Gianni Bocca

Beneficial Effects of Growth Hormone Treatment on Cognition in Children with Prader-Willi Syndrome: A Randomized Controlled Trial and Longitudinal Study

BACKGROUND Knowledge about the effects of GH treatment on cognitive functioning in children with Prader-Willi syndrome (PWS) is limited. METHODS Fifty prepubertal children aged 3.5 to 14 yr were studied in a randomized controlled GH trial during 2 yr, followed by a longitudinal study during 4 yr of GH treatment. Cognitive functioning was measured biennially by short forms of the WPPSI-R or WISC-R, depending on age. Total IQ (TIQ) score was estimated based on two subtest scores. RESULTS During the randomized controlled trial, mean sd scores of all subtests and mean TIQ score remained similar compared to baseline in GH-treated children with PWS, whereas in untreated controls mean subtest sd scores and mean TIQ score decreased and became lower compared to baseline. This decline was significant for the Similarities (P = 0.04) and Vocabulary (P = 0.03) subtests. After 4 yr of GH treatment, mean sd scores on the Similarities and Block design subtests were significantly higher than at baseline (P = 0.01 and P = 0.03, respectively), and scores on Vocabulary and TIQ remained similar compared to baseline. At baseline, children with a maternal uniparental disomy had a significantly lower score on the Block design subtest (P = 0.01) but a larger increment on this subtest during 4 yr of GH treatment than children with a deletion. Lower baseline scores correlated significantly with higher increases in Similarities (P = 0.04) and Block design (P < 0.0001) sd scores. CONCLUSIONS Our study shows that GH treatment prevents deterioration of certain cognitive skills in children with PWS on the short term and significantly improves abstract reasoning and visuospatial skills during 4 yr of GH treatment. Furthermore, children with a greater deficit had more benefit from GH treatment.

Efficacy and Safety of Long-Term Continuous Growth Hormone Treatment in Children with Prader-Willi Syndrome

BACKGROUND Children with Prader-Willi syndrome (PWS) have abnormal body composition and impaired growth. Short-term GH treatment has beneficial effects. OBJECTIVES The aim of the study was to investigate effects of long-term continuous GH treatment on body composition, growth, bone maturation, and safety parameters. SETTING We conducted a multicenter prospective trial. DESIGN Fifty-five children with a mean +/- sd age of 5.9 +/- 3.2 yr were followed during 4 yr of continuous GH treatment (1 mg/m(2) . d). Data were annually obtained in one center: fat percentage (fat%) and lean body mass (LBM) by dual-energy x-ray absorptiometry, height, weight, head circumference, bone age, blood pressure, and fasting IGF-I, IGF binding protein-3, glucose, insulin, glycosylated hemoglobin, total cholesterol, high-density lipoprotein, and low-density lipoprotein. sd scores (SDS) were calculated according to Dutch and PWS reference values (SDS and SDS(PWS)). RESULTS Fat%SDS was significantly lower after 4 yr of GH treatment (P < 0.0001). LBMSDS significantly increased during the first year (P = 0.02) but returned to baseline values the second year and remained unchanged thereafter. Mean +/- sd height normalized from -2.27 +/- 1.2 SDS to -0.24 +/- 1.2 SDS (P < 0.0001). Head circumference SDS increased from -0.79 +/- 1.0 at start to 0.07 +/- 1.1 SDS after 4 yr. BMISDS(PWS) significantly decreased. Mean +/- sd IGF-I and the IGF-I/IGF binding protein-3 ratio significantly increased to 2.08 +/- 1.1 and 2.32 +/- 0.9 SDS, respectively. GH treatment had no adverse effects on bone maturation, blood pressure, glucose homeostasis, and serum lipids. CONCLUSIONS Our study in children with PWS shows that 4 yr of continuous GH treatment (1 mg/m(2) . d) improves body composition by decreasing fat%SDS and stabilizing LBMSDS and head circumference SDS and normalizes heightSDS without adverse effects. Thus, long-term continuous GH treatment is an effective and safe therapy for children with PWS.

