Health related quality of life associated with extreme obesity in adolescents - results from the baseline evaluation of the YES-study.

BACKGROUND: Obesity can significantly reduce health-related quality of life (HRQoL) and may lead to numerous health problems even in youths. This study aimed to investigate whether HRQoL varies among youths with obesity depending on grade of obesity and other factors. METHODS: For the Youths with Extreme obesity Study (YES) (2012-2014), a prospective multicenter cohort study, a baseline sample of 431 obese and extremely obese adolescents and young adults (age 14 to 24 years, BMI ≥30 kg/m2) was recruited at four German university medical centers and one job center. Obesity grade groups (OGG) were defined according to BMI (OGG I: 30-34.9 kg/m2, OGG II: 35-39.9 kg/m2, OGG III (extreme obesity): ≥40 kg/m2). HRQoL was measured with the Euroqol-5D-3 L (EQ-5D-3 L), DISABKIDS chronic generic (DCGM-31) and the KINDLR obesity module. Differences between OGGs were assessed with logistic and linear regression models, adjusting for age, sex, and study center in the base model. In a second regression analysis, we included other characteristics to identify possible determinants of HRQoL. RESULTS: Three hundred fifty-two adolescents (mean age: 16.6 (±2.4), mean BMI: 39.1 (±7.5) kg/ m2) with available HRQoL data were analysed. HRQoL of youths in all OGGs was markedly lower than reference values of non-obese adolescents. Adjusting for age and sex, HRQoL of youths in OGG III significantly impaired compared to OGG I. Youths in OGG III were 2.15 times more likely to report problems with mobility in the EQ-5D-3 L than youths in OGG I. A mean difference of 9.7 and 6.6 points between OGG III and I were found for DCGM-31 and KINDL respectively and 5.1 points between OGG II and I for DCGM-31. Including further variables into the regression models, showed that HRQoL measured by DCGM-31 was significantly different between OGGs. Otherwise, female sex and having more than 4 h of daily screen time were also associated with lower HRQoL measured by DCGM-31 and KINDL. CONCLUSION: HRQoL of adolescents with obesity is reduced, but HRQoL of adolescents with extreme obesity is particularly affected. Larger and longitudinal studies are necessary to understand the relation of extreme obesity and HRQoL, and the impact of other lifestyle or socioeconomic factors. TRIAL REGISTRATION: Clinicaltrials.gov NCT01625325; German Clinical Trials Register (DRKS) DRKS00004172.

Prevalence and phenotypic characterization of MC4R variants in a large pediatric cohort.

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.

Rapid improvement of hepatic steatosis after initiation of leptin substitution in a leptin-deficient girl.

BACKGROUND: Leptin deficiency is associated with severe obesity and metabolic disturbances. Increased liver fat content has been reported in only one case beforehand, even though hepatic steatosis is a typical comorbidity of common obesity. It is also frequent in patients with lipodystrophy where it resolves under leptin therapy. SUBJECT AND METHODS: In 2010, we reported a leptin-deficient patient with a novel homozygous mutation in the leptin gene and severe hepatic steatosis. We have now studied serum changes and changes in liver fat content during the substitution with recombinant methionyl human leptin. RESULTS: After 23 weeks of leptin substitution, elevated transaminases, total cholesterol and low-density lipoprotein levels normalized. After 62 weeks, homeostasis model assessment of insulin resistance improved from 10.7 to 6.0 and body fat mass dropped from 50.2 to 37.8%. Liver fat content was drastically reduced from 49.7 to 9.4%. The first changes in liver fat content were detectable after 3 days of therapy. CONCLUSION: Our patient showed a remarkable reduction of liver fat content during the treatment with recombinant methionyl human leptin. These changes occurred rapidly after initiation of the substitution, which implies that leptin has a direct effect on hepatic lipid metabolism in humans as it is seen in rodents.

Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism.

BACKGROUND: Leptin deficiency leads to midluteal-phase defect or reduced testicular volume in adults, despite normal gonadotropin levels. All children documented to date with leptin deficiency were prepubertal with physiologically low gonadotropins prior to therapy. A direct effect of leptin on pubertal development in a leptin-naive adolescent has not yet been shown. METHODS: In 2010, we reported the first connatal leptin-deficient adolescent girl with clinically and chemically proven hypogonadotropic hypogonadism. In this study, we evaluated the effect of recombinant methionyl human leptin substitution. RESULTS: Initially, the patient had prepubertal basal and stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, low growth hormone and insulin-like growth factor 1 (IGF1) levels and no pulsatile secretion of LH and FSH. After 11 weeks of therapy, basal and stimulated LH and FSH levels rose to pubertal values and nocturnal pulsatility was initiated. After 76 weeks of therapy, menstruation occurred at the age of 16.3 years. Pulsatile nocturnal growth hormone secretion, stimulated growth hormone secretion and IGF1 values also normalized. CONCLUSION: We describe here the first adolescent with hypogonadotropic hypogonadism due to connatal leptin deficiency. Leptin substitution led to a rapid induction of gonadotropin secretion and menarche. These data are further proof of the concept that leptin is needed for a timely maturation of the hypothalamic/pituitary/gonadal axis.

