Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency.

PURPOSE: We aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency. METHODS: We used next-generation sequencing to identify variants in all pedigrees. Expression of Rnpc3/RNPC3 was analyzed by in situ hybridization on murine/human embryonic sections. CRISPR/Cas9 was used to generate mice carrying the p.Leu483Phe pathogenic variant in the conserved murine Rnpc3 RRM2 domain. RESULTS: We described 15 patients from 9 pedigrees with biallelic pathogenic variants in RNPC3, encoding a specific protein component of the minor spliceosome, which is associated with a hypopituitary phenotype, including severe growth hormone (GH) deficiency, hypoprolactinemia, variable thyrotropin (also known as thyroid-stimulating hormone) deficiency, and anterior pituitary hypoplasia. Primary ovarian insufficiency was diagnosed in 8 of 9 affected females, whereas males had normal gonadal function. In addition, 2 affected males displayed normal growth when off GH treatment despite severe biochemical GH deficiency. In both mouse and human embryos, Rnpc3/RNPC3 was expressed in the developing forebrain, including the hypothalamus and Rathke's pouch. Female Rnpc3 mutant mice displayed a reduction in pituitary GH content but with no reproductive impairment in young mice. Male mice exhibited no obvious phenotype. CONCLUSION: Our findings suggest novel insights into the role of RNPC3 in female-specific gonadal function and emphasize a critical role for the minor spliceosome in pituitary and ovarian development and function.

The pubertal growth spurt is diminished in children with severe obesity.

BACKGROUND: At the population level, there is a negative linear correlation between childhood body mass index (BMI) and pubertal height gain. However, in children with obesity, there are no studies showing whether the severity of obesity affects pubertal height gain. Moreover, how obesity in childhood affects pubertal timing is controversial, especially in boys. We aimed to investigate the impact of severe obesity in childhood on the pubertal growth spurt in both sexes. METHODS: The study group consisted of 68 patients (32 boys) with childhood onset obesity followed in a Spanish university hospital. The QEPS growth model was used to calculate pubertal growth function estimates for each individual. The highest individual prepubertal BMI SDS value was related to the age at onset of pubertal growth and pubertal height gain. Results were compared to analyses from individuals in a community-based setting (n = 1901) with different weight status. RESULTS: A higher peak BMI in childhood was associated with less specific pubertal height gain in children with moderate-to-extreme obesity. For boys, the higher the BMI, the earlier the onset of pubertal growth. For girls with obesity, this correlation was not linear. CONCLUSIONS: Obesity in childhood impairs the pubertal growth spurt in a severity-related fashion. IMPACT: The higher the BMI in childhood, the lower the pubertal height gain in children with moderate-to-extreme obesity. For boys with obesity, the higher the BMI, the earlier the onset of pubertal growth. The results contribute to the research field of how weight status in childhood is related to pubertal timing and pubertal growth. The results have implications for understanding how childhood obesity is related to further growth.

Heterozygous rare genetic variants in non-syndromic early-onset obesity.

BACKGROUND: Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions. OBJECTIVE: We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes to non-syndromic severe early-onset obesity (EOO; body mass index (BMI) >+3 standard deviation score, <3 years). METHODS: Using a pooled DNA-sequencing approach, we screened for RSVs in 15 obesity candidate genes in a series of 463 EOO patients and 480 controls. We also analysed exome data from 293 EOO patients from the "Viva la Familia" (VLF) study as a replication dataset. RESULTS: Likely or known pathogenic RSVs were identified in 23 patients (5.0%), with 7 of the 15 genes (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) harbouring RSVs only in cases (3.67%) and none in controls. All were heterozygous changes, either de novo (one in BDNF) or inherited from obese parents (seven maternal, three paternal), and no individual carried more than one variant. Results were replicated in the VLF study, where 4.10% of probands carried RSVs in the overrepresented genes. RSVs in five genes were either absent (LEP) or more common in controls than in cases (ADRB3, LEPR, PCSK1 and PCSK2) in both obese datasets. CONCLUSIONS: Heterozygous RSVs in several candidate genes of the melanocortin pathway are found in ~5.0% patients with EOO. These results support the clinical utility of genetic testing to identify patients who might benefit from targeted therapeutic intervention.

Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants.

Obesity is a multifactorial disorder with high heritability (50-75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity.

Natural History of Perinatal and Infantile Hypophosphatasia: A Retrospective Study.

OBJECTIVE: To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia. STUDY DESIGN: Medical records from academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age <6 months were eligible: vitamin B6-dependent seizures, respiratory compromise, or rachitic chest deformity (NCT01419028). Patient demographics and characteristics, respiratory support requirements, invasive ventilator-free survival, and further complications of hypophosphatasia were followed for up to the first 5 years of life. RESULTS: Forty-eight patients represented 12 study sites in 7 countries; 13 patients were alive, and 35 were dead (including 1 stillborn). Chest deformity, respiratory distress, respiratory failure (as conditioned by the eligibility criteria), failure to thrive, and elevated calcium levels were present in >70% of patients between birth and age 5 years. Vitamin B6-dependent seizures and respiratory distress and failure were associated significantly (P < .05) with the risk of early death. Serum alkaline phosphatase activity in all 41 patients tested (mean [SD]: 18.1 [15.4] U/L) was below the mean lower limit of normal of the reference ranges of the various laboratories (88.2 U/L). Among the 45 patients with relevant data, 29 had received respiratory support, of whom 26 had died at the time of data collection. The likelihood of invasive ventilator-free survival for this cohort decreased to 63% at 3 months, 54% at 6 months, 31% at 12 months, and 25% at 5 years. CONCLUSIONS: Patients with perinatal or infantile hypophosphatasia and vitamin B6-dependent seizures, with or without significant respiratory distress or chest deformities, have high morbidity and mortality in the first 5 years of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01419028.

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature.

OBJECTIVE: Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis. DESIGN AND METHODS: This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN-positive individuals. RESULTS: A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies. CONCLUSIONS: ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias.

Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia.

Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene (ALPL). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a severe skeletal dysplasia. Thirty-six (43.3%) probands were found to have pathogenic ALPL mutations. Eleven previously unreported mutations were identified, thus adding to the ever increasing list of ALPL mutations. Seven of these eleven were inherited in an autosomal dominant manner while the remaining four were observed in the homozygous state. Thus, this study includes a large number of well-characterized patients with hypophosphatasemia which has permitted us to study the genotype:phenotype correlation. Accurate diagnosis of patients with a clinical suspicion of HPP is crucial as not only is the disease life-threatening but the patients may be offered bone targeted enzymatic replacement therapy. © 2017 Wiley Periodicals, Inc.

The impact of intrauterine and extrauterine weight gain in premature infants on later body composition.

BackgroundThe impact of intrauterine and extrauterine growth on later insulin resistance and fat mass (FM) in very low birth weight (VLBW) infants is not well established. The aim of our study was to evaluate the effects of intrauterine and early/late extrauterine growth on later insulin resistance and body composition in VLBW infants from 6 months' corrected age (CA) to 36 months.MethodsProspective measurements of body composition by dual-energy X-ray absorptiometry and insulin resistance by homeostasis model assessment insulin resistance (HOMA-IR) along with other fasting plasma biochemistries were made in 95 VLBW infants at 6, 12, 18, and 24 months' CA and 36 months' postnatal age. Mixed-effect models were used to evaluate the effects of age, sex, maturation status, and Δweight SD score on percentage FM (PFM), FM index (FMI), fat-free mass index (FFMI), and HOMA-IR.ResultsPFM and FMI were negatively associated with a decrease in weight-SD scores from birth to 36 weeks' postmenstrual age (PMA; P=0.001) and from 36 weeks' PMA to 6 months' CA (P=0.003). PFM and FMI were higher in AGA than in small for gestational age (SGA) infants. HOMA-IR was not associated with the Δweight-SD scores in either period.ConclusionsCatch-down growth in terms of weight is associated with persistently lower adiposity but not insulin resistance up to 36 months of age.

A proteomic approach to obesity and type 2 diabetes.

