Susan E. Myers

Two years of growth hormone therapy in young children with Prader-Willi syndrome: physical and neurodevelopmental benefits.

Infants with Prader–Willi syndrome (PWS) typically display failure to thrive and decreased muscle mass with excess body fat for age. Growth hormone (GH) therapy in children with PWS improves, but does not normalize, body composition and muscle strength and agility. The objective of this study was to determine the effects of earlier GH therapy on anthropometric measurements, body composition, and psychomotor development in affected PWS infants and toddlers. Twenty‐five subjects, ages 4–37 months, were randomized to 2 years of GH therapy (1 mg/m2/day) or 1 year of observation without GH treatment and then placed on GH (1.5 mg/m2·day) for 1 year only. Anthropometric measurements were obtained by standard methods: percent body fat, lean body mass, and total body bone mineral density by dual x‐ray absorptiometry; motor constructs of mobility and stability by the Toddler Infant Motor Evaluation; and cognitive and language function by the Capute Scales of Infant Language and Cognitive Development. GH‐treated PWS subjects demonstrated normalization of length/height standard deviation scores (SDS), faster head growth, increased lean body mass accrual, and decreased percent body fat (P < 0.005 for all parameters), as well as improved language (P = 0.05) and cognitive (P = 0.02) quotient Z‐scores compared with similarly aged untreated PWS subjects after 1 year into the study. PWS subjects treated before their first birthday spoke their first words at a mean age of 14.4 ± 2.8 months and walked independently at 23.3 ± 4.8 months. GH therapy was well‐tolerated; however, one PWS subject experienced scoliosis progression. As greater benefits were seen in our study with early treatment, prompt referral to a pediatric endocrinologist for consideration of GH therapy is recommended for PWS at an early age.

Growth Hormone Treatment of Adults with Prader-Willi Syndrome and Growth Hormone Deficiency Improves Lean Body Mass, Fractional Body Fat, and Serum Triiodothyronine without Glucose Impairment: Results from the United States Multicenter Trial

CONTEXT GH replacement in Prader-Willi syndrome (PWS) children has well-defined benefits and risks and is used extensively worldwide. Its use in PWS adults has been limited by documentation of benefits and risks, as determined by larger multisite studies. OBJECTIVES Our objective was to evaluate the effectiveness and safety of GH in GH-deficient genotype-positive PWS adults. DESIGN We conducted a 12-month open-label multicenter trial with 6-month dose-optimization and 6-month stable treatment periods. SETTING The study was conducted at outpatient treatment facilities at four U.S. academic medical centers. PATIENTS Lean and obese PWS adults with diverse cognitive skills, behavioral traits, and living arrangements were recruited from clinical populations. INTERVENTION Human recombinant GH (Genotropin) was initiated at 0.2 mg/d with monthly 0.2-mg increments to a maximum 1.0 mg/d, as tolerated. MAIN OUTCOMES MEASURES Lean body mass and percent fat were measured by dual-energy x-ray absorptiometry. RESULTS Lean body mass increased from 42.65 +/- 2.25 (se) to 45.47 +/- 2.31 kg (P < or = 0.0001), and percent fat decreased from 42.84 +/- 1.12 to 39.95 +/- 1.34% (P = 0.025) at a median final dose of 0.6 mg/d in 30 study subjects who completed 6-12 months of GH. Mean fasting glucose of 85.3 +/- 3.4 mg/dl, hemoglobin A1c of 5.5 +/- 0.2%, fasting insulin of 5.3 +/- 0.6 microU/ml, area under the curve for insulin of 60.4 +/- 7.5 microU/ml, and homeostasis model assessment of insulin resistance of 1.1 +/- 0.2 were normal at baseline in 38 study initiators, including five diabetics, and remained in normal range. Total T(3) increased 26.7% from 127.0 +/- 7.8 to 150.5 +/- 7.8 ng/dl (P = 0.021) with normalization in all subjects, including six (20%) with baseline T(3) values at least 2 sd below the mean. Mildly progressive ankle edema was the most serious treatment-emergent adverse event (five patients). CONCLUSIONS This multicenter study demonstrates that GH improves body composition, normalizes T(3), and is well tolerated without glucose impairment in PWS genotype adults.

Astrocytic and neuronal biochemical markers in the sera of subjects with diabetes mellitus.

To determine if clinical diabetes is associated with disruption of the blood-brain barrier (BBB) and/or brain injury, enzyme-linked immunoassays and Western blots were used to measure serum levels of S100B, NSE and their auto-antibodies in type 1 and type 2 diabetic subjects. Serum S100B concentrations in type 2 diabetic subjects, but not in type 1 diabetic subjects, were significantly lower than those found in healthy controls. There were no significant differences in serum NSE levels of either type 1 or type 2 diabetics compared to healthy controls. However, there was a significant increase in antibodies to NSE in both type 1 and type 2 diabetic subjects compared to controls, whereas diabetics and controls had equally very low levels of anti S100B auto-antibodies. These studies suggest that diabetes in humans may be associated with alterations in the BBB integrity that allow the emergence of antibodies against neuronal antigens.

