Growth pattern in Kabuki syndrome with a KMT2D mutation.

Kabuki syndrome is a multiple congenital malformation syndrome with a spectrum of clinical features including short stature. Since there is no growth data on Kabuki syndrome patients with a proven KMT2D gene mutation, further research on growth and growth patterns is indicated. Data for this growth study on subjects with Kabuki syndrome were collected from referring clinicians. Subjects were eligible for inclusion in the study if the following criteria were met: a genetically confirmed diagnosis of Kabuki syndrome and no current treatment with growth hormones or other drugs that could influence growth. We present a report on growth data (n = 39) in Kabuki syndrome patients. The data showed that postnatal growth retardation is a clinical feature in all cases. All Kabuki syndrome subjects showed a growth deflection during childhood and a diminution of the pubertal growth spurt. A genotype-phenotype correlation was not observed. Further research is required in order to determine whether a defect in the growth hormone/IGF-I axis and estrogen receptor plays a role in the growth retardation. © 2016 Wiley Periodicals, Inc.

Arm Span and Its Relation to Height in a 2- to 17-Year-Old Reference Population and Heterozygous Carriers of ACAN Variants.

BACKGROUND/OBJECTIVES: In the clinical assessment of a short or tall child, estimating body disproportion is useful to assess the likelihood of a primary growth disorder, e.g., skeletal dysplasia. Our objectives were (1) to use data from the Maastricht study on healthy children (2-17 years) to calculate relative arm span (AS) for height (H) to serve as age references for clinical purposes; (2) to assess its age and sex dependency; and (3) to investigate relative AS adjustment for age and sex in individuals with ACAN haploinsufficiency. METHODS: The Maastricht study data (2,595 Caucasian children, 52% boys, 48% girls) were re-analysed to produce reference tables and graphs for age and sex of AS - H and AS/H. Published information on AS/H in Europeans was used as reference data for adults. Relative AS from 33 patients with ACAN haploinsufficiency were plotted against reference data and expressed as standard deviation score (SDS) for age and sex. RESULTS: Mean AS - H from 2 to 17 years increased from -1.2 to +1.5 cm in boys and from -4.8 to +1.6 cm in girls. Mean AS/H increased from 0.9848 to 1.0155 in boys and from 0.9468 to 1.0028 in girls. Mean AS/H in patients with ACAN haploinsufficiency was approximately 1.0, 1.5 and 0.5 SDS in young children, adolescents and 20- to 50-year-olds, respectively, and normal thereafter. CONCLUSIONS: These reference charts can be used for 2- to 17-year-old children/adolescents. Carriers of ACAN haploinsufficiency have an elevated mean AS/H in childhood and adolescence and a slightly elevated ratio till 50 years.

The effect of sibutramine on energy expenditure and body composition in obese adolescents.

CONTEXT: Childhood obesity is now considered to be an epidemic. Drug therapy in this age group remains a topic of research. OBJECTIVE: The objective of this study was to examine the effect of treatment with sibutramine (10 mg) on body composition and energy expenditure in obese adolescents. DESIGN: The study was conducted as a randomized, double-blind, placebo-controlled trial. SETTING: The study was set in an obesity research center. PATIENTS: The patients were 24 obese adolescents (age 12-17 yr, 11 boys); four patients withdrew. INTERVENTION: Intervention was sibutramine (Meridia) or placebo in combination with an energy-restricted diet and exercise plan for 12 wk, followed by an identical, but medication-free, treatment period (follow-up). MAIN OUTCOME MEASURE: Change in body mass index (BMI) sd score (BMI-SDS) was the principal measure of efficacy. Body composition and total energy expenditure were measured by stable isotopes and further calculated according to the four-component model, using underwater weighing and dual x-ray absorptiometry. Basal metabolic rate (BMR) was measured by ventilated hood and adjusted for sex and body composition (BMRadj). RESULTS: After intervention, the decrease in BMI-SDS was comparable in both groups. During follow-up, BMI further decreased in the placebo group but stabilized in the sibutramine group. Changes in the percentage of fat mass were not different between both groups. BMRadj decreased in the placebo group and remained constant in the sibutramine group. During follow-up, BMRadj decreased in the sibutramine group and increased in the placebo group. Changes in total energy expenditure were not significantly different. CONCLUSION: The effect of sibutramine on BMI-SDS was not significant. Sibutramine may diminish the decrease in BMRadj associated with energy restriction in obese adolescents.