Eight Years of Growth Hormone Treatment in Children With Prader-Willi Syndrome : Maintaining the Positive Effects

BACKGROUND The most important reason for treating children with Prader-Willi syndrome (PWS) with GH is to optimize their body composition. OBJECTIVES The aim of this ongoing study was to determine whether long-term GH treatment can counteract the clinical course of increasing obesity in PWS by maintaining the improved body composition brought during early treatment. SETTING This was a multicenter prospective cohort study. METHODS We have been following 60 prepubertal children for 8 years of continuous GH treatment (1 mg/m(2)/d ≈ 0.035 mg/kg/d) and used the same dual-energy x-ray absorptiometry machine for annual measurements of lean body mass and percent fat. RESULTS After a significant increase during the first year of GH treatment (P < .0001), lean body mass remained stable for 7 years at a level above baseline (P < .0001). After a significant decrease in the first year, percent fat SD score (SDS) and body mass index SDS remained stable at a level not significantly higher than at baseline (P = .06, P = .14, resp.). However, body mass index SDSPWS was significantly lower after 8 years of GH treatment than at baseline (P < .0001). After 8 years of treatment, height SDS and head circumference SDS had completely normalized. IGF-1 SDS increased to +2.36 SDS during the first year of treatment (P < .0001) and remained stable since then. GH treatment did not adversely affect glucose homeostasis, serum lipids, blood pressure, and bone maturation. CONCLUSION This 8-year study demonstrates that GH treatment is a potent force for counteracting the clinical course of obesity in children with PWS.

Results of a Multidisciplinary Treatment Program in 3-Year-Old to 5-Year-Old Overweight or Obese Children: A Randomized Controlled Clinical Trial

OBJECTIVE To assess the effects of a multidisciplinary intervention program for 3-year-old to 5-year-old overweight and obese children compared with a usual-care program. DESIGN Randomized controlled clinical trial conducted from October 2006 to March 2008. SETTING Groningen Expert Center for Kids with Obesity at Beatrix Childrens Hospital, University Medical Center Groningen. PARTICIPANTS Seventy-five children (29 overweight, 46 obese) aged 3 to 5 years. INTERVENTION A multidisciplinary intervention program vs a usual-care program. Anthropometry was performed and body composition was determined by bioelectrical impedance analysis and ultrasonography at the start and end of the 16-week program and 12 months after starting the intervention. MAIN OUTCOME MEASURES The actual weight reduction, change in body mass index (BMI, calculated as weight in kilograms divided by height in meters squared), BMI z score, body fat percentage, and visceral fat in the multidisciplinary intervention group compared with a usual-care group. RESULTS At the end of the treatment program, children in the multidisciplinary intervention group showed a greater decrease in BMI, BMI z score, and waist circumference z score compared with children in the usual-care group. At 12 months, children in the intervention group showed greater decreases in BMI, BMI z score, waist circumference, and waist circumference z score compared with children in the usual-care group. Visceral fat showed a trend toward a higher decrease. CONCLUSIONS A multidisciplinary intervention program in 3-year-old to 5-year-old overweight and obese children had beneficial effects on anthropometry and body composition. The positive effects were still present 12 months after the start of the intervention. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN47185691.

The results of CHD7 analysis in clinically well-characterized patients with Kallmann syndrome

CONTEXT Kallmann syndrome (KS) and CHARGE syndrome are rare heritable disorders in which anosmia and hypogonadotropic hypogonadism co-occur. KS is genetically heterogeneous, and there are at least eight genes involved in its pathogenesis, whereas CHARGE syndrome is caused by autosomal dominant mutations in only one gene, the CHD7 gene. Two independent studies showed that CHD7 mutations can also be found in a minority of KS patients. OBJECTIVE We aimed to investigate whether CHD7 mutations can give rise to isolated KS or whether additional features of CHARGE syndrome always occur. DESIGN We performed CHD7 analysis in a cohort of 36 clinically well-characterized Dutch patients with KS but without mutations in KAL1 and with known status for the KS genes with incomplete penetrance, FGFR1, PROK2, PROKR2, and FGF8. RESULTS We identified three heterozygous CHD7 mutations. The CHD7-positive patients were carefully reexamined and were all found to have additional features of CHARGE syndrome. CONCLUSION The yield of CHD7 analysis in patients with isolated KS seems very low but increases when additional CHARGE features are present. Therefore, we recommend performing CHD7 analysis in KS patients who have at least two additional CHARGE features or semicircular canal anomalies. Identifying a CHD7 mutation has important clinical implications for the surveillance and genetic counseling of patients.

