Jeremy Pomeroy

Considerable advances have been made in our understanding of Bardet–Biedl syndrome (BBS), particularly in its core clinical features and molecular genetics, warranting an update to the existing diagnostic criteria framework. Using a rigorous, evidence‐based, and consensus‐driven process, a multidisciplinary group of international experts and patient‐led organizations developed an updated diagnostic algorithm. This algorithm provides practical, updated guidance for clinicians, including a pathway for accurately incorporating genetic findings into the diagnostic process. We recommend that a clinical diagnosis requires either 4 major criteria or 3 major and 2 minor criteria. Revised major criteria are retinal dystrophy, obesity (or overweight in individuals < 2 years old), congenital anomalies of the kidney and urinary tract or chronic kidney disease, hypogonadism/genital anomalies, neurodevelopmental/neurocognitive manifestations, and postaxial polydactyly. The diagnosis can also be established with a positive genetic testing result in patients exhibiting ≥ 1 major criterion, provided that genetic findings should be interpreted in the context of the patient's clinical presentation, age, family history, and overlap with related ciliopathies. These consensus criteria offer a simple algorithm incorporating updated definitions for major and minor criteria and genetic testing to support a timely and accurate diagnosis of patients with BBS, inform genetic counseling, and potentially facilitate earlier access to treatment. Trial Registration: CRIBBS Registry; ClinicalTrials.gov : NCT02329210

Objective: This analysis aimed to assess the efficacy of setmelanotide over 52 weeks in patients with Bardet‐Biedl syndrome (BBS) compared with an external natural history cohort from the international Clinical Registry Investigating BBS (CRIBBS). Methods: Patients with BBS ≥ 6 years of age ( n = 29) treated with setmelanotide for 52 weeks in a phase 3 trial (NCT03746522) and a propensity‐score matched external control cohort ( n = 58) from CRIBBS were included. Responder rate at week 52 was defined as ≥ 0.3‐point decrease in BMI z ‐score (patients ≤ 18 years) or ≥ 10% body weight reduction (adults). Secondary outcomes included changes in BMI, BMI z ‐score, and body weight. Results: A significantly greater proportion of patients treated with setmelanotide met the primary endpoint compared with control patients (58.6% vs. 6.9%; p < 0.001). In pediatric patients, 71.4% achieved the primary endpoint vs. 10.7% of controls ( p < 0.001); in adults, corresponding numbers were 46.7% vs. 3.3% ( p = 0.001). Secondary outcomes demonstrated consistent benefits of setmelanotide treatment. Sensitivity analysis using inverse probability of treatment weighting confirmed these findings. Conclusions: This indirect comparison provides additional strong evidence that setmelanotide significantly improves weight outcomes in patients with BBS. These findings further support its clinical benefit over 52 weeks in managing obesity associated with BBS. Trial Registration: ClinicalTrials.gov identifier: NCT03746522

Summary: Background: To date, research on the natural history of hyperphagia, weight gain and health outcomes in individuals with Bardet‐Biedl syndrome (BBS) has been limited. Understanding these characteristics is important for disease burden management.Objectives: The international Clinical Registry Investigating BBS (CRIBBS) is a registry of individuals with BBS to investigate the severity of hyperphagia, the natural history of weight gain and the frequency of obesity‐associated health outcomes in paediatric individuals with BBS.Methods: Paediatric participants (n = 186), 17.2% had a higher weight classification from the first to the last assessment. Increasing hyperphagia severity was associated with increasing obesity. The prevalence of cardiac, diabetic, endocrine and renal health outcomes increased with obesity class.Conclusion: Hyperphagia and obesity are highly prevalent in children with BBS. Many children with BBS also experience adverse health outcomes. Timely diagnosis and targeted treatment of hyperphagia and obesity are needed.