Growth Hormone Therapy in Children with Kabuki Syndrome: 1-year Treatment Results.

BACKGROUND/AIMS: Kabuki syndrome (KS) is a rare genetic malformation syndrome, resulting in characteristic features such as short stature. We investigate whether growth hormone (GH) treatment increases linear height and influences body proportions in KS children. METHODS: In this prospective study, 18 genetically confirmed prepubertal KS children (9 females and 9 males) aged from 3.8 to 10.1 years (mean 6.8 ± 2.1 years) were treated with recombinant human GH (rhGH) for 1 year. Calculations for height, height velocity, BMI, sitting height, and subischial leg length were made. Bone age, insulin-like growth factor (IGF-I), and IGF binding protein 3 (IGFBP-3) were also measured. RESULTS: This study showed an increase in height standard deviation score (SDS) for the whole group from -2.40 to -1.69 (p < 0.05) after 1 year of rhGH treatment. The change in height SDS within 1 year was >0.7 SDS for 10 subjects and >0.5 SDS for 3 subjects. The mean IGF-I SDS at the start of the study was -0.70 (±1.07), which increased after 12 months to 1.41 (±0.91) (p < 0.05). KS children who received rhGH at a younger age displayed significantly greater increases in height than those who started when they were older. The same was true for both gene mutation KMT2D versus KDM6A and for GH deficiency versus non-GH deficiency KS children (p < 0.05). Throughout the course of rhGH treatment, the subjects' body proportions remained normal. CONCLUSIONS: All participants experienced catch-up growth during the year of rhGH treatment, but without an influence on body proportions.

Growth Hormone Stimulation Tests in Children with Kabuki Syndrome.

BACKGROUND/AIMS: Kabuki syndrome is a multiple congenital malformation syndrome with a variety of clinical features including short stature. The cause of this postnatal short stature remains unknown. METHODS: Eighteen children with genetically proven Kabuki syndrome (8 boys and 10 girls; ages 3.3-9.9 years, with a mean of 6.7 years) who underwent growth hormone (GH) stimulation tests were evaluated in a prospective study. Two GH stimulation tests were conducted, including insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) serum levels. GH stimulation peaks in relation to age, sex, height, body mass index (BMI), IGF-I, and IGFBP-3 SD scores (SDS) were analyzed. RESULTS: Five of the 18 children (27.8%) were biochemically GH deficient. This was not correlated with BMI SDS. Of all patients, only 1 had an IGF-I below -2 SD and did not fulfill the GH deficiency criteria. The mean IGF-I level was below normal (-0.8 SD). All subjects had normal IGFBP-3 levels. CONCLUSIONS: The utility of performing GH stimulation tests on Kabuki syndrome children as an indication of GH status in short stature is questionable. IGF-I levels did correlate neither with the GH stimulation peak nor consequently with the diagnosis of GH deficiency.

Obesity in childhood: A secular trend or an epidemic disease?

The concern about obesity in children has increased worldwide. The question arises, whether this trend to obesity already starts during the prenatal period and to what extent the increase of weight is related to a secular trend in height. For neonatal data, three studies, performed in The Netherlands, with neonatal data of birth weights were compared. For postnatal data, weight, height and body mass index (BMI) of two nationwide studies, performed in the Netherlands, were analyzed. No differences between birth weights were found between 1970 and 2007. In postnatal data a trend of increasing weight and BMI in both boys and girls starts from five years onwards. The secular trend in height starts from the age of two and a half years onward in both boys and girls. The increase in weight is more pronounced than the increase in height. No prenatal secular trend could be detected in The Netherlands. Postnatal, the secular trend is obvious for weight, height and BMI. The increase in skewness of the weight distribution may be ascribed to a metabolic disturbance of the population.

