Differentiating monogenic and syndromic obesities from polygenic obesity: Assessment, diagnosis, and management.

Background: Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality, and reduced quality of life. The most common form is polygenic obesity, which results from interactions between multiple gene variants and environmental factors. Highly penetrant monogenic and syndromic obesities result from rare genetic variants with minimal environmental influence and can be differentiated from polygenic obesity depending on key symptoms, including hyperphagia; early-onset, severe obesity; and suboptimal responses to nontargeted therapies. Timely diagnosis of monogenic or syndromic obesity is critical to inform management strategies and reduce disease burden. We outline the physiology of weight regulation, role of genetics in obesity, and differentiating characteristics between polygenic and rare genetic obesity to facilitate diagnosis and transition toward targeted therapies. Methods: In this narrative review, we focused on case reports, case studies, and natural history studies of patients with monogenic and syndromic obesities and clinical trials examining the efficacy, safety, and quality of life impact of nontargeted and targeted therapies in these populations. We also provide comprehensive algorithms for diagnosis of patients with suspected rare genetic causes of obesity. Results: Patients with monogenic and syndromic obesities commonly present with hyperphagia (ie, pathologic, insatiable hunger) and early-onset, severe obesity, and the presence of hallmark characteristics can inform genetic testing and diagnostic approach. Following diagnosis, specialized care teams can address complex symptoms, and hyperphagia is managed behaviorally. Various pharmacotherapies show promise in these patient populations, including setmelanotide and glucagon-like peptide-1 receptor agonists. Conclusion: Understanding the pathophysiology and differentiating characteristics of monogenic and syndromic obesities can facilitate diagnosis and management and has led to development of targeted pharmacotherapies with demonstrated efficacy for reducing body weight and hunger in the affected populations.

Special considerations for the child with obesity: An Obesity Medicine Association (OMA) clinical practice statement (CPS) 2024.

Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) details assessment and management of the child with overweight or obesity. The term "child" is defined as the child between 2 and 12 years of age. Because children are in a continual state of development during this age range, we will specify when our discussion applies to subsets within this age range. For the purposes of this CPS, we will use the following definitions: overweight in the child is a body mass index (BMI) ≥ 85th and <95th percentile, obesity in the child is a BMI ≥95th percentile, and severe obesity is a BMI ≥120% of the 95th percentile. Methods: The information and clinical guidance in this OMA Clinical Practice Statement are based on scientific evidence, supported by medical literature, and derived from the clinical perspectives of the authors. Results: This OMA Clinical Practice Statement provides an overview of prevalence of disease in this population, reviews precocious puberty in the child with obesity, discusses the current and evolving landscape of the use of anti-obesity medications in children in this age range, discusses the child with obesity and special health care needs, and reviews hypothalamic obesity in the child. Conclusions: This OMA Clinical Practice Statement on the child with obesity is an evidence based review of the literature and an overview of current recommendations. This CPS is intended to provide a roadmap to the improvement of the health of children with obesity, especially those with metabolic, physiological, psychological complications and/or special healthcare needs. This CPS addresses treatment recommendations and is designed to help the clinician with clinical decision making.

Special considerations for the adolescent with obesity: An obesity medicine association (OMA) clinical practice statement (CPS) 2024.

Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) details special considerations for the management of the adolescent with obesity. The information in this CPS is based on scientific evidence, supported by medical literature, and derived from the clinical experiences of members of the OMA. Methods: The scientific information and clinical guidance in this CPS are based on scientific evidence, supported by the medical literature, and derived from the clinical perspectives of the authors. Results: This OMA Clinical Practice Statement addresses special considerations in the management and treatment of adolescents with overweight and obesity. Conclusions: This OMA Clinical Practice Statement on the adolescent with obesity is an overview of current recommendations. These recommendations provide a roadmap to the improvement of the health of adolescents with obesity, especially those with metabolic, physiological, and psychological complications. This CPS also addresses treatment recommendations and is designed to help the provider with clinical decision making.

Clinical review: Guide to pharmacological management in pediatric obesity medicine.

