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Background: Evidence from in vitro and rodent studies suggests that leptin, a key signal of long-term energy reserves, promotes IGF1 synthesis and linear growth. This effect of leptin has not been fully investigated in humans. The aim of our study was to investigate the effect of leptin substitution on growth factors and linear growth in children with congenital leptin deficiency (CLD)., Methods: In this cohort study we included eight pediatric patients (six males), age 0.9-14.8 years, who were diagnosed with CLD and received leptin substitution at our University Medical Center. We calculated standard deviation scores (SDS) for serum levels of IGF1 and IGFBP3, IGF1/IGFBP3 molar ratio, and height at baseline (T0) and 12 months (T12) after the initiation of substitution with metreleptin., Results: All patients had severe obesity (BMI-SDS mean ± SD: 4.14 ± 1.51) at T0 and significant BMI-SDS reduction to 2.47 ± 1.05 at T12. At T0, all patients were taller than the mid-parental median, yet had low IGF1 and IGF1/IGFBP3 molar ratios (IGF1-SDS[Formula: see text] T0 : -1.58 ± 0.92, IGF1/IGFBP3 molar ratio-SDS[Formula: see text] T0 : -1.58 ± 0.88). At T12, IGF1-SDS increased significantly (∆ T0-12 : 1.63 ± 1.40, p = 0.01), and IGFBP3-SDS and IGF1/IGFBP3 molar ratio-SDS showed a trend toward an increase. In the three children within the childhood growth period (post-infancy, pre-puberty) height-SDS increased (∆height-SDS T0-12 : 0.57 ± 0.06, p = 0.003) despite substantial weight loss., Conclusions: These results in CLD patients are contrary to observations in children with idiopathic obesity who typically have above-mean IGF1 levels that decrease with weight loss, and therefore suggest that leptin increases IGF1 levels and promotes linear growth.

Objective: Obesity is associated with many cardiovascular risk factors (CVRF) in childhood. There is an ongoing discussion whether there is a linear relationship between degree of overweight and deterioration of CVRFs justifying body mass index (BMI) cut-offs for treatment decisions., Methods: We studied the impact of BMI-SDS on blood pressure, lipids, and glucose metabolism in 76,660 children (aged 5-25 years) subdivided in five groups: overweight (BMI-SDS 1.3 to <1.8), obesity class I (BMI-SDS 1.8 to <2.3), class II (BMI-SDS 2.3-2.8), class III (BMI-SDS > 2.8-3.3), and class IV (BMI-SDS > 3.3). Analyses were stratified by age and sex., Results: We found a relationship between BMI-SDS and blood pressure, triglycerides, HDL cholesterol, liver enzymes, and the triglycerides-HDL-cholesterol ratio at any age and sex. Many of these associations lost significance when comparing children with obesity classes III and IV: In females < 14 years and males < 12 years triglycerides and glucose parameters did not differ significantly between classes IV and III obesity. Prevalence of dyslipidemia was significantly higher in class IV compared to class III obesity only in females ≥ 14 years and males ≥ 12 years but not in younger children. In girls < 14 years and in boys of any age, the prevalences of type 2 diabetes mellitus did not differ between classes III and IV obesity., Conclusions: Since a BMI above the highest BMI cut-off was not associated consistently with dyslipidemia and disturbed glucose metabolism in every age group both in boys and girls, measurements of CVRFs instead of BMI cut-off seem preferable to guide different treatment approaches in obesity such as medications or bariatric surgery.

Objective: We aimed to determine the prevalence of melanocortin-4 receptor (MC4R) variants in a large German cohort of children with obesity in a pediatric outpatient clinic and to ascertain whether there is a specific phenotype associated with loss-of-function variants as previously reported., Study Design: Eight hundred and ninety-nine patients from our pediatric obesity clinic were screened for MC4R variants by DNA sequencing after PCR amplification. Retrospective statistical analysis of anthropometric and metabolic characteristics was performed, comparing patients with and without MC4R variants across the entire cohort (n=586) as well as in case-control analysis using patients with common sequence MC4R individually matched for age, sex and body mass index standard deviation score (SDS) (n=11 case-control pairs)., Results: We identified heterozygous variants within the coding region of the MC4R gene in n=22 (2.45%) patients. Fourteen (1.56%) had a variant that impaired receptor function. One new frameshift (p.F152Sfs), an yet unpublished nonsense mutation (p.Q156X) and one nonsynonymous variation (p.V65E) described in the Mouse Genome Database were detected. Across the whole cohort, at all ages, mean height SDS in subjects with impaired receptor function was higher than in patients with common sequence MC4R. In matched individuals, this trend persisted (8 of the 11 pairs) within the case-control setting. No differences were found regarding metabolic characteristics., Conclusions: The observed prevalence of mutations causing impaired receptor function in this large cohort is comparable to other pediatric cohorts. MC4R deficiency tends to lead to a taller stature, confirming previous clinical reports. The association of MC4R mutations with a distinct phenotype concerning metabolic characteristics remains questionable.

Objective: To investigate clinical and laboratory markers of pubertal development in a large sample of obese children and adolescents., Methods: Analysis of parameters of sexual maturation in 1232 obese individuals (582 boys) aged 6-18 years (mean 13.0+/-2.42 years). Clinical evaluation of pubertal stage and determination of bone age in a subset (227 patients)., Results: Mean Height--standard deviation scores (height-SDS) was positive during childhood and reached zero approximately at age 14 years followed by a turn to negative mean height-SDS in both genders. Accordingly, bone age was accelerated until age 14. No significant differences in average time points of occurrence of pubic hair stages PH 2 to PH 4 in boys and PH 2 to PH 5 in girls were observed as compared to references of the First Zurich Longitudinal Study. In girls, breast stage B 3 was reached earlier (11.6 vs 12.2 years, P=0.03). In boys, mean volume of testis revealed no significant deviation from reference. Mean dehydroepiandrosterone sulfate (DHEAS) levels were elevated in boys (within age ranges 8-10 years and 12-16 years, P<0.02) and in girls (within age ranges 6-8 years and 12-18 years, P<0.005) and mean testosterone levels in boys >12 years were lower as compared to reference ranges (all P-values <0.0001)., Conclusion: The study data suggest normal development of pubarche and gonadarche in obese German boys and normal timing of pubarche in girls. Breast development in obese girls seems to be slightly advanced. In obese boys, an obvious dissociation of clinical and laboratory parameters of pubertal development was observed. Despite significantly increased height-SDS and increased DHEAS levels, gonadal development was normal and testosterone levels were decreased. Elevated DHEAS levels in both genders may contribute to the acceleration of bone maturation, a lower final body height and could increase cardiovascular risk.