Growth Standards of Infants With Prader-Willi Syndrome

OBJECTIVE: To generate and report standardized growth curves for weight, length, head circumference, weight/length, and BMI for non–growth hormone–treated white infants (boys and girls) with Prader-Willi syndrome (PWS) between 0 and 36 months of age. The goal was to monitor growth and compare data with other infants with PWS. METHODS: Anthropometric measures (N = 758) were obtained according to standard methods and analyzed from 186 non–growth hormone–treated white infants (108 boys and 78 girls) with PWS between 0 and 36 months of age. Standardized growth curves were developed and the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles were calculated by using the LMS (refers to λ, μ, and σ) smoothing procedure method for weight, length, head circumference, weight/length, and BMI along with the normative 50th percentile using Centers for Disease Control and Prevention national growth data from 2003. The data were plotted for comparison purposes. RESULTS: Five separate standardized growth curves (weight, length, head circumference, weight/length, and BMI) representing 7 percentile ranges were developed from 186 non–growth hormone–treated white male and female infants with PWS aged 0 to 36 months, and the normative 50th percentile was plotted on each standardized infant growth curve. CONCLUSIONS: We encourage the use of these growth standards when examining infants with PWS and evaluating growth for comparison purposes, monitoring for growth patterns, nutritional assessment, and recording responses to growth hormone therapy, commonly used in infants and children with PWS.

Leptin concentrations in Prader-Willi syndrome before and after growth hormone replacement

This study explored leptin concentrations in Prader‐Willi syndrome (PWS), a genetic disorder characterized by significant obesity and presumed hypothalamic dysfunction. The potential interaction of leptin metabolism with the growth hormone (GH) axis was also studied.

Physical effects of growth hormone treatment in children with Prader-Willi syndrome.

A randomized, controlled study of 54 children (age, 4‐16 years) with Prader‐Willi syndrome was conducted to assess the potential beneficial effects of growth hormone (GH) treatment. After observation for 6 months, the children were randomized to receive GH at a dose of 3 IU/m2/day (1 mg/m2/day) (n= 35) or no intervention (n= 19). The effects of GH treatment on linear growth, body composition, muscle strength, pulmonary function and resting energy expenditure were assessed. The levels of GH secreted in resonse to clonidine stimulation were universally low, and mean (± SD) insulin‐like growth factor I SDS was ‐1.2 ± 0.8 pretreatment. In children treated for 1 year, mean height velocity SDS significantly increased from ‐1.0 ± 2.5 to 4.6 ± 2.9 (p < 0.0001), mean percentage body fat decreased from 46.3 ± 8.4% to 38.4 ± 10.7% (p < 0.001), mean lean body mass increased from 20.5 ± 6.3 kg to 25.6 ± 4.3 kg (p <0.01) and respiratory muscle function and physical strength imporved. Mean respiratory quotients significantly decreased from 0.81 to 0.77 (p < 0.001); however, resting energy expenditure did not change. Therefore, GH therapy appears to reduce some of the physical disabilities experienced by children with Prader‐Willi syndrome.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial

There are no treatments for the extreme hyperphagia and obesity in Prader–Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib.

Prader-Willi Syndrome and Growth Hormone Therapy: Take a Deep Breath and Weigh the Data

See related article, p 263 cardinal feature is the early onset, unrelenting, treatment-refractory hyperphagia leading to morbid obesity and attendant comorbidities. In addition, however, PWS is characterized by infantile hypotonia and failure to thrive, followed by short stature, hypogonadism, abnormal body composition, sleep and respiratory abnormalities (including impaired ventilatory control, central and obstructive apnea, and excessive daytime sleepiness), and behavioral difficulties. Until recently, a markedly decreased life span was expected, primarily resulting from complications of obesity. With better management and the introduction of GHRT,most affected individuals can now expect a relatively normal life span with better quality of life. In this issue of The Journal, Al-Saleh et al highlight 3 issues that continue to plague those charged with providing responsible care to this population: (1) the incidence and cause of sudden unexpected death (SED) in those affected; (2) whether GHRT raises the risk for obstructive sleep apnea (OSA) in patients with PWS and, if so, does this lead to an increased risk of SED; and (3) the appropriate medical management for minimizing any treatment-related risks. Some historical background is necessary to frame these issues. During the past 15 years, GHRT has become the standard of care for most children with PWS. Randomized, controlled studies in the late 1990s documented accelerated growth velocity, increased muscle mass and strength, decreased fat mass, increased physical activity, behavior improvements, and improved respiratory function. Pharmacia and Upjohn obtained Food and Drug Administration approval for GHRT for PWS in 2000. Soon thereafter, reports of SED in children in the early phases of GHRT emerged. Three theories were introduced to explain these deaths: (1) Growth hormone (GH)-mediated tonsillar or soft tissue hypertrophy leading to fatal OSA; (2) a rise in basal metabolic rate with a resultant rise in oxygen demand; and (3) a normalization of body hydration with augmentation of volume load.