Introduction: Newer pharmacotherapy agents (anti-obesity medication [AOM]) are revolutionizing the management of children and adolescents with obesity. Previously, treatment based on intensive behavioral therapy involved many patient and family contact hours and yielded improvements in obesity status of 1-3 percent of the 95th percentile of the body mass index (BMI). Newer AOMs are yielding more clinically significant improvement of 5-18 percent. This review provides guidance for practitioners in the care of children and adolescents with obesity who frequently have complex medical and behavioral health care needs. Specifically, we discuss the use of newer AOMs in these complex patients. Methods: This review details an approach to the care of the child and adolescent with obesity using AOMs. A shared decision-making process is presented in which the provider and the patient and family collaborate on care. Management of medical and behavioral components of the disease of obesity in the child are discussed. Results: Early aggressive treatment is recommended, starting with an assessment of associated medical and behavioral complications, weight promoting medications, use of AOMs and ongoing care. Intensive behavioral therapy is foundational to treatment, but not a specific treatment. Patients and families deserve education on expected outcomes with each therapeutic option. Conclusions: The use of new AOMs in children and adolescents has changed expected clinical outcomes in the field of pediatric obesity management. Clinically significant improvement in obesity status occurs when AOMs are used early and aggressively. Ongoing, chronic care is the model for optimizing outcomes using a shared decision-making between provider and patient/family. Depending on the experience and comfort level of the primary care practitioner, referral to an obesity medicine specialist may be appropriate, particularly when obesity related co-morbidities are present and pharmacotherapy and metabolic and bariatric surgery are considerations.

Cerebellar metastatic papillary thyroid carcinoma in a pediatric patient with complex congenital heart disease.

This case describes the first pediatric case of metastatic papillary thyroid carcinoma (PTC) to the cerebellum as the presenting sign of cancer in a child with CHARGE syndrome and complex congenital heart disease. Diagnostic radiation exposure as a strong risk factor for PTC is discussed.

Metabolic, behavioral health, and disordered eating comorbidities associated with obesity in pediatric patients: An Obesity Medical Association (OMA) Clinical Practice Statement 2022.

Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) details metabolic, behavioral health, and disordered eating comorbidities associated with obesity in children. This CPS will be followed by a companion CPS covering further comorbidities, including genetics and social consequences related to overweight and obesity. These CPSs are intended to provide clinicians with an overview of clinical practices applicable to children and adolescents with body mass indices greater than or equal to the 95th percentile for their ages, particularly those with adverse consequences resulting from increased body mass. The information in this CPS is based on scientific evidence, supported by the medical literature, and derived from the clinical experiences of members of the OMA. Methods: The scientific information and clinical guidance in this CPS is based upon referenced evidence and derived from the clinical perspectives of the authors. Results: This OMA statement details metabolic, behavioral health, and disordered eating comorbidities associated with obesity in children. It provides clinical information regarding identifying and treating metabolic, behavioral health, and disordered eating comorbidities associated with obesity in children over the 95th percentile of weight/height for age. Conclusions: This OMA clinical practice statement details metabolic, behavioral health, and disordered eating comorbidities associated with obesity in children and provides an overview of current recommendations. These recommendations lay out a roadmap to the improvement of the health of children and adolescents with obesity, especially those with metabolic, physiological, and psychological complications.

Medication-induced weight gain and advanced therapies for the child with overweight and obesity: An Obesity Medicine Association (OMA) Clinical Practice Statement 2022.

Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) details medication-induced weight gain and advanced therapies for the child with overweight or obesity. Methods: The scientific information and clinical guidance in this CPS are based on scientific evidence, supported by the medical literature, and derived from the clinical perspectives of the authors. Results: This OMA Clinical Practice Statement addresses medication-induced weight gain and advanced therapies for the child with overweight or obesity. Conclusions: This OMA Clinical Practice Statement on medication induced-weight gain and advanced therapies for the child with overweight or obesity is an overview of current recommendations. These recommendations provide a roadmap to the improvement of the health of children and adolescents with obesity, especially those with metabolic, physiological, and psychological complications. This CPS also addresses treatment recommendations. This section is designed to help the provider with clinical decision making.