Anosmia Predicts Hypogonadotropic Hypogonadism in CHARGE Syndrome

OBJECTIVE To test the hypothesis that a smell test could predict the occurrence of hypogonadotropic hypogonadism (HH) in patients with CHARGE syndrome, which is a variable combination of ocular coloboma, heart defects, choanal atresia, retardation of growth/development, genital hypoplasia, and ear anomalies or hearing loss caused by mutations in the CHD7 (chromodomain helicase DNA binding protein 7) gene. STUDY DESIGN We performed endocrine studies and smell testing (University of Pennsylvania Smell Identification Test) in 35 adolescent patients with molecularly confirmed CHARGE syndrome. RESULTS Complete data on smell and puberty were available for 15 patients; 11 patients had both anosmia and HH, whereas 4 patients had normosmia/hyposmia and spontaneous puberty. In addition, 7 boys were highly suspected of having HH (they were too young for definite HH diagnosis, but all had cryptorchidism, micropenis, or both) and had anosmia. The type of CHD7 mutation could not predict HH because a father and daughter with the same CHD7 mutation were discordant for HH and anosmia. CONCLUSION Anosmia and HH were highly correlated in our cohort, and therefore smell testing seems to be an attractive method for predicting the occurrence of HH in patients with CHARGE syndrome. The use of this test could prevent delay of hormonal pubertal induction, resulting in an age-appropriate puberty.

Waist-to-height ratio, waist circumference and BMI as indicators of percentage fat mass and cardiometabolic risk factors in children aged 3–7 years

OBJECTIVE To assess whether waist-to-height-ratio (WHtR) is a better estimate of body fat percentage (BF%) and a better indicator of cardiometabolic risk factors than BMI or waist circumference (WC) in young children. METHODS WHtR, WC and BMI were measured by trained staff according to standardized procedures. (2)H2O and (2)H2(18)O isotope dilution were used to assess BF% in 61 children (3-7 years) from the general population, and bioelectrical impedance (Horlick equation) was used to assess BF% in 75 overweight/obese children (3-5 years). Cardiometabolic risk factors, including diastolic and systolic blood pressure, HOMA2-IR, leptin, adiponectin, triglycerides, total cholesterol, HDL- and LDL-cholesterol, TNFα and IL-6 were determined in the overweight/obese children. RESULTS In the children from the general population, after adjustments for age and gender, BMI had the highest explained variance for BF% compared to WC and WHtR (R(2) = 0.32, 0.31 and 0.23, respectively). In the overweight/obese children, BMI and WC had a higher explained variance for BF% compared to WHtR (R(2) = 0.68, 0.70 and 0.50, respectively). In the overweight/obese children, WHtR, WC and BMI were all significantly positively correlated with systolic blood pressure (r = 0.23, 0.30, 0.36, respectively), HOMA2-IR (r = 0.53, 0.62, 0.63, respectively), leptin (r = 0.70, 0.77, 0.78, respectively) and triglycerides (r = 0.33, 0.36, 0.24, respectively), but not consistently with other parameters. CONCLUSION In young children, WHtR is not superior to WC or BMI in estimating BF%, nor is WHtR better correlated with cardiometabolic risk factors than WC or BMI in overweight/obese children. These data do not support the use of WHtR in young children.

