Mitchell-Riley Syndrome : Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations

Aims/HypothesisCaused by biallelic mutations of the gene encoding the transcription factor RFX6, the rare Mitchell-Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function. MethodsClinical records were analyzed and described in detail. The functional impact of two RFX6(R181W) and RFX6(V506G) variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function. ResultsAll four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6(V506G) and RFX6(R181W) mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function. Conclusions/InterpretationMultidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.Peer reviewe

Results of an International Survey on Feeding Management in Infants With Short Bowel Syndrome-Associated Intestinal Failure

Objectives: Short bowel syndrome (SBS) is a complex and rare condition (incidence 1200/100,000 live births) that requires a multidisciplinary team approach to management. In January 2019, the first European Reference Network on Rare and Inherited Congenital Anomalies (ERNICA) Intestinal Failure (IF) workshop was held. Several questions about the strategies used in managing IF associated with SBS were devised. The aim of our study was to collect data on the enteral feeding strategies adopted by the ERNICA centres. Methods: A questionnaire (36 questions) about strategies used to introduce enteral nutrition post-operatively and start complementary food/solids in infants with SBS associated IF was developed and sent to 24 centres in 15 countries that participated in the ERNICA-IF workshop. The answers were collated and compared with the literature. Results: There was a 100% response rate. In infants, enteral nutrition was introduced as soon as possible, ideally within 24–48 hours post-small intestinal surgical resection. In 10 of 24 centres, bolus feeding was used, in nine continuous, and in five a combination of both. Twenty-three centres used mothers’ own milk as the first choice of feed with extensively hydrolysed feed, amino acid-based feed, donor human milk or standard preterm/term formula as the second choice. Although 22 centres introduced complementary/solid food by 6 months of age, food choice varied greatly between centres and appeared to be culturally based. Conclusions: There is diversity in post-surgical enteral feeding strategies among centres in Europe. Further multi-centre studies could help to increase evidence-based medicine and management on this topic

Clinical predictors of radiographic abnormalities among infants with bronchiolitis in a paediatric emergency department

International audienceBackgroundAcute viral respiratory exacerbation is one of the most common conditions encountered in a paediatric emergency department (PED) during winter months. We aimed at defining clinical predictors of chest radiography prescription and radiographic abnormalities, among infants with bronchiolitis in a paediatric emergency department.MethodsWe conducted a prospective cohort study of children less than 2 years of age with clinical bronchiolitis, who presented for evaluation at the paediatric emergency department of an urban general hospital in France. Detailed information regarding historical features, examination findings, and management were collected. Clinical predictors of interest were explored in multivariate logistic regression models.ResultsAmong 410 chest radiographs blindly interpreted by two experts, 40 (9.7%) were considered as abnormal. Clinical predictors of chest radiography achievement were age (under three months), feeding difficulties, fever over 38°C, hypoxia under than 95% of oxygen saturation, respiratory distress, crackles, and bronchitis rales. Clinical predictors of radiographic abnormalities were fever and close to significance hypoxia and conjunctivitis.ConclusionOur study provides arguments for reducing chest radiographs in infants with bronchiolitis. For infants with clinical factors such as age less than three months, feeding difficulties, respiratory distress without hypoxia, isolated crackles or bronchitis rales, careful clinical follow-up should be provided instead of chest radiography

Dietary Patterns, Ultra-processed Food, and the Risk of Inflammatory Bowel Diseases in the NutriNet-Santé Cohort

