Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation.

A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.

Celia's encephalopathy and c.974dupG in BSCL2 gene: a hidden change in a known variant.

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy (PELD)) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7. For years, different authors have reported cases of congenital generalized lipodystrophy due to the variant c.974dupG in BSCL2 associated with neurological manifestations of variable severity, although some of them clearly superimposable to PELD. To identify the molecular mechanisms responsible for these neurological alterations in two patients with c.974dupG. Clinical characterization, biochemistry, and neuroimaging studies of two girls carrying this variant. In silico analysis, PCR amplification, and BSCL2 cDNA sequencing. BSCL2-201 transcript expression, which lacks exon 7, by qPCR in fibroblasts from the index case, from a healthy child as a control and from two patients with PELD, and in leukocytes from the index case and her parents. One with a severe encephalopathy including a picture of intellectual deficiency, severe language impairment, myoclonic epilepsy, and lipodystrophy as described in PELD, dying at 9 years and 9 months of age. The other 2-year-old patient showed incipient signs of neurological involvement. In silico and cDNA sequencing studies showed that variant c.974dupG gives rise to skipping of exon 7. The expression of BSCL2-201 in fibroblasts was significantly higher in the index case than in the healthy child, although less than in the case with homozygous PELD due to c.985C>T variant. The expression of this transcript was approximately half in the healthy carrier parents of this patient. The c.974dupG variant leads to the skipping of exon 7 of the BSCL2 gene and is responsible for a variant of Celia's encephalopathy, with variable phenotypic expression.

Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations.

CONTEXT: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. OBJECTIVE: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. PATIENTS AND METHODS: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. RESULTS: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. CONCLUSIONS: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

Isolated Large Cell Calcifying Sertoli Cell Tumor in a Young Boy, not Associated with Peutz-Jeghers Syndrome or Carney Complex.

BACKGROUND: Large cell calcifying sertoli cell tumor (LCCSCT) is an exceedingly rare lesion of the testicle. It is most often seen in patients with Carney complex (CNC) or Peutz-Jeghers syndrome (PJS). We now report the first pediatric patient with what appears to be bilateral LCCSCT and no other conditions or a genetic syndrome, such as PJS or CNC, have been associated with it. METHODS: A 10-year-old boy was found to have a right testicular mass during a routine pediatric examination; he underwent right orchiectomy. He was then evaluated clinically for PJS or CNC and underwent genetic testing. His tumor was studied by immunohistochemistry for the expression of calretinin, NY-ESO-1, inhibin, CD99, S100, PLAP, AE1/AE3, Bcl-2, p53, and Mib1. RESULTS: Patient did not have clinical features or genetic abnormalities of CNC and PJS. Microscopic features showed large, round or cubical intratubular and aggregated tumor cells with prominent nuclear atypia, large and prominent nucleoli and extensive calcification. In the Immunohistochemical studies, calretinin and inhibin alpha were up regulated in LCCSCT as compared to the adjacent benign Sertoli cells. Meanwhile, NY-ESO-1 and CD99 were down-regulated in LCCSCT. Focally and weakly positive S100 was found in the tumor tissue, but no S100 expression was present in the adjacent Sertoli cells. There was no expression of PLAP, P53, Bcl-2, Mib1 and AE1/AE3 in LCCSCT and adjacent Sertoli cells. Micro-calcifications were found in the other gonad by ultrasonography, suggesting LCCSCT. CONCLUSION: LCCSCT is a rare testicular neoplasm, and may present in isolated rather than in more typical association with syndromes such as CNC and PJS.

Use of aromatase inhibitors in large cell calcifying sertoli cell tumors: effects on gynecomastia, growth velocity, and bone age.

CONTEXT: Large cell calcifying Sertoli cell tumors (LCCSCT) present in isolation or, especially in children, in association with Carney Complex (CNC) or Peutz-Jeghers Syndrome (PJS). These tumors overexpress aromatase (CYP19A1), which leads to increased conversion of delta-4-androstenedione to estrone and testosterone to estradiol. Prepubertal boys may present with growth acceleration, advanced bone age, and gynecomastia. OBJECTIVE: To investigate the outcomes of aromatase inhibitor therapy (AIT) in prepubertal boys with LCCSCTs. DESIGN: Case series of a very rare tumor and chart review of cases treated at other institutions. SETTING: Tertiary care and referral center. PATIENTS: Six boys, five with PJS and one with CNC, were referred to the National Institutes of Health for treatment of LCCSCT. All patients had gynecomastia, testicular enlargement, and advanced bone ages, and were being treated by their referring physicians with AIT. INTERVENTIONS: Patients were treated for a total of 6-60 months on AIT. MAIN OUTCOME MEASURES: Height, breast tissue mass, and testicular size were all followed; physical examination, scrotal ultrasounds, and bone ages were obtained, and hormonal concentrations and tumor markers were measured. RESULTS: Tumor markers were negative. All patients had decreases in breast tissue while on therapy. Height percentiles declined, and predicted adult height moved closer to midparental height as bone age advancement slowed. Testicular enlargement stabilized until entry into central puberty. Only one patient required unilateral orchiectomy. CONCLUSIONS: Patients with LCCSCT benefit from AIT with reduction and/or elimination of gynecomastia and slowing of linear growth and bone age advancement. Further study of long-term outcomes and safety monitoring are needed but these preliminary data suggest that mammoplasty and/or orchiectomy may be foregone in light of the availability of medical therapy.