The incidence of obesity and type diabetes 2 has increased dramatically resulting in an increased interest in its biomedical relevance. However, the mechanisms that trigger the development of diabetes type 2 in obese patients remain largely unknown. Scientific, clinical and pharmaceutical communities are dedicating vast resources to unravel this issue by applying different omics tools. During the last decade, the advances in proteomic approaches and the Human Proteome Organization have opened and are opening a new door that may be helpful in the identification of patients at risk and to improve current therapies. Here, we briefly review some of the advances in our understanding of type 2 diabetes that have occurred through the application of proteomics. We also review, in detail, the current improvements in proteomic methodologies and new strategies that could be employed to further advance our understanding of this pathology. By applying these new proteomic advances, novel therapeutic and/or diagnostic protein targets will be discovered in the obesity/Type 2 diabetes area.

Predictors of adherence to follow-up and treatment success in childhood obesity.

INTRODUCTION: Management of childhood obesity, based upon behavioural, physical activity and dietary guidance, usually achieves limited success and is hindered by a high attrition rate. The identification of potential predictors of either weight loss or early weight management attrition could help develop personalised management plans in order to improve patient outcomes. PATIENTS AND METHODS: We conducted a retrospective study in a cohort of 1300 patients with obesity managed in speciality clinics for up to 5 years with outpatient conservative treatment. We studied the family background and personal characteristics (demographic, behavioural, psychosocial, anthropometric and metabolic) of patients who dropped out before completing the first year of the programme and patients who achieved significant weight loss, with a separate analysis of patients who achieved substantial reductions in weight compared to the rest of the cohort. RESULTS: The mean age of the patients in the cohort was 10.46 years (SD, 3.48) the mean BMI z-score 4.01 (SD, 1.49); 52.8% of the patients were male, 53.3% were prepubertal, 75.8% were Caucasian and 19% Latin. We found a higher proportion of Latinla ethnicity and compulsive eating in the group of patients with early attrition from the weight management follow-up. In the group of patients with substantial weight loss, a greater proportion were male, there was a higher frequency of dietary intake control at home and obesity was more severe, and the latter factor was consistently observed in patients who achieved substantial weight loss at any point of the follow-up. CONCLUSIONS: Some family and personal characteristics in childhood obesity are associated with an increased risk of early withdrawal from follow-up or a greater probability of successful outcomes; however, the predictive value of these variables is limited.

Common and uncommon mouse models of growth hormone deficiency.

Mouse models of growth hormone deficiency (GHD) have provided important tools for uncovering the various actions of GH. Nearly 100 years of research using these mouse lines has greatly enhanced our knowledge of the GH/IGF-1 axis. Some of the shared phenotypes of the five "common" mouse models of GHD include reduced body size, delayed sexual maturation, decreased fertility, reduced muscle mass, increased adiposity, and enhanced insulin sensitivity. Since these common mouse lines outlive their normal-sized littermates - and have protection from age-associated disease - they have become important fixtures in the aging field. On the other hand, the twelve "uncommon" mouse models of GHD described herein have tremendously divergent health outcomes ranging from beneficial aging phenotypes (similar to those described for the common models) to extremely detrimental features (such as improper development of the CNS, numerous sensory organ defects, and embryonic lethality). Moreover, advancements in next generation sequencing technologies have led to the identification of an expanding array of genes that are recognized as causative agents to numerous rare syndromes with concomitant GHD. Accordingly, this review provides researchers with a comprehensive up-to-date collection of the common and uncommon mouse models of GHD that have been used to study various aspects of physiology and metabolism associated with multiple forms of GHD. For each mouse line presented, the closest comparable human syndromes are discussed providing important parallels to the clinic.

Prepubertal children with obesity have high free IGF-1 levels and accelerated growth despite reduced pappalysin levels.