International audienceBackgroundThe incidence of inflammatory bowel diseases (IBDs) tended to increase for several decades. Diet is suspected to be a major determinant of the occurrence of these diseases. This prospective study aimed to assess the associations among occurrence of IBD, dietary patterns, and ultra-processed food in the French NutriNet-Santé cohort.MethodsParticipants of the NutriNet-Santé cohort who completed at least three 24-hour dietary records were included. Incident IBD cases were identified from 3 questionnaires and confirmed by phone or email interview. Major dietary patterns (DPs) were computed using a principal component analysis (PCA) based on 29 food groups’ consumption, whereas proportions of ultra-processed foods (UPFs) were obtained using the NOVA classification. Multivariable Poisson models were performed to evaluate associations among DP quintiles, UPF proportion (UPFp) in the diet, and incident IBD.ResultsA total of 105,832 participants were included, contributing 238,924 person-years in a mean follow-up of 2.3 ± 2.2 years. Among them, 75 participants reported an incident IBD. Three major DPs were retained: “healthy,” “traditional,” and “western.” No significant association was found for DPs and UPFp after adjustments for covariates.ConclusionsIn this study, neither DPs nor UPF proportion in the diet were significantly associated with the risk of incident IBD after adjustments for covariates. Further studies are needed to investigate the long-term association between diet and IBD

Combined use of creatinine and cystatin C improves the detection of renal dysfunction in children undergoing home parenteral nutrition

International audienceBackground Renal dysfunction can complicate home parenteral nutrition (HPN). The aims were, in the context of pediatric HPN, to assess renal function using the measured glomerular filtration rate (mGFR), determine the most accurate formula(s) to estimate GFR, and identify possible underlying mechanisms of renal impairment.Methods A retrospective study was performed in 2 centers. Patients receiving HPN and aged 2-16 years without medical history of nephropathy were included. GFR was measured using iohexol clearance. Estimated GFR (eGFR) was calculated using creatinine, cystatin C-based, and combined (eGFR(cr+cyst)) Schwartz formulas.Results A total of 36 patients (18 females) were included; they received HPN for 8 (2-16) years. The primary digestive disease was short-bowel syndrome for 16 (44%) patients, gastrointestinal motility disorder for 10 (28%), or congenital diarrhea for 10 (28%). The median (range) mGFR was 99 (33-136) ml/min/1.73 m(2); 9 (25%) patients had mildly decreased mGFR (= 60 ml/min/1.73 m(2)), and 2 (6%) had mildly to severely decreased mGFR (<60 ml/min/1.73 m(2)). The eGFR(cr+cyst) formula was the most accurate and precise to estimate GFR. A significant negative correlation between mGFR and PN duration was found for patients receiving PN for 6-7/7 days (P = .008). Activation of the renin-angiotensin system was identified in 15 of 36 (42%) patients.Conclusion Renal dysfunction was frequent and correlated with the duration of PN only for patients with the most severe intestinal failure. The use of eGFR(cr+cyst) improves its detection in these patients. Chronic dehydration may be an underlying mechanism

Combined Immunodeficiency in Patients With Trichohepatoenteric Syndrome

International audienceThe syndromic diarrhea/trichohepatoenteric syndrome (SD/THE) is a rare and multi-system genetic disorder caused by mutation in SKIV2L or in TTC37, two genes encoding subunits of the putative human SKI complex involved in RNA degradation. The main features are intractable diarrhea of infancy, hair abnormalities, facial dysmorphism, and intrauterine growth restriction. Immunologically this syndrome is associated with a hypogammaglobulinemia leading to an immunoglobulin supplementation. Our immune evaluation of a large French cohort of SD/THE patient revealed several immunological defects. First, switched memory B lymphocytes count is very low. Second, IFN-gamma production by T and NK cells is impaired and associated with a reduced degranulation of NK cells. Third, T cell proliferation was abnormal in 3/6 TTC37-mutated patients. These three patients present with severe EBV infection and a transient hemophagocytosis which may be related to these immunological defects. Moreover, an immunological screening of patients with clinical features of SD/THE could facilitate both diagnosis and therapeutic management of these patients

Demographics of the study population (<i>n</i> = 697).

<p>Demographics of the study population (<i>n</i> = 697).</p

Age-related respiratory rate, from Liu et al. [10].

<p>Age-related respiratory rate, from Liu et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096189#pone.0096189-Liu1" target="_blank">[10]</a>.</p

Effect of chest radiography on antibiotic use.

<p>Effect of chest radiography on antibiotic use.</p