Genetic, maternal and placental factors in the association between birth weight and physical fitness: a longitudinal twin study.

BACKGROUND: Adult cardiorespiratory fitness and muscle strength are related to all-cause and cardiovascular mortality. Both are possibly related to birth weight, but it is unclear what the importance is of genetic, maternal and placental factors in these associations. DESIGN: Peak oxygen uptake and measures of strength, flexibility and balance were obtained yearly during adolescence (10-18 years) in 114 twin pairs in the Leuven Longitudinal Twin Study. Their birth weights had been collected prospectively within the East Flanders Prospective Twin Survey. RESULTS: We identified linear associations between birth weight and adolescent vertical jump (b = 1.96 cm per kg birth weight, P = 0.02), arm pull (b = 1.85 kg per kg birth weight P = 0.03) and flamingo balance (b = -1.82 attempts to stand one minute per kg birth weight, P = 0.03). Maximum oxygen uptake appeared to have a U-shaped association with birth weight (the smallest and largest children had the lowest uptake, P = 0.01), but this association was no longer significant after adjustment for parental BMI. Using the individual twin's deviation from his own twin pair's average birth weight, we found positive associations between birth weight and adolescent vertical jump (b = 3.49, P = 0.0007) and arm pull (b = 3.44, P = 0.02). Δ scores were calculated within the twin pairs as first born twin minus second born twin. Δ birth weight was associated with Δ vertical jump within MZ twin pairs only (b = 2.63, P = 0.009), which indicates importance of placental factors. CONCLUSIONS: We found evidence for an association between adolescent physical performance (strength, balance and possibly peak oxygen uptake) and birth weight. The associations with vertical jump and arm pull were likely based on individual, more specifically placental (in the case of vertical jump) factors. Our results should be viewed as hypothesis-generating and need confirmation, but potentially support preventive strategies to optimize birth weight, for example via placental function, to target later fitness and health.

Genetic and environmental factors in associations between infant growth and adult cardiometabolic risk profile in twins.

BACKGROUND: Accelerated infant growth is associated with an altered, mostly adverse adult cardiometabolic risk profile. The importance of genetic and environmental factors to these associations is unclear. OBJECTIVE: The objective was to examine the importance of genetic and environmental factors in the associations between infant growth and adult cardiometabolic risk factors (anthropometric characteristics, lipids, insulin sensitivity, leptin, blood pressure, and fibrinogen) in twins. DESIGN: Cardiometabolic risk factors were assessed in 240 twin pairs (aged 18-34 y) from the East Flanders Prospective Twin Survey. Infant growth was defined as change in weight z score. We regressed intrapair differences in growth during 4 growth windows (0-1, 1-6, 6-12, and 12-24 mo) against intrapair differences in the risk factors in monozygotic and dizygotic twins separately. RESULTS: Within monozygotic twin pairs only, associations between infant growth and most adult lipids, glucose, leptin, and blood pressure (eg, systolic blood pressure: b = 5.95 mm Hg per change in z score, P = 0.01 in monozygotic twins; b = -1.64, P = 0.82 in dizygotic twins from 12 to 24 mo) were found. Within dizygotic twin pairs only, associations between growth and triglycerides and fibrinogen (eg, fibrinogen: b = 0.07 ln mg/dL per change in z score, P = 0.31 in monozygotic twins; b = 0.79, P = 0.01 in dizygotic twins from 0 to 1 mo) were identified. Most associations showed a detrimental effect of accelerated growth, but beneficial associations were also identified (eg, total-to-high-density-lipoprotein cholesterol ratio: b = -0.22 per change in z score from 1 to 6 mo, P = 0.008 in monozygotic twins). CONCLUSION: Our data showed that environmental factors play a role in the associations between infant growth and most adult lipids, glucose, leptin, and blood pressure, whereas genetic factors are involved regarding triglycerides and fibrinogen.