Introduction: This is a secondary cross-sectional analysis of participants’ baseline data from the Baby-Act Trial to compare energy and macronutrients intake by feeding type. This was a cluster-randomized clinical trial among pregnant women and their infants participating in the Puerto Rico WIC program to test the clinical effectiveness of an intervention that addressed various infant obesity risk factors during the first year of life. Methods: Participants completed at baseline a sociodemographic questionnaire and a validated infant food frequency questionnaire (FFQ). The FFQ was analyzed for type of feeding (exclusively fed breastmilk, fed breastmilk and formula, or exclusively fed infant formula) and for energy and macronutrient intake (protein, carbohydrate, and fat). Analysis of covariance was used to compare intake type of feeding, adjusting for maternal age. race, education, number of previous children, gestational length, and pre-pregnancy BMI. Results: The present analysis included 368 mother–infant pairs. Mean age of mothers was 26.7 years and of infants 0.7 months. Ten infants fed complementary foods were removed from the analyses. A total of 39.9% of infants were exclusively breastmilk-fed, 47.2% were fed breastmilk and infant formula, and 12.8% were exclusively formula-fed (n = 358). Intake of energy, protein, fat, and carbohydrates was significantly lower in infants fed only breastmilk compared to infants fed a combination of breastmilk and infant formula, and intake of protein and carbohydrates were lower in infants fed a combination of breastmilk and infant formula compared to infants fed only infant formula, after adjusting for important confounders. Conclusions: Very early infant feeding practices are associated with differences in dietary intake. The long-term health implications of this findings need to be further studied.

Objectives There are limited interventions for preventing excessive infant weight gain among Hispanic and low-income populations. Here, we describe the development/implementation of the Baby-Act trial, a multi-component/multi-model intervention for preventing excessive infant weight gain in low-income Hispanics. We also report adherence/fidelity, lessons learned, and future applications. Methods We conducted a cluster-randomized controlled trial among mother/infant participants of the WIC program in Puerto Rico. The intervention included responsive feeding, infant activation, healthy sleep, and limiting sedentary behaviors using behavioral change theories. It was implemented as a multi-modal approach from pregnancy to the first year of life through weekly online interactive lessons (n = 56) that focused on one of the topics, reinforced with weekly text messages and monthly calls with a dietitian. Adherence/fidelity was recorded as the number of lessons/calls completed and text messages sent/received in the order designed. Results Adherence from 207 participants was 45.7% for pregnancy lessons and 31.4% for baby lessons (higher in months 0–3 and for lessons that suggested uploading images/videos). On average, 19 lessons were completed (with 3.6 lessons completed on the same day instead of once per week). Adherence to calls was 42.3% (higher in the first months, 49.0%). On average, each participant completed 5 calls. Lessons/calls/texts were completed/received as designed; 99.3% of text messages were sent. Conclusions Adherence to all intervention components was low, but all participants received the main messages because the topics were repeated continuously. Future studies should reduce the frequency of lessons, include more text messages, and more sharing of videos/photos. Clinicaltrials.gov NCT03517891.

Purpose of review: Bardet Biedl syndrome (BBS) is a rare disease characterized by obesity and hyperphagia. Despite the very high prevalence of paediatric and adult obesity in this population, the prevalence of diabetes mellitus is not well described. Recent findings: Studies in small and moderately large cohorts suggest a high prevalence of traditional risk factors for diabetes mellitus in people with BBS. People with BBS appear to have a high prevalence of insulin resistance and metabolic syndrome. Small cohort studies have identified high rates of sleep disordered breathing, including sleep apnoea syndrome. Recent research has characterized traditional behavioural risk factors such as sleep hygiene and physical inactivity in people with BBS. High rates of insufficient sleep and prolonged sedentary time suggest behavioural targets of interventions to treat or prevent diabetes mellitus. Hyperphagia, likely caused by defects in the hypothalamic melanocortin-4 receptor (MC4R) neuronal pathway, pose additional challenges to behavioural interventions to prevent diabetes mellitus. Summary: Understanding the prevalence of diabetes mellitus and other metabolic disorders in people with BBS and the impact of traditional risk factors on glucose regulation are important to developing effective treatments in this population.

Background: Overweight and obesity are common features of the rare disease Bardet–Biedl syndrome (BBS). Sleep and physical activity are behaviors that might impact overweight and obesity and thus may play a key role in the health and well-being of people with BBS. Objectively-measured sleep and physical activity patterns in people with BBS are not well known. We evaluated objectively-measured sleep and physical activity patterns in the largest cohort to date of people with BBS. Results: Short sleep duration, assessed using wrist-worn accelerometers, was common in both children and adults with BBS. Only 7 (10%) of adults and 6 (8%) of children met age-specific sleep duration recommendations. Most adults 64 (90%) achieved recommended sleep efficiency. The majority of children 26 (67%) age 6–12 years achieved recommended sleep efficiency, but among children age 13–18, only 18 (47%). In both adults and children, sleep duration was significantly negatively correlated with duration of prolonged sedentary time. In children age 6–12 sleep duration was also significantly related to total activity score, children with lower sleep duration had lower total activity scores. Conclusions: Insufficient sleep duration is very common in people with BBS. Prolonged sedentary time and short sleep duration are both potentially important health-related behaviors to target for intervention in people with BBS.