BACKGROUND: Prepubertal children with obesity frequently have enhanced growth, accelerated skeletal maturation and changes in the GH-IGF axis. However, the involvement of pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC1, STC2) as regulators of IGF bioavailability has not been studied in obesity. OBJECTIVE: We aimed to determine the effects of childhood obesity and weight reduction on serum levels of PAPP-A, PAPP-A2, STC1 and STC2 and their relationship with IGF bioavailability, growth, and other components of the GH-IGF system. PATIENTS AND METHODS: Prepubertal children with severe obesity (150, 50% males/females, age: 7.72 ± 2.05 years, BMI z-score: 4.95 ± 1.70, height z-score: 1.28 ± 1.04) were studied at diagnosis and after a minimum of 0.5 BMI z-score reduction. Two hundred and six healthy age- and sex-matched children were used as controls. RESULTS: Children with obesity had decreased serum concentrations of PAPP-A, PAPP-A2 and STC2, but increased total and free IGF-I (fIGF-I), intact IGFBP-3, ALS, IGF-II and insulin levels, with no difference in the free/total IGF-I ratio. Neither the standardized BMI nor height correlated with any biochemical parameter analyzed. A decrease in IGF-II, insulin, and ALS with an increase in IGFBP-2 and -5, STC2 and PAPP-A were observed after weight loss. CONCLUSION: Increased circulating total and free IGF-I, insulin and IGF-II may all contribute to the increased rate of prepubertal growth and bone maturation observed in children with obesity, with STC2 possibly being involved.

Identifying subgroups of childhood obesity by using multiplatform metabotyping.

Introduction: Obesity results from an interplay between genetic predisposition and environmental factors such as diet, physical activity, culture, and socioeconomic status. Personalized treatments for obesity would be optimal, thus necessitating the identification of individual characteristics to improve the effectiveness of therapies. For example, genetic impairment of the leptin-melanocortin pathway can result in rare cases of severe early-onset obesity. Metabolomics has the potential to distinguish between a healthy and obese status; however, differentiating subsets of individuals within the obesity spectrum remains challenging. Factor analysis can integrate patient features from diverse sources, allowing an accurate subclassification of individuals. Methods: This study presents a workflow to identify metabotypes, particularly when routine clinical studies fail in patient categorization. 110 children with obesity (BMI > +2 SDS) genotyped for nine genes involved in the leptin-melanocortin pathway (CPE, MC3R, MC4R, MRAP2, NCOA1, PCSK1, POMC, SH2B1, and SIM1) and two glutamate receptor genes (GRM7 and GRIK1) were studied; 55 harboring heterozygous rare sequence variants and 55 with no variants. Anthropometric and routine clinical laboratory data were collected, and serum samples processed for untargeted metabolomic analysis using GC-q-MS and CE-TOF-MS and reversed-phase U(H)PLC-QTOF-MS/MS in positive and negative ionization modes. Following signal processing and multialignment, multivariate and univariate statistical analyses were applied to evaluate the genetic trait association with metabolomics data and clinical and routine laboratory features. Results and Discussion: Neither the presence of a heterozygous rare sequence variant nor clinical/routine laboratory features determined subgroups in the metabolomics data. To identify metabolomic subtypes, we applied Factor Analysis, by constructing a composite matrix from the five analytical platforms. Six factors were discovered and three different metabotypes. Subtle but neat differences in the circulating lipids, as well as in insulin sensitivity could be established, which opens the possibility to personalize the treatment according to the patients categorization into such obesity subtypes. Metabotyping in clinical contexts poses challenges due to the influence of various uncontrolled variables on metabolic phenotypes. However, this strategy reveals the potential to identify subsets of patients with similar clinical diagnoses but different metabolic conditions. This approach underscores the broader applicability of Factor Analysis in metabotyping across diverse clinical scenarios.

Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results.