Sexual dimorphisms in the associations of BMI and body fat with indices of pubertal development in girls and boys.

CONTEXT: The effect of obesity and concomitant insulin resistance on pubertal development is incompletely elucidated. OBJECTIVE: To determine how measures of adiposity and insulin resistance are associated with pubertal maturation in boys and girls. SETTING AND DESIGN: Breast and pubic hair Tanner stage and testicular volume by orchidometry were determined by physical examination in 1066 children. Ovarian volume was estimated by trans-abdominal ultrasound. Fat mass, skeletal age, and fasting serum for insulin and glucose, total T, estradiol, estrone, dehydroepiandrosterone-sulfate, and androstenedione were measured at the National Institutes of Health Clinical Research Center. Convenience sample; 52% obese, 59% female. RESULTS: Logistic regression identified a significant interaction between sex and obesity for prediction of pubertal development (P ≤ .01). There was a negative association between boys' testicular volume and body mass index (BMI)/fat mass but a positive association between girls' breast stage and BMI/fat mass. Ovarian volume in girls was positively associated with insulin resistance but not with BMI/fat mass. There was a positive association between obesity and measures of estrogen exposure (breast development and skeletal age) in both sexes. Positive correlations were seen for girls between BMI and pubic hair development and between insulin resistance and T production, whereas adiposity was negatively associated with pubic hair in boys. CONCLUSIONS: Significant sexual dimorphisms in the manifestations of pubertal development are seen in obese girls and boys. Two known effects of obesity, increased peripheral conversion of low-potency androgens to estrogens by adipose tissue-aromatase and increased insulin resistance, may be in large part responsible for these differences.

Use of PET/CT with cosyntropin stimulation to identify and localize adrenal rest tissue following adrenalectomy in a woman with congenital adrenal hyperplasia.

CONTEXT: Adrenalectomy is an experimental treatment option for select patients with congenital adrenal hyperplasia who have failed medical therapy. After adrenalectomy, adrenal rest tissue can remain in extraadrenal locations, cause recurrent hyperandrogenism, and be difficult to localize. OBJECTIVE: The aim of the study was to investigate the usefulness of positron emission tomography/computerized tomography (PET/CT) in identifying adrenal rest tissue. SUBJECT: A female with salt-wasting 21-hydroxylase deficiency who had bilateral adrenalectomy at age 17 yr presented with hyperandrogenism at age 32 yr. Pelvic magnetic resonance imaging and ultrasound imaging were nondiagnostic for the source of androgen production. METHODS AND RESULTS: A baseline F-18 labeled fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT scan showed no active uptake; however, a second scan preceded by a 250-µg cosyntropin injection identified three areas of active uptake near both ovaries. Subsequent ovarian venous sampling showed elevations in 17-hydroxyprogesterone, androstenedione, and 21-deoxycortisol in both ovarian veins compared to a peripheral vein at baseline and more so after cosyntropin administration. At laparoscopy, three well-circumscribed nodules (2.4 × 0.9 × 1.3 cm, 1.2 × 1.5 × 1.5 cm, and 2 × 1.5 × 1 cm) lying lateral to the fallopian tubes adjacent to the broad ligaments were removed. The paraovarian nodules and previously removed adrenal glands had similar histology and immunohistochemistry. Postoperatively, androgen concentrations were undetectable, with no response to cosyntropin stimulation. CONCLUSIONS: Patients with CAH after an adrenalectomy may experience recurrent hyperandrogenism due to adrenal rest tissue. 18F-FDG PET/CT with cosyntropin stimulation accurately identified adrenal rest tissue not visualized with conventional imaging, allowing for successful surgical resection.

Pediatric obesity: etiology and treatment.

