Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Etude rétrospective de 19 cas de néoplasies après transplantation rénale pédiatrique (évaluation des facteurs de risque)

PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Membrane progestin receptors α and γ in renal epithelium

AbstractSex hormones have broader effects than regulating reproductive functions. Recent identification of membrane progestin receptors expressed in kidney prompted us to investigate their putative involvement in the renal effects of this hormone. We first focused our investigations on mPRα and γ by analyzing three parameters 1/ their distribution along the mouse nephron and their subcellular location in native kidney, 2/ the ability of progesterone to stimulate ERK pathway and/or Ca2+ release from internal stores in native kidney structures and 3/ the cellular localization of mPRα and its molecular determinants in heterologous expression system. We observed that 1/ mPRα expression is restricted to proximal tubules of both male and female mice whereas mPRγ exhibits a much broader expression all along the nephron except the glomerulus, 2/ mPRα and γ are not localized at the plasma membrane in native kidney, 3/ this expression does not permit either progesterone-induced ERK phosphorylation or Ca2+ release and 4/ in HEK transfected cells, mPRα localizes in the endoplasmic reticulum (ER) due to a C-terminal ER retention motif (−KXX). Therefore, we have characterized mPRs in kidney but their role in renal physiology remains to be elucidated

Managing Cow’s Milk Protein Allergy with an Extensively Hydrolyzed Formula: Results from a Prospective, Non-Interventional Study in France (EVA Study)

Symptoms related cow’s milk proteins allergy (CMPA) usually improve between two to four weeks following an elimination diet, firstly with extensively hydrolyzed formulas (eHF). The aim of the EVA study was to observe the evolution of CMPA-related symptoms in real life after initiation of a whey-based extensively hydrolyzed formula (w-eHF, Althéra®, Nestlé Health Science, Switzerland). This cross-sectional prospective non-interventional study was carried out alongside paediatricians in private practice in France between June 2019 and June 2020. Infants aged 0–3 years presenting with confirmed diagnosis or clinical symptoms suggesting CMPA were enrolled. Data were collected at enrolment (baseline visit) and three to five weeks later (follow-up visit). Symptoms were assessed using the Cow’s Milk-related Symptom Score (CoMiSS®). The per protocol population included 135 infants. The average number of symptoms per infant significantly decreased under the study formula (from 2.81 to 1.36, p < 0.001) and the proportions of infants with any CMPA related symptoms decreased. Daily crying and regurgitation showed the largest decline, respectively −44.4% and −31.85% (p < 0.001). These results describe the early management of symptoms suspected to be related to CMPA in routine practice that was rarely described in the literature. The number and severity of symptoms decreased most of the cases after commencing the study formula

Comparison of Symptom Control in Pediatric Gastroparesis using Endoscopic Pyloric Botulinum Toxin Injection and Dilatation

International audienceObjectives: The objective of this study was to assess the tolerance and efficacy of endoscopic intrapyloric botulinum toxin injection compared with pyloric dilatation in children with gastroparesis.Methods: This was a retrospective descriptive multicentre study that included pediatric patients treated between 2010 and 2018 at four tertiary hospitals.Results: Data were collected for 24 patients. The median age at diagnosis was 2.5 years (range 0.5–4.7). A total of 46 endoscopic procedures were performed. The endoscopic procedure was multiple in 63% of patients. Among the interventions, 76% were successful and 15% were unsuccessful. The recurrence rate was 57% and the median time to recurrence was 3.7 months (0.1–73). The efficacy did not differ significantly between the two methods at the first intervention and as a second-line treatment. The recurrence rate also did not differ significantly between the two methods. No complications were reported. The median follow-up was 19.8 months (1.7–61.7).Conclusions: In this retrospective multicentre study, endoscopic management of gastroparesis by balloon dilatation or botulinum toxin was safe in children and seemed to be partially efficient within the first months. Symptoms recurred frequently and required repetition of the interventions

Comparison of Symptom Control in Pediatric Gastroparesis using Endoscopic Pyloric Botulinum Toxin Injection and Dilatation

International audienceObjectives: The objective of this study was to assess the tolerance and efficacy of endoscopic intrapyloric botulinum toxin injection compared with pyloric dilatation in children with gastroparesis.Methods: This was a retrospective descriptive multicentre study that included pediatric patients treated between 2010 and 2018 at four tertiary hospitals.Results: Data were collected for 24 patients. The median age at diagnosis was 2.5 years (range 0.5–4.7). A total of 46 endoscopic procedures were performed. The endoscopic procedure was multiple in 63% of patients. Among the interventions, 76% were successful and 15% were unsuccessful. The recurrence rate was 57% and the median time to recurrence was 3.7 months (0.1–73). The efficacy did not differ significantly between the two methods at the first intervention and as a second-line treatment. The recurrence rate also did not differ significantly between the two methods. No complications were reported. The median follow-up was 19.8 months (1.7–61.7).Conclusions: In this retrospective multicentre study, endoscopic management of gastroparesis by balloon dilatation or botulinum toxin was safe in children and seemed to be partially efficient within the first months. Symptoms recurred frequently and required repetition of the interventions