BACKGROUND: Bardet-Biedl syndrome is a rare genetic disease associated with hyperphagia and early-onset, severe obesity. There is limited evidence on how hyperphagia and obesity affect health-related quality of life in patients with Bardet-Biedl syndrome, and on how management of these symptoms may influence disease burden. This analysis evaluated changes in health-related quality of life in adults and children with Bardet-Biedl syndrome in a Phase 3 trial following 1 year of setmelanotide treatment (ClinicalTrials.gov identifier: NCT03746522). METHODS: Patients with Bardet-Biedl syndrome and obesity received 52 weeks of treatment with setmelanotide and completed various self-reported health-related quality of life measures. Patients aged < 18 years or their caregiver completed the Pediatric Quality of Life Inventory (PedsQL; meaningful improvement, 4.4-point change); adults aged ≥ 18 years completed the Impact of Weight on Quality of Life Questionnaire-Lite (IWQOL-Lite; meaningful improvement range, 7.7-12-point change). Descriptive outcomes were reported in patients with data both at active treatment baseline and after 52 weeks of treatment. RESULTS: Twenty patients (< 18 years, n = 9; ≥ 18 years, n = 11) reported health-related quality of life at baseline and 52 weeks. For children and adolescents, PedsQL score mean change from baseline after 52 weeks was + 11.2; all patients with PedsQL impairment at baseline (n = 4) experienced clinically meaningful improvement. In adults, IWQOL-Lite score mean change from baseline was + 12.0. Of adults with IWQOL-Lite impairment at baseline (n = 8), 62.5% experienced clinically meaningful improvement. In adults, IWQOL-Lite score was significantly correlated with changes in percent body weight (P = 0.0037) and body mass index (P = 0.0098). CONCLUSIONS: After 1 year of setmelanotide, patients reported clinically meaningful improvements across multiple health-related quality of life measures. This study highlights the need to address the impaired health-related quality of life in Bardet-Biedl syndrome, and supports utility of setmelanotide for reducing this burden. Trial Registration NCT03746522. Registered November 19, 2018, https://clinicaltrials.gov/ct2/show/NCT03746522 .

Increased IGFBP proteolysis, IGF-I bioavailability and pappalysin levels in children with Prader-Willi syndrome.

CONTEXT: Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. OBJECTIVE: We determined serum levels of PAPP-As and STCs in association with IGF axis components in pre- and pubertal patients with PWS, also analyzing the effect of GH treatment. METHODS: Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at six months of treatment in 11 children. RESULTS: Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and higher concentrations of free IGF-I, IGFBP-5 and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. CONCLUSION: The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients.

Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period.

BACKGROUND: Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients. METHODS: This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m2 for those aged ≥16 years). Patients were randomly assigned (1:1) using a numerical randomisation code to receive up to 3·0 mg of subcutaneous setmelanotide or placebo once per day during the 14-week double-blind period, followed by open-label setmelanotide for 52 weeks. The primary endpoint, measured in the full analysis set, was the proportion of patients aged 12 years or older who reached at least a 10% reduction in bodyweight from baseline after 52 weeks of setmelanotide treatment. This study is registered with ClinicalTrials.gov, NCT03746522. FINDINGS: Between Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment. INTERPRETATION: Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome. FUNDING: Rhythm Pharmaceuticals.

Pappalysins and Stanniocalcins and Their Relationship With the Peripheral IGF Axis in Newborns and During Development.

CONTEXT: Pappalysins (PAPP-A, PAPP-A2) modulate body growth by increasing insulin-like growth factor I (IGF-I) bioavailability through cleavage of insulin-like growth factor binding proteins (IGFBPs) and are inhibited by stanniocalcins (STC1, STC2). Normative data on these novel factors, as well as on free IGF-I and uncleaved fractions of IGFBPs, are not well established. OBJECTIVE: This work aimed to determine serum concentrations of PAPP-A, PAPP-A2, STC1, and STC2 in relationship with other growth hormone (GH)-IGF axis parameters during development. METHODS: Full-term newborns (150; gestational age: 39.30 ±â€…1.10 weeks), 40 preterm newborns (30.87 ±â€…3.35 weeks), and 1071 healthy individuals (aged 1-30 years) were included in the study and divided according to their Tanner stages (males and females): I:163 males, 154 females; II:100 males, 75 females; III:83 males, 96 females; IV: 77 males, 86 females; and V:109 males,128 females. RESULTS: Serum concentrations of PAPP-A, PAPP-A2, STC1, STC2, IGFBP-2, total IGFBP-4, and total IGFBP-5 were elevated at birth and declined throughout childhood. In postnatal life, PAPP-A2 concentrations decreased progressively in concomitance with the free/total IGF-I ratio; however, stanniocalcin concentrations remained stable. PAPP-A2 concentrations positively correlated with the free/total IGF-I ratio (r = +0.28; P < .001) and negatively with the intact/total IGFBP-3 ratio (r = -0.23; P < .001). PAPP-A concentrations inversely correlated with intact/total IGFBP-4 ratio (r = -0.21; P < .001), with PAPP-A concentrations being lower in females at all ages. Association studies indicate the importance of stanniocalcins and pappalysins in the control of this axis in an age-specific manner. CONCLUSION: This study provides reference values of pappalysins and stanniocalcins, which modulate IGF-I activity by changing the concentrations of cleaved and uncleaved IGFBPs.