Insulin Resistance and Cardiovascular Risk Factors in 3- to 5-Year-Old Overweight or Obese Children

Background/Aims: The increasing rate of overweight and obesity is alarming. The complications of overweight and obesity at a young age are largely unknown. We aimed to assess the prevalence of insulin resistance (IR) and cardiovascular risk factors among overweight and obese children aged 3-5 years. Methods: The study population consisted of 75 children (29 overweight, 46 obese). We performed anthropometry and bioelectrical impedance analysis as an indicator of body composition. IR was determined by the updated Homeostasis Model Assessment of Insulin Resistance (HOMA2-IR). Cardiovascular risk factors were defined by the presence of increased serum triglycerides, blood pressure, and HOMA2-IR and by a decreased serum HDL cholesterol. Results: An elevated HOMA2-IR was found in 7.7% of the children. HOMA2-IR was correlated with body mass index (r = 0.63), waist circumference (r = 0.62) and percentage body fat (r = 0.58) (all p < 0.001). Cardiovascular risk factors were present in 6.9% (triglycerides) to 74.3% (hypertension) of the children. Conclusion: IR and cardiovascular risk factors are already evident in many 3- to 5-year-old overweight and obese children. IR is strongly related to body composition.

Bone Mineral Density and Effects of Growth Hormone Treatment in Prepubertal Children with Prader-Willi Syndrome : A Randomized Controlled Trial

BACKGROUND Bone mineral density (BMD) is unknown in children with Prader-Willi syndrome (PWS), but is decreased in adults with PWS. In patients with GH deficiency, BMD increases during GH treatment. OBJECTIVES The aim of the study was to evaluate BMD in children with PWS and to study the effects of GH treatment. DESIGN We conducted a randomized controlled GH trial. Forty-six prepubertal children were randomized into either a GH-treated group (1.0 mg/m(2) . d) or a control group for 2 yr. At start, 6, 12, and 24 months of study, total body and lumbar spine BMD were measured by dual-energy x-ray absorptiometry, and lumbar spine bone mineral apparent density (BMAD) was calculated. RESULTS Baseline total body and lumbar spine BMD sd score (SDS) were normal [mean (sd), -0.2 SDS (1.1) and -0.4 SDS (1.2), respectively]. BMADSDS, which corrects for short stature, was also normal [mean (sd), 0.40 SDS (1.1)]. Total body BMDSDS decreased during the first 6 months of GH (P < 0.0001), but increased during the second year of treatment. After 24 months of study, total body and lumbar spine BMDSDS, and the BMADSDS did not significantly differ between GH-treated children and randomized controls (P = 0.30, P = 0.44, and P = 0.47, respectively). Results were similar when corrected for body mass index SDS. Repeated measurements analysis showed a significant positive association between IGF-I SDS and total body and lumbar spine BMDSDS, but not with BMADSDS. CONCLUSIONS Our results show that prepubertal children with PWS have a normal BMD. GH treatment had no effect on BMD, except for a temporary decrease of total body BMDSDS in the first 6 months.

Bone Mineral Density in Children and Adolescents With Prader-Willi Syndrome: A Longitudinal Study During Puberty and 9 Years of Growth Hormone Treatment

CONTEXT Longitudinal data on bone mineral density (BMD) in children and adolescents with Prader-Willi Syndrome (PWS) during long-term GH treatment are not available. OBJECTIVE This study aimed to determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS), and bone mineral apparent density of the lumbar spine (BMADLS) in children with PWS. DESIGN AND SETTING This was a prospective longitudinal study of a Dutch PWS cohort. PARTICIPANTS Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years participated in the study. INTERVENTION The children received GH treatment, 1 mg/m(2)/day (≅ 0.035 mg/kg/d). MAIN OUTCOME MEASURES BMDTB, BMDLS, and BMADLS was measured by using the same dual-energy x-ray absorptiometry machine for all annual measurements. RESULTS In the prepubertal group, BMDTB standard deviation score (SDS) and BMDLSSDS significantly increased during 4 years of GH treatment whereas BMADLSSDS remained stable. During adolescence, BMDTBSDS and BMADLSSDS decreased significantly, in girls from the age of 11 years and in boys from the ages of 14 and 16 years, respectively, but all BMD parameters remained within the normal range. Higher Tanner stages tended to be associated with lower BMDTBSDS (P = .083) and a significantly lower BMADLSSDS (P = .016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS. CONCLUSIONS This long-term GH study demonstrates that BMDTB, BMDLS, and BMADLS remain stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 years in girls and 14 years in boys unless there is a normal progression of puberty.