This article reviews factors that contribute to excessive weight gain in children and outlines current knowledge regarding approaches for treating pediatric obesity. Most of the known genetic causes of obesity primarily increase energy intake. Genes regulating the leptin signaling pathway are particularly important for human energy homeostasis. Obesity is a chronic disorder that requires long-term strategies for management. The foundation for all treatments for pediatric obesity remains restriction of energy intake with lifestyle modification. There are few long-term studies of pharmacotherapeutic interventions for pediatric obesity. Bariatric surgical approaches are the most efficacious treatment but, because of their potential risks, are reserved for those with the most significant complications of obesity.

Links between mothers' and children's disinhibited eating and children's adiposity.

Few studies have examined relationships between parents' and children's specific disinhibited eating behaviors. We investigated links among mothers' and children's binge/loss of control eating, eating in the absence of hunger, and children's adiposity in 305 non-treatment-seeking youth, aged 8-17 years (13.62±2.65 years; 49.8% female) and their mothers. Youths' loss of control eating and eating in the absence of hunger were assessed by interview and self-report questionnaire. Children's adiposity was assessed with BMI-z and air displacement plethysmography. Maternal binge eating, eating in the absence of hunger and highest, non-pregnant BMI were self-reported. In structural equation models controlling for mothers' BMI, mothers' binge eating related to children's loss of control eating, and mothers' eating in the absence of hunger related to children's eating in the absence of hunger. Mothers' binge eating and children's eating in the absence of hunger were unrelated, as were mothers' eating in the absence of hunger and children's loss of control. Further, mothers' binge eating was indirectly related to children's adiposity through children's loss of control eating. Likewise, mothers' eating in the absence of hunger indirectly related to children's adiposity through children's eating in the absence of hunger. Mothers and children share similar, specific disinhibited eating styles.

Acute effects of betahistine hydrochloride on food intake and appetite in obese women: a randomized, placebo-controlled trial.

BACKGROUND: Central nervous system histaminergic tone is thought to play a role in appetite regulation. In animal models, histamine receptor 1 (HRH1) agonists and histamine receptor 3 (HRH3) antagonists decrease food intake. OBJECTIVE: The objective of this study was to examine the acute effects of betahistine hydrochloride (an HRH1 agonist and HRH3 antagonist) on food intakes and appetites. DESIGN: The study was a proof-of-concept, randomized, double-blinded, placebo-controlled, dose-ranging study performed to examine the effects of betahistine in women with class I or II obesity [body mass index (BMI; in kg/m²) of 30-39.99]. After a 24-h placebo run-in period, subjects received a placebo (n = 19) or 48 (n = 19), 96 (n = 17), or 144 (n = 21) mg betahistine/d for 24 h. Treatment was followed by a buffet test meal to assess energy intake. Hunger, satiety, and desire to eat were measured after consuming the meal by using visual analog scales. Data were analyzed by using regression models with the assumption that there would be an increasing effect of betahistine doses. Analyses were adjusted for age, log fat and lean mass, food preferences, and intake during a buffet test meal obtained during the placebo run-in period. RESULTS: Of the 79 obese women (mean ± SD age: 42 ± 11 y; BMI: 35 ± 3) enrolled in the study, 76 women completed the study. The betahistine dose did not significantly change intakes from those observed during the run-in period of the buffet test meal (P = 0.78). Hunger, fullness, and desire to eat (all P > 0.62) similarly showed no differences according to the betahistine dose. CONCLUSIONS: Betahistine did not produce an effect on food intakes or appetites. More potent histaminergic modulators may be required to elucidate the possible role of histaminergic pathways in human obesity. This trial was registered at clinicaltrials.gov as NCT00459992.

Treatment of paediatric hyperthyroidism but not hypothyroidism has a significant effect on weight.

OBJECTIVE: Thyroid hormones are involved in metabolic regulation, but the degree to which they affect body weight and body mass index (BMI) in children is unclear. We examined the effect of hypo- and hyperthyroidism on weight and BMI at the time of diagnosis and after appropriate treatment. DESIGN: Prospective and retrospective case series. PATIENTS: Children referred for thyroid dysfunction were enrolled prospectively if their total or free T4 was elevated with TSH <0·05 mIU/ml (N = 57) or if they had a subnormal total or free T4 and TSH >20 (N = 29). RESULTS: Almost all patients had at least 2 classic signs or symptoms including goitre, but hyperthyroid patients had more symptoms. Mean BMI z scores at the time of diagnosis did not significantly differ between the two groups. Males with hyperthyroidism complained of weight loss more frequently and had a lower pretreatment BMI z score than hyperthyroid females. Hypothyroid patients lost a minimal amount of weight by the first follow-up (mean of 0·3 kg) and on average gained weight by the second follow-up visit. In contrast hyperthyroid patients gained a mean of 3·4 kg at the first follow-up visit and a mean of 7·1 kg by the second. CONCLUSIONS: Correction of hypothyroidism resulted in minimal weight loss, suggesting that hypothyroidism does not cause significant weight gain in children. In contrast, correction of the hyperthyroid state had a somewhat greater impact on weight status. These results are consistent with prior reports but surprising given the opposite metabolic effects of hypo- and hyperthyroidism.