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

A combination of circulating chemokines as biomarkers of obesity-induced insulin resistance at puberty.

BACKGROUND: In obesity adipose tissue undergoes structural re-modelling leading to a chronic low-grade inflammatory state linked to insulin resistance (IR). OBJECTIVE: We aimed to develop a clinically relevant biomarker model for stratifying IR in adolescents with obesity. METHODS: Cytokines [tumour cell derived factor 1α, monocyte chemoattract protein (MCP) 1, eotaxin and fractalkine], growth factors [brain-derived neurotrophic factor, pro-fibrotic platelet-derived growth factor (PDGF-BB) and insulin-like growth factor 1] and biochemical/metabolic factors were analysed in serum of 143 pubertal patients with obesity (50% IR; 50% non-IR) and 33 controls. Factor analysis, correlation, binary logistic regression and receiver operating characteristic analysis were used to evaluate combinations of these biomarkers as possible diagnostic tools for IR. RESULTS: Two biomarker IR models combining levels of triglycerides (TG)/HDL, eotaxin, MCP-1 and PDGF-BB in pubertal patients with obesity of both sexes were defined. Altered levels of MCP-1, eotaxin, and PDGF-BB constitute a main component that determines 27.7% of the variance explaining IR. Growth and inflammatory factors comprise two other components linked to the first, together accounting for 59.2% of the variance determining IR. CONCLUSIONS: PDGF-BB, MCP-1, eotaxin, TG and cholesterol concentrations constitute a solid panel of biomarkers associated with IR in pubertal children with obesity that could be useful in their stratification in a clinical setting for stratification.

Conservative Treatment for Childhood and Adolescent Obesity: Real World Follow-Up Profiling and Clinical Evolution in 1300 Patients.

Background: Limited therapeutic tools and an overwhelming clinical demand are the major limiting factors in pediatric obesity management. The optimal protocol, environment, body mass index (BMI) change targets and duration of obesity-oriented interventions remain to be elucidated. Aims: We aimed to characterize the singularities of follow-up, anthropometric and metabolic evolution of a large cohort of pediatric patients with obesity in a specialized university hospital outpatient obesity unit. Patients and methods: Follow-up duration (up to seven years), attrition rate and anthropometric and metabolic evolution of 1300 children and adolescents with obesity were studied. An individualized analysis was conducted in patients attaining a high level of weight loss (over 1.5 BMI-SDS (standard deviation score) and/or 10% of initial weight; n = 252; 19.4%) as well as in "metabolically healthy" patients (n = 505; 38.8%). Results: Attrition rate was high during the early stages (11.2% prior to and 32.5% right after their initial metabolic evaluation). Mean follow-up time was 1.59 ± 1.60 years (7% of patients fulfilled 7 years). The highest BMI reduction occurred in the first year (-1.11 ± 0.89 SDS, p < 0.001 in 72.5% of patients). At the end of the follow-up, improvements in glucose and lipid metabolism parameters were observed (both p < 0.05), that were highest in patients with the greatest weight reduction (all p < 0.01), independent of the time spent to achieve weight loss. The pubertal growth spurt negatively correlated with obesity severity (r = -0.38; p < 0.01) but patients attaining adult height exceeded their predicted adult height (n = 308, +1.6 ± 5.4 cm; p < 0.001). "Metabolically healthy" patients, but with insulin resistance, had higher blood pressure, glucose, uric acid and triglyceride levels than those without insulin resistance (all p < 0.05). Preservation of the "metabolically healthy" status was associated with BMI improvement. Conclusions: Behavioral management of children with obesity can be effective and does not impair growth but is highly conditioned by high attrition. The best results regarding BMI reduction and metabolic improvement are achieved in the first year of intervention and can be preserved if follow-up is retained.