Retinol binding protein 4 is associated with adiposity-related co-morbidity risk factors in children.

OBJECTIVE: In adults, elevated levels of retinol binding protein 4 (RBP4) have been associated with biochemical markers of adiposity-related co-morbidities including insulin resistance, dyslipidemia, hypertension, and abdominal obesity. This study examined the relationship between RBP4 and risk factors for co-morbidities of adiposity in a population of ethnically diverse children in early- to mid-adolescence in the public school system of New York City. MATERIALS/METHODS: We analyzed anthropometric (body mass index, % body fat, waist circumference), metabolic (lipids, glucose), and inflammatory (TNF-alpha, interleukin-6, C-reactive protein, adiponectin) markers for adiposity-related co-morbidities and serum alanine aminotransferase (ALT) in 106 school children (65 males, 41 females) 11-15 years of age (mean +/- SD = 13.0 +/- 0.1 years) who were enrolled in the Reduce Obesity and Diabetes (ROAD) project. Insulin sensitivity was assessed by quantitative insulin sensitivity check index. Insulin secretory capacity was measured as acute insulin response and glucose disposal index. RESULTS: Serum RBP4 was significantly correlated directly with ALT, triglycerides, and triglyceride z-score, and inversely correlated with adiponectin. Correlations with ALT and adiponectin remained significant when corrected for % body fat, age, and gender. There were significant ethnic differences in the relationship of RBP4 to ALT, glucose disposal index and adiponectin. CONCLUSIONS: In early- to mid-adolescents, circulating concentrations of RBP4 are correlated with multiple risk factors for adiposity-related co-morbidities. The observation that many associations persisted when corrected for % body fat, suggests that RBP4 can be viewed as an independent marker of adiposity-related co-morbidity risk in children.

Pediatric Endocrinology in the Time of COVID-19: Considerations for the Rapid Implementation of Telemedicine and Management of Pediatric Endocrine Conditions.

BACKGROUND: Pediatric endocrine practices had to rapidly transition to telemedicine care at the onset of the novel coronavirus disease 2019 (COVID-19) pandemic. For many, it was an abrupt introduction to providing virtual healthcare, with concerns related to quality of patient care, patient privacy, productivity, and compensation, as workflows had to change. SUMMARY: The review summarizes the common adaptations for telemedicine during the pandemic with respect to the practice of pediatric endocrinology and discusses the benefits and potential barriers to telemedicine. Key Messages: With adjustments to practice, telemedicine has allowed providers to deliver care to their patients during the COVID-19 pandemic. The broader implementation of telemedicine in pediatric endocrinology practice has the potential for expanding patient access. Research assessing the impact of telemedicine on patient care outcomes in those with pediatric endocrinology conditions will be necessary to justify its continued use beyond the COVID-19 pandemic.

Long-term follow-up of gonadal dysfunction in morbidly obese adolescent boys after bariatric surgery.

Background Elevated body mass index (BMI) is associated with hypogonadism in men but this is not well described in adolescents. The aim is to evaluate gonadal dysfunction and the effects of weight loss after gastric banding in obese adolescent boys. Methods Thirty-seven of 54 boys (age 16.2±1.2 years, mean BMI 48.2 kg/m2) enrolled at the Center for Adolescent Bariatric Surgery at Columbia University Medical Center had low total testosterone for Tanner 5 <350 ng/dL. Sixteen had long-term hormonal data for analysis at baseline (T0), 1 year (T1) and 2 years (T2) post-surgery. T-tests, chi-squared (χ2) tests, correlation and linear mixed models were performed. Results At T0, the hypogonadal group had higher systolic blood pressure (SBP) (75th vs. 57th percentile, p=0.02), fasting insulin (19 vs. 9 µIU/mL, p=0.0008) and homeostatic index of insulin resistance (HOMA-IR) (4.2 vs. 1.9, p=0.009) compared to control group. Total testosterone was negatively correlated with fasting insulin and HOMA-IR. In the long-term analysis, BMI, weight, waist circumference (WC), and % excess weight decreased at T1 and T2 compared to T0. Mean total testosterone at T0, T1 and T2 were 268, 304 and 368 ng/dL, respectively (p=0.07). There was a statistically significant negative correlation between BMI and testosterone after 2 years (r=-0.81, p=0.003). Conclusions Low testosterone levels but unaltered gonadotropins are common in this group and associated with insulin resistance. While a significant increase in testosterone was not found over time, the negative relationship between BMI and testosterone persisted, suggesting there may be an optimal threshold for testosterone production with respect to BMI. Long-term studies are needed.