Eating in the absence of hunger in adolescents: intake after a large-array meal compared with that after a standardized meal.

BACKGROUND: Eating in the absence of hunger (EAH) is typically assessed by measuring youths' intake of palatable snack foods after a standard meal designed to reduce hunger. Because energy intake required to reach satiety varies among individuals, a standard meal may not ensure the absence of hunger among participants of all weight strata. OBJECTIVE: The objective of this study was to compare adolescents' EAH observed after access to a very large food array with EAH observed after a standardized meal. DESIGN: Seventy-eight adolescents participated in a randomized crossover study during which EAH was measured as intake of palatable snacks after ad libitum access to a very large array of lunch-type foods (>10,000 kcal) and after a lunch meal standardized to provide 50% of the daily estimated energy requirements. RESULTS: The adolescents consumed more energy and reported less hunger after the large-array meal than after the standardized meal (P values < 0.001). They consumed ≈70 kcal less EAH after the large-array meal than after the standardized meal (295 ± 18 compared with 365 ± 20 kcal; P < 0.001), but EAH intakes after the large-array meal and after the standardized meal were positively correlated (P values < 0.001). The body mass index z score and overweight were positively associated with EAH in both paradigms after age, sex, race, pubertal stage, and meal intake were controlled for (P values ≤ 0.05). CONCLUSION: EAH is observable and positively related to body weight regardless of whether youth eat in the absence of hunger from a very large-array meal or from a standardized meal. This trial was registered at clinicaltrials.gov as NCT00631644.

Puberty and observed energy intake: boy, can they eat!

BACKGROUND: Anecdotal reports suggest that adolescent males consume large quantities of food to meet the growth demands of pubertal development. However, limited experimental data exist to support this impression. OBJECTIVE: The objective was to measure energy intakes of youth at different pubertal stages. DESIGN: Participants were 204 volunteers (50.5% male) aged 8-17 y. Pubertal development was categorized by physical examination into prepuberty (males: testes < 4 mL; females: Tanner breast stage 1), early-mid puberty (males: testes = 4-12 mL; females: Tanner breast stages 2-3), or late puberty (males: testes >12 mL; females: Tanner breast stages 4-5). Energy intake was measured as consumption from a 9835-kcal food array during 2 lunch time meals. RESULTS: Males consumed more energy than did females across all pubertal stages (P < 0.001). Intake increased with pubertal development (P < 0.001), but the timing and magnitude of change varied by sex (P = 0.02). Males' unadjusted energy intake was greater in late puberty (mean +/- SE: 1955 +/- 70 kcal) than in prepuberty (1287 +/- 90 kcal) or early-mid puberty (1413 +/- 92 kcal) (P < 0.001). Females' unadjusted energy intake tended to be lower among prepubertal girls (905 +/- 140 kcal) than among females in early-mid puberty (1278 +/- 82 kcal, P = 0.07) or late puberty (1388 +/- 68 kcal, P = 0.01). After adjustment for fat-free mass, fat mass, height, overweight status, race, and meal instruction, the main effect of sex (P < 0.001) remained significant, but the effect of puberty was not significant (P = 0.66). CONCLUSIONS: The observed intake patterns are congruent with known sexual dimorphisms for body composition, peak growth velocity, and pubertal development. Consistent with their higher energy requirements, males can consume significantly larger amounts of food than females, especially during later puberty. This trial was registered at clinicaltrials.gov as NCT00320177.

Pediatric obesity: etiology and treatment.

This article reviews factors that contribute to excessive weight gain in children and outlines current knowledge regarding approaches for treating pediatric obesity. Most of the known genetic causes of obesity primarily increase energy intake. Genes regulating the leptin signaling pathway are particularly important for human energy homeostasis. Obesity is a chronic disorder that requires long-term strategies for management. The foundation for all treatments for pediatric obesity remains restriction of energy intake with lifestyle modification. There are few long-term studies of pharmacotherapeutic interventions for pediatric obesity. Bariatric surgical approaches are the most efficacious treatment but, because of their potential risks, are reserved for those with the most significant complications of obesity.