Loss of enteroendocrine cells in autoimmune-polyendocrine-candidiasis-ectodermal-dystrophy (APECED) syndrome with gastrointestinal dysfunction.

BACKGROUND: Enteroendocrine (EE) cells are necessary for the regulation of gastrointestinal function. The lack of intestinal enteroendocrine cells in enteroendocrine cell dysgenesis causes severe malabsorptive diarrhea. Autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) is often accompanied by gastrointestinal (GI) symptoms. AIMS: We hypothesized that an autoimmune attack against the cells of the GI-associated diffuse endocrine system may be a specific feature of GI dysfunction in APECED disorders. METHODS: Biopsies were obtained during routine diagnostic endoscopy from 35 pediatric patients with gastrointestinal symptoms as well as from five healthy controls; biopsies were immunostained for chromogranin A and serotonin. Four patients were classified as APECED syndrome on molecular and clinical grounds. RESULTS: Immunohistological analysis of biopsies along the GI tract (stomach, duodenum, colon) immunostained with chromogranin A and serotonin revealed a widespread reduction or complete loss of EE cells in all four patients with APECED syndrome suffering from severe diarrhea, vomiting, malabsorption, or constipation. In contrast, EE cells were present in pediatric patients with similar gastrointestinal symptoms caused by inflammatory bowel disease, celiac disease, lymphocytic colitis, and autoimmune disorders without endocrinopathy or graft vs. host disease of the gut. CONCLUSIONS: The reduction of EE cells is a specific and important early event in the pathogenesis of APECED with GI dysfunction. We propose a diagnostic algorithm integrating clinics, genetics and immunohistology.

Reference values and early determinants of intra-abdominal fat mass in primary school children.

BACKGROUND: Intra-abdominal fat (IAF) is a valuable predictor of cardiovascular morbidity. However, neither reference values nor determinants are known in children. METHODS: IAF was assessed as sonographically measured intra-abdominal depth in 1,046 children [median age 7.6 years, interquartile range (IQR) 7.2-7.9; 54% boys] of the URMEL-ICE study. RESULTS: The intraclass correlation coefficient for intraobserver agreement was 0.93. The median IAF showed a significant gender difference (boys: 54.6 mm, IQR 50.1-59.3, vs. girls: 51.7 mm, IQR 46.3-56.4; p < 0.001). Age- and gender-specific centiles were generated. IAF showed a positive correlation to systolic blood pressure [regression coefficient (ß) = 0.24 mm Hg/mm; p < 0.001] and a negative correlation to HDL cholesterol (ß = -0.01 mmol/l/mm; p < 0.001). IAF showed a positive association with increased paternal and maternal BMI (ß = 0.28 mm/kg/m(2) and 0.27 mm/kg/m(2); p < 0.001), increased weight gain in the first 2 years of life (ß = 3.04 mm; p < 0.001), and maternal smoking during pregnancy (ß = 2.4 mm; p = 0.001). Increased parental education was negatively associated with IAF (maternal: ß = -0.65 mm/degree; p = 0.004, and paternal: ß = -0.61 mm/degree; p = 0.002). CONCLUSION: Sonography was a reliable tool to estimate IAF. Factors influencing IAF included rapid infant weight gain, smoking during pregnancy, and parental BMI and education. Since IAF showed an association with cardiovascular risk factors even in prepubertal children, it might become a valuable predictor of cardiovascular vulnerability.

Novel homozygous AIRE mutation in a German patient with severe APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder typically presenting with chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal failure variably accompanied by other symptoms. APECED is caused by a mutation in the autoimmune regulator gene (AIRE). Today over 60 different mutations are known world-wide, most of them localized in exons 2, 8, and 10. We report here a German girl with rheumatoid factor positive arthritis, chronic mucocutaneous candidiasis, autoimmune hepatitis, chronic diarrhea, vitiligo, hypothyroidism, hypoparathyroidism, and adrenal failure who is homozygous for a novel mutation at the end of exon 3 of the AIRE gene (c.462G>A), within the conserved splice donor sequence. This mutation probably introduces a frameshift after amino acid 154 (p.Pro154fs) by skipping exon 4. In addition, we analyzed five other family members out of three generations for the AIRE gene mutation and for polymorphisms in the cytotoxic T lymphocyte antigen 4 (CTLA4) gene region and lymphoid protein tyrosine phosphatase (PTPN22) gene, which are associated with the occurrence of sporadic autoimmune Addison's disease, type 1 diabetes mellitus, and generalized vitiligo.