Insulinoma masquerading as a loss of consciousness in a teenage girl: case report and literature review.

BACKGROUND: Hypoglycemia due to a pancreatic beta cell neoplasm - insulinoma, is uncommon with only a few cases described. We report on a previously healthy 15-year-old Hispanic female with insulinoma who presented with a loss of consciousness due to hypoglycemia unawareness. CASE PRESENTATION: EM was first brought to the emergency department (ED) after she was found unresponsive at home with point of care (POC) glucose of 29 mg/dL(1.6 mmol/L) documented by emergency medical services (EMS) upon arrival. After treatment with dextrose and normal laboratory evaluation, including complete blood count, basal metabolic profile and urine drug screen, she was sent home with recommendations to follow-up the next day with an endocrinologist. Due to insurance issues, the family did not keep the appointment. Two days later, she returned to the ED with POC of 19 mg/dL (1.05 mmol/L). Detailed history review identified vague fatigue, excessive sleepiness, poor oral intake and weight gain for a 2-3 month period and no suspicion for drug, alcohol or prescription medication abuse. Family history of multiple endocrine neoplasia was negative. Physical examination revealed mild acanthosis nigricans and a body mass index of 32.8 kg/m2 (98th percentile). Laboratory evaluation showed elevated insulin with low cortisol and growth hormone levels at the time of hypoglycemia. Abdominal magnetic resonance imaging revealed a pancreatic mass, also supported by ultrasound, computed tomography and positron emission tomography scans. The patient underwent a partial pancreatectomy with removal of a well-circumscribed insulinoma from the anterior-superior aspect of the pancreatic neck confirmed by histology. Hypoglycemia resolved post-operatively and she remained euglycemic during a 48-h cure fast. At her 3-month follow-up visit, she had no symptoms of hypoglycemia. CONCLUSION: Documented hypoglycemia in an otherwise healthy adolescent should be fully investigated before discharging a patient. Even a short duration of symptoms should prompt, in-depth diagnostic evaluations to rule out a potentially life threatening diagnosis of insulinoma.

Premature pubarche in a child with abnormal 3ß-hydroxysteroid dehydrogenase function and Klinefelter syndrome: the intriguing relationship between androgen deficiency and excess.

Disorders of androgen excess may coexist with disorders of androgen deficiency, such as Klinefelter syndrome, and can create diagnostic and therapeutic challenges.

Luteoma of pregnancy associated with nearly complete virilization of genetically female twins.

OBJECTIVE: To describe a pregnancy that was complicated by the virilization of the mother and two 46XX infants. METHODS: We outline the clinical presentation and diagnosis of the virilization of a mother and her twins, reviewing pertinent literature. RESULTS: We report the case of a 40-year-old Caucasian female who conceived a trichorionic triplet pregnancy through in vitro fertilization (IVF) but underwent cytoreduction at 13 weeks of gestation, leaving a diamniotic dichorionic twin pregnancy. At 16 weeks of gestation the mother experienced increasing acne, facial hair, and deepening of her voice. Due to preeclampsia, the twins were delivered via caesarean section at 33 weeks of gestation. The infants had male-appearing external genitalia (Prader score IV-V) but no palpable gonads. Congenital adrenal hyperplasia was ruled out for both twins and they were both found to have a uterus and a 46XX karyotype. Maternal testosterone level was elevated at birth (1,981 ng/dL), but the infants had normal levels. Maternal testosterone levels returned to normal after delivery, consistent with a luteoma of pregnancy, although imaging was negative for a mass. CONCLUSION: This is the second reported case of complete virilization associated with a luteoma of pregnancy. Whether or not IVF and related procedures increase the risk for a luteoma and whether or not fetal reduction procedures disrupt placental aromatases and increase the risk of virilization in the face of elevated androgen levels are questions that require further research.

