onlywith long-term use, or remotely after the drug has been discontinued (7). This full spectrum of potential rhGH adverse effects is not comprehensively elucidated by PMSSs due to: 1) inherent weaknesses in patient cohort surveillance dependent on physician reports; 2) changes in rhGH dosage and/or recipient characteristics that may alter risk for adverse effects; and 3) failure to capture adverse events that only become manifest after treatment. A separate but important issue unique to rhGH treatment is to define a “tolerable” level of risk for the newest and potentially largest rhGH-treated group in the future—essentially healthy, but short children. As noted by others (8), there are potential pitfalls in relying on data from PMSSs such as the NCGS. Patient enrollment is often incomplete; approximately 75% of eligible rhGH product-treated children are tracked by the

Growth-Attenuation Therapy: Principles for Practice

Publication of an account of growth attenuation with high-dose estrogen in a child with profound physical and cognitive disability brought widespread attention to a common and complex issue faced by families caring for similarly affected children, namely, the potentially negative effect of the increasing size of a child on the ability of his or her family to provide independent care, which in turn makes it more difficult for parents to keep the child in the home and involved in family activities. In this article we explore the scientific rationale for, effectiveness and safety of, and ethical considerations bearing on growth-attenuation treatment of children with profound and permanent cognitive disability. Informed responses to key clinically relevant questions are proposed. Our analysis suggests that growth attenuation is an innovative and sufficiently safe therapy that offers the possibility of an improved quality of life for nonambulatory children with profound cognitive disability and their families. Pediatricians and other care providers should include discussion of these options as part of anticipatory guidance around the age of 3 years so that, if elected, potential clinically meaningful benefits of growth-attenuation therapy can be realized. Because of the publicity and debate surrounding the first reported case, ethics consultation is recommended.

Oxandrolone Improves Height Velocity and BMI in Patients with Cystic Fibrosis

Objective. To evaluate the effectiveness of oxandrolone in improving the nutritional status and linear growth of pediatric patients with cystic fibrosis (CF). Methods. Medical records of patients with CF treated with oxandrolone were reviewed for height z score, height velocity (HV), BMI z score, weight velocity (WV), Tanner stage, pulmonary function, liver enzyme levels, and any reported adverse events. Data were compared before (pre-Ox) and after (Ox) oxandrolone using a paired t-test. Results. 5 subjects (ages 8.5–14.5 years) were treated with oxandrolone 2.5 mg daily for 8–38 months. After 8–12 months of treatment, there was a statistically significant improvement in HV ( cm/yr,  cm/yr, ) and BMI z score (, , ). Both height z score (, , ) and WV ( kg/yr, Ox  kg/yr, ) showed beneficial trends that did not reach statistical significance. No adverse events were reported. Conclusions. In this brief clinical report, oxandrolone improved the HV and BMI z score in patients with CF. Larger studies are needed to determine if oxandrolone is an effective, safe, and affordable option to stimulate appetite, improve weight gain, and promote linear growth in patients with CF.

The influence of fitness on insulin resistance in obese children.

An increasingly pervasive environment of reduced activity and easy access to high caloric food is leading to an epidemic of poor cardiovascular fitness, obesity, insulin resistance and type 2 diabetes (T2DM) in children. Studies have shown that insulin resistance (IR) to be an independent predictor for morbidity as well as mortality. These serve as a strong stimulus for public health strategies to improve fitness in children and adolescents. Methods to assess IR, improve IR and understand complications are increasingly important in children.

Respiratory Depression in Young Prader Willi Syndrome Patients following Clonidine Provocation for Growth Hormone Secretion Testing

Objectives. To determine the sedative and respiratory effects of clonidine when used to evaluate growth hormone (GH) secretion in children with Prader Willi Syndrome (PWS). Methods. The study prospectively evaluated children with PWS who received clonidine (0.15 mg/) to assess GH responsiveness. Patients were studied up to four times over three years. Vital signs, oxygen saturation, and sedation level were recorded at baseline and every five minutes following clonidine. Changes between baseline and post-clonidine were evaluated using a repeated measurement analysis. Results. Sixty studies were performed on 17 patients, mean age months. The mean SD dose of clonidine was  mg ( mcg/kg). All patients achieved a sedation score of 4 to 5 (drowsy to asleep). Mean declines in respiratory rate ( breaths/min; ), and oxygen saturation (%; ) occurred following clonidine. Five patients (29%) experienced oxygen saturations 94% on nine occasions. Three oxygen desaturations were accompanied by partial airway obstruction. Conclusions. Clonidine doses to assess GH secretion often exceed doses used for sedation and result in significant respiratory depression in some children with PWS. There was no association between oxygen desaturation and BMI.