Feasibility of open abdomen surgery treatment for near fatal necrotizing enterocolitis in preterm infants

International audienceIntroduction: Necrotizing Enterocolitis (NEC) remained a dramatic complication leading to death or neonatal morbidities in preterms. For some, Intra-Abdominal Hypertension (IAH) and Abdominal Compartment Syndrome worsened the multi-organ failure. An open abdomen surgery could be an alternative to conventional surgical treatment to move beyond this stage.Objectives: To retrospectively describe the clinical course, pre- and post-operative features of preterms suffering from severe NEC with IAH treated by open abdomen surgery and referred to our center from October 2007 to September 2019. Our secondary objective is to identify various risk factors for mortality in this population.Methods: Data on neonatal, clinical, biological, pre and post-operative features and outcome were collected. Univariate analyses were performed to compare their pre and post-operative features stratifying on outcome.Results: Among 29 included patients, 14 (48%) survived to discharge without short bowel syndrome. Death was associated with an earlier postnatal age at NEC (16.3 ± 9.1 versus 31.3 ± 25.9 days; p = 0.004) and followed a withdrawal of treatment in 60% of cases. Surgery was associated with a significant improvement of respiratory and hemodynamic features (decrease of mean ventilator pressure from 13.1 ± 5.4 to 11.3 ± 4.0 cmH2O, p < 0.001), oxygen requirement (mean FiO2 decreased from 65.0% ± 31.2 to 49.0% ± 24.6, p < 0.001) and inotropic score (from 38.6 ± 70.1 to 29.9 ± 64.3, p < 0.001). In the survival group, pre and post-operative findings exhibited a significant increase of serum lactate concentrations from 2.7 ± 1.6 to 11.0 ± 20.3 mmol/L (p = 0.02) but a similar pH.Conclusion: Open abdomen surgery could be considered to rescue preterms with near fatal NEC. IAH and Abdominal Compartment Syndrome in these preterms should be investigated through further studies

Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency

International audienceMutations in the tetratricopeptide repeat domain 7A (TTC7A) gene cause very early onset inflammatory bowel diseases (VOIBD) or multiple intestinal atresia associated with immune deficiency of various severities, ranging from combined immune deficiency to mild lymphopenia. In this manuscript, we report the clinical, biological and molecular features of a patient born from consanguineous parents, presenting with recurrent lymphoproliferative syndrome and pan-hypergammaglobulinemia associated with chronic intestinal pseudo obstruction (CIPO). Genetic screening revealed the novel c.974G>A (p.R325Q) mutation in homozygosity in the TTC7A gene. The patient's phenotype differs significantly from that previously associated with TTC7A deficiency in humans. It becomes closer to the one reported in the ttc7a-deficient mice that invariably develop a proliferative lymphoid and myeloid disorder. Functional studies showed that the extreme variability in the clinical phenotype couldn't be explained by the cellular phenotype. Indeed, the patient's TTC7A mutation, as well as the murine-ttc7 mutant, have the same functional impact on protein expression, DNA instability and chromatin compaction, as the other mutations that lead to classical TTC7A-associated phenotypes. Co-inheritance of genetic variants may also contribute to the unique nature of the patient's phenotype. The present case report shows that the clinical spectrum of TTC7A deficiency is much broader than previously suspected. Our findings should alert the physicians to consider screening of TTC7A mutations in patients with lymphoproliferative syndrome and hypergammaglobulinemia and/or chronic intestinal pseudo-obstruction

Novel mutations in TTC37 associated with Tricho-Hepato-Enteric syndrome

International audienceThe Tricho-Hepato-Enteric (THE) syndrome is an autosomal recessive condition marked by early and intractable diarrhea, hair abnormalities and immune defects. Mutations in TTC37 which encodes the putative protein Thespin, have recently been associated with THE syndrome. In this paper, we extend the pattern of TTC37 mutations by the description of 11 novel mutations in 9 patients with a typical THE syndrome. The mutations were spread along the gene sequence, none of them being recurrent. Different types of mutation were observed: frameshift mutations, splice site altering mutations or missense mutations, most of them leading to the creation of a premature stop codon. Concurrently, we investigated the pattern of TTC37 expression in a panel of normal human tissues and showed that this gene is widely expressed, with high levels in vascular tissues, lymph node, pituitary, lung and intestine. In contrast, TTC37 is not expressed in the liver, an organ which is not consistently affected in THE syndrome. Lastly, we suggested a model for the putative structure of the unknown Thespin protein