Gonadal dysfunction in morbidly obese adolescent girls.

OBJECTIVE: To describe gonadal dysfunction and evaluate polycystic ovary syndrome (PCOS) and its association with metabolic syndrome (MeS) among girls in a morbidly obese adolescent population. DESIGN: In a cross-sectional study of 174 girls, height, weight, waist circumference, Tanner stage, reproductive hormones, carbohydrate and lipid markers, drug use, and menstrual history were obtained at baseline. Exclusion criteria were menarcheal age <2 years, hormonal contraceptive or metformin use, Tanner stage <4, and incomplete data on PCOS or MeS classification. SETTING: University medical center outpatient clinic. PATIENT(S): Ninety-eight girls ages 13-19.6 years, Tanner 5, average body mass index of 46.6 kg/m(2), menarche at 11.4 years, and average menarcheal age of 5 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Polycystic ovary syndrome and MeS. RESULT(S): Ninety-eight girls were divided into four groups: PCOS by National Institutes of Health criteria (PCOSN, n = 24), irregular menses only (n = 25), elevated T (≥55 ng/dL) only (n = 6), and obese controls (n = 43). Metabolic syndrome by modified Cook criteria affected 32 girls or 33% overall: 6 of 24 PCOSN, 7 of 25 irregular menses only, 4 of 6 elevated T only, and 15 of 43 obese controls. Polycystic ovary syndrome by National Institutes of Health criteria and its individual components were not associated with MeS after adjusting for body mass index. CONCLUSION(S): Unlike obese adults, PCOSN and its individual components were not associated with MeS in the untreated morbidly obese adolescent population.

Weight loss after bariatric surgery in morbidly obese adolescents with MC4R mutations.

OBJECTIVE: To determine the frequency of Melanocortin 4 Receptor (MC4R) mutations in morbidly obese adolescents undergoing bariatric surgery and compare weight loss outcomes in patients with and without mutations. DESIGN AND METHODS: In this prospective cohort study, 135 adolescent patients evaluated for bariatric surgery were screened for MC4R mutations; 56 had 12-month postoperative data available for analysis. RESULTS: MC4R mutations were detected in five of the 135 patients (3.7%); four underwent restrictive bariatric surgery. For the three patients with gastric banding, percent excess weight loss (%EWL) postoperatively was 36.0% at 5 years in one, 47% at 4 years in the second, and 85% at 1 year in the third. For the patient with gastric sleeve resection, %EWL of 96% was attained at 1 year postoperatively. The four MC4R cases had a higher, although nonsignificant, %EWL compared to 52 nonmatched controls at 12 months postoperatively (48.6% vs. 23.4%; P < 0.37). When matched by age, sex, and race to 14 controls, there was no significant difference in %EWL (P < 0.31), BMI change (P < 0.27), or absolute weight loss (P < 0.20). CONCLUSION: The frequency of MC4R mutations is similar to prior studies, with affected patients showing beneficial weight loss outcomes.

Recombinant human leptin does not alter gut hormone levels after gastric bypass but may attenuate sweet cravings.

Bariatric surgery improves glucose homeostasis and alters gut hormones partly independent of weight loss. Leptin plays a role in these processes; levels are decreased following bariatric surgery, creating a relative leptin insufficiency. We previously showed that leptin administration in a weight-reduced state after Roux-en-Y gastric bypass (RYGB) caused no further weight loss. Here, we discuss the impact of leptin administration on gut hormones, glucostasis, and appetite. Weight stable women after RYGB were randomized to receive placebo or recombinant human metreleptin (0.05 mg/kg twice daily). At weeks 0 and 16, a liquid meal challenge was performed. Glucose, insulin, C-peptide, GLP-1, PYY, glucagon, and ghrelin (total, acyl, and desacyl) were measured fasting and postprandially. Appetite was assessed using a visual analog scale. Mean post-op period was 53 ± 2.3 months; mean BMI was 34.6 ± 0.2 kg/m(2). At 16 weeks, there was no significant change in weight within or between groups. Fasting PYY was significantly different between groups and the leptin group had lower sweets craving at week 16 than the placebo group (P < 0.05). No other differences were observed. Leptin replacement does not alter gut hormones or glucostasis but may diminish sweet cravings compared to placebo in this population of post-RYGB women.

