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International audience; Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.

Background Peanut allergy (PA) management was improved by the introduction of molecular allergology, but guidelines for Mediterranean patients are lacking. We aimed at evaluating peanut component-resolved diagnosis as a diagnostic and prognostic tool in children from Southern France. Methods In 181 pediatric patients, PA diagnosis was founded on medical history, skin prick testing, serum-specific IgE to Arachis hypogea extract and components, Pru p 4, and plant carbohydrates, and oral food challenge. Allergen microarray was also performed in 68 of these patients. Results In peanut-allergic children (n = 117), IgE to Ara h 6 were most prevalent (64%), followed by Ara h 2 (63%), Ara h 1 (60%), and Ara h 9 (52%). Ara h 6 was the best predictor of PA. The second best predictor was the ratio of Ara h 2 IgE to peanut IgE (cutoff 0.113). Persistent childhood PA was associated with complex molecular profiles. Comparison of singleplex and microarray results showed poor concordance for Ara h 2 and Ara h 9. Conclusion Ara h 6 and Ara h 2 are the best predictors of PA at diagnosis in Mediterranean pediatric patients. Ara h 1, Ara h 8, and molecular complexity are associated with PA persistence.

International audience; Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease.

The 1991 introduction of 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC) as a treatment for hereditary tyrosinemia type 1 (HT-1), a disorder of tyrosine catabolism, has radically modified the natural history of this disorder. Despite the dramatic improvements in survival, outcomes and quality of life seen with NTBC treatment, HT-1 remains a chronic disorder with several long-term complications, including, a persistent (albeit low) risk of hepatocellular carcinoma and suboptimal neuropsychological outcomes. There remain unsolved key-questions concerning the long-term outcomes of patients with HT-1, which closely depend on the quality of follow-up in these patients. In the absence of published guidelines, we investigated the follow-up methods used for French and Belgian patients with HT-1. A simple questionnaire providing a rapid overview of follow-up procedures was sent to the 19 physicians in charge of HT-1 patients treated with NTBC and low-tyrosine diet in France and Belgium. Several areas of heterogeneity (especially liver imaging, slit lamp examination, neuropsychological evaluation and maximal plasma tyrosine level accepted) were observed. In an attempt to improve long-term management and outcome of patients with HT-1, we proposed follow-up recommendations.

Introduction Screening for sickle cell disease, the most common of recessive autosomic hemoglobin disorders, allows detection of sickle cell disease SCD (homozygous sickle cell disease, compound heterozygote SC, and S β-thalassemia) in a target population. Our objective was to evaluate its effectiveness at the Nice University Hospital. Population and methods This prospective study was conducted between 1 January 2000 and 31 December 2008. The national targeted newborn screening, run together with the Guthrie test on the 3rd day of life, offered at-risk newborns (based on ethnicity and family history), allow the detection of qualitative hemoglobin abnormalities. A confirmatory test is performed when positive. Gender, ethnicity, type of hemoglobin found, zygosity, age at diagnosis, the presence at a 2nd consultation of the families identified, and acceptance of the confirmatory test were collected and analyzed. Results A total of 19,775 children were born in Nice University Hospital during this period, among whom screening detected 151 hemoglobinopathies: 139 heterozygotes and 12 major sickle cell syndrome (9 SS and 3 S β-thalassemia). The prevalence of SCD on the targeted and the total population was, respectively, 1 out of 659 and 1 out of 1648 and the prevalence of heterozygotes was 1 out of 57 and 1 out of 142. The sex ratio was close to 1. Hemoglobin S predominated (74% of pathogens Hb). The Maghreb and sub-Saharan Africa were the 2 main areas of origin. One hundred and four of 151 families, including 12 cases of SCD, returned to consultation after they received a letter requesting attendance at a 2nd consultation. For 80 children, the confirmatory test was accepted. Feedback was possible for 72 of the 80 families. Discussion The number of children screened is increasing, thanks to better awareness among medical staff. The prevalence of SCD and heterozygotes found in Nice University Hospital is similar to what is described in the literature. With screening, early diagnosis allows early treatment at the age of 2 months before the occurrence of complications, reducing morbidity and mortality. Conclusion Screening for sickle cell disease appears effective in Nice. It seems necessary to continue focusing on the importance of screening among maternity healthcare actors.

The diagnosis of cystic fibrosis (CF) is based on a characteristic clinical picture in association with a sweat chloride (Cl(-)) concentration greater than 60 mmol/L or the identification of two CF-causing mutations. A challenging problem is the significant number of children for whom no definitive diagnosis is possible because they present with symptoms suggestive of CF, a sweat chloride level in the intermediate range between 30 and 60 mmol/L, and only one or no identified CF-causing mutation.To investigate the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the airways of children with intermediate sweat tests and inconclusive genetic findings in correlation with clinical phenotype and genotype.We developed a composite nasal potential difference (NPD) diagnostic score to discriminate patients with CF from non-CF patients. We tested NPD in 50 children (age, 6 mo to 18 yr) with equivocal diagnoses and correlated the NPD diagnostic score with clinical phenotypes and genotypes.Fifteen of the 50 children had NPD scores in the CF range. Eight of the 15 carried two CFTR mutations compared with only 5 of the 35 children with normal NPD scores (P = 0.01). They were significantly younger at evaluation and had recurrent lower respiratory tract infections, chronic productive coughs, and chronic Staphylococcus aureus colonization significantly more often than the 35 children with normal NPD results.Evaluation of CFTR function in the nasal epithelium of children with inconclusive CF diagnoses can be a useful diagnostic tool and help clinicians to individualize therapeutic strategy.

Resume Aux frontieres de l’organisme, les tissus epitheliaux, en relation avec les structures de l’immunite innee, decident du maintien ou de la rupture de l’etat de tolerance immunitaire. Parmi ces tissus frontieres, les voies aeriennes et digestives occupent une place de choix. Le couple epithelium–immunite est implique dans les defenses de l’hote contre les micro-organismes. Sa dysregulation est cruciale dans la creation, la reponse et la perpetuation des reactions inflammatoires d’origine allergique. La modelisation de ces systemes offre des opportunites pour mieux comprendre leur fonctionnement physiologique et leur dereglement lors des maladies allergiques. Les modeles animaux ont permis certaines avancees, mais la grande specificite de la biologie humaine a montre les limites de ces approches. L’utilisation de cultures abordant un seul type cellulaire est aussi limitee, c’est pourquoi il convient de developper des modeles ex vivo derives de cellules humaines permettant de mimer ces situations de cooperations cellulaires. Malgre la complexite des interactions, ces etudes nous semblent les seules permettant des avancees physiopathologiques et pharmacologiques susceptibles d’avoir une traduction directe pour les patients allergiques dans le futur.

Aims The French national programme for neonatal screening of sickle cell disease is applied to newborns ‘at risk’, defined as those born to parents originating from sub-Saharan Africa, the Mediterranean area, the Arabic peninsula, the French overseas islands and the Indian subcontinent. The selection is performed by the nurse in charge of blood sampling by interviewing the mother about the family9s geographical origins. The mean rate of testing in France is 25%, ranging from 2% to 50% depending on the region. This study aimed to evaluate the effectiveness of selection during this screening programme. Methods False-negative cases were identified using two different approaches: first, a regional prospective study aimed at screening all newborns, selected and non-selected, in a restricted area, representing 3% of national births; second, a retrospective national survey to identify false-negative cases. Results The regional study indicated that selective screening leads to a carrier frequency that is twice as high in the selected population as compared with the non-selected population (1.23% versus 0.62%). The local and national surveys revealed that, during a 6-year period, 28 affected children failed to be selected, leading to a false-negative rate of 2.1%. In contrast to what was expected, most of the cases were due to the failing of the data collection process and not to the misdiagnosis of the risk. Conclusions These results show that selective neonatal screening for sickle cell disease is feasible if very careful attention is paid to the selective step.

Infliximab (IFX) is efficacious in inducing remission in severe forms of pediatric Crohn's disease (CD). Adult studies indicate that IFX is also safe and well tolerated as maintenance therapy. The present study aimed to evaluate in a prospective manner the efficacy and safety of IFX as maintenance therapy of severe pediatric CD comparing scheduled and "on demand" treatment strategies.Forty children with CD (nonpenetrating, nonstricturing as well as penetrating forms, mean age: 13.9 +/- 2.2 years) with a severe flare-up (Harvey-Bradshaw Index [HBI]or =5, erythrocyte sedimentation rate [ESR]20 mm/h) despite well-conducted immunomodulator therapy (n = 36 azathioprine, n = 1 mercaptopurine, n = 3 methotrexate) combined with steroids were included in this randomized, multicenter, open-label study. Three IFX infusions (5 mg/kg) were administered at week (W)0/W2/W6. At W10, clinical remission (HBI5) and steroid withdrawal were analyzed and IFX responders were randomized to maintenance therapy over 1 year: group A, scheduled every 2 months; group B, "on demand" on relapse.In all, 34/40 children came into remission during IFX induction therapy (HBI: 6.7 +/- 2.5 (WO) vs. 1.1 +/- 1.5 (W10); P0.001). At the end of phase 2, 15/18 (83%) patients were in remission in group A compared to 8/13 (61%) children in group B (P0.01), with a mean HBI of 0.5 versus 3.2 points (group A versus B, P = 0.011). In group A, 3/13 (23.1%) children experienced a relapse compared to 11/12 (92%) children in group B. No severe adverse event occurred during this trial.IFX is well tolerated and safe as maintenance therapy for pediatric CD, with a clear advantage when used on a scheduled 2-month basis compared to an "on demand" basis.

OBJECTIVES To investigate the effect of ursodeoxycholic acid (UDCA) in children with liver disease associated with ZZ alpha1-antitrypsin (AAT) deficiency. PATIENTS AND METHODS A total of 42 affected children received UDCA (30 mg x kg x day(-1)) and underwent clinical and biochemical follow-up at least yearly. RESULTS In group 1, 22 children whose mean initial gamma-glutamyl-transpeptidase (GGT) was 7.4 x N normalized serum liver test results after a mean treatment of 2.6 years. In 16 of these children, UDCA was discontinued. Relapse was observed in 11 children, and liver test results returned to normal after UDCA resumption. In the other 5 children, liver test results remained normal during a mean period of 2.5 years. In group 2, 11 children (mean initial GGT 12.8 x N) had improved liver test results after a mean treatment of 2.3 years. In group 3, 9 children (mean initial GGT 33.8 x N) had no liver test result improvement and evolution toward cirrhosis, requiring liver transplantation in 7. Most of the children in group 1 had normal results of clinical examination after UDCA treatment, versus none in group 3 (P < or = 0.00001). Initial GGT (P < or = 0.002) and total bilirubin (P < or = 0.05) levels were significantly lower in group 1 than in group 3. Combined initial values of GGT < or =5