Randomized double-blind placebo-controlled study of leptin administration after gastric bypass.

OBJECTIVE: Obese individuals have high levels of circulating leptin and are resistant to the weight-reducing effect of leptin administration at physiological doses. Although Roux-en-Y gastric bypass (RYGB) is an effective weight loss procedure, there is a plateau in weight loss and most individuals remain obese. This plateau may be partly due to the decline in leptin resulting in a state of relative leptin insufficiency. The main objective of this study was to determine whether leptin administration to post-RYGB patients would promote further weight reduction. DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled cross-over study of 27 women who were at least 18 months post-RYGB and lost on average 30.8% of their presurgical body weight. Subjects received either leptin or placebo via subcutaneous injection twice daily for 16 weeks, then crossed over to receive the alternate treatment for 16 weeks. RESULTS: Weight change after 16 weeks of placebo was not significantly different from that after 16 weeks of leptin. No changes were observed in percent fat mass, resting energy expenditure, thyroid hormones, or cortisol levels. CONCLUSION: Contrary to our hypothesis, we did not observe a significant effect of leptin treatment on body weight in women with relative hypoleptinemia after RYGB.

Leptin administration does not prevent the bone mineral metabolism changes induced by weight loss.

The objective was to examine the effects of weight loss and leptin administration following weight loss on calciotropic hormones and bone turnover. This was a prospective, single-blinded study of 12 subjects (8 women, 4 men; 2 nonobese, 10 obese; age range, 19-46 years) who were studied on an inpatient basis while maintaining their usual weight [Wt(initial)] and during maintenance of 10% weight loss while receiving twice-daily injections of either a placebo [Wt(-10%P)] or replacement doses of leptin [Wt(-10%L)]. The main outcome measures were markers of bone formation (bone alkaline phosphatase and procollagen type 1 amino terminal propeptide) and resorption (N-telopeptide) as well as parathyroid hormone, calcium, and 25-hydroxy vitamin D measured from fasting morning serum. As expected, serum leptin declined with weight loss. Bone alkaline phosphatase decreased by 12.3% ± 3.9% between Wt(initial) and Wt(-10%P) and remained suppressed after leptin administration (both P < .01 compared with baseline). N-telopeptides increased by 37.2% ± 11.3% from Wt(initial) to Wt(-10%L) (P < .01). Procollagen type 1 amino terminal propeptide, parathyroid hormone, calcium, and 25-hydroxy vitamin D did not change. These results suggest that both decreased bone formation and increased bone resorption underlie bone loss associated with weight loss. Leptin administration did not prevent the uncoupling of bone remodeling that accompanies weight loss.

Effect of laparoscopic adjustable gastric banding on metabolic syndrome and its risk factors in morbidly obese adolescents.

We examined the effect of laparoscopic adjustable gastric banding (LAGB) on weight loss, inflammatory markers, and components of the Metabolic Syndrome (MeS) in morbidly obese adolescents and determined if those with MeS lose less weight post-LAGB than those without. Data from 14-18 yr adolescents were obtained at baseline, 6 and 12 months following LAGB. Significant weight loss and improvements in MeS components were observed 6 months and one year following LAGB. The incidence of MeS declined 56.8% after 6 months and 69.6% after 12 months. There was no significant difference in amount of weight lost post-LAGB between those with and without MeS at either timepoint. Correlations between change in weight parameters and components of MeS in those with and without MeS at baseline were examined and found to vary by diagnostic category. LAGB is effective for short-term improvement in weight, inflammatory markers, and components of MeS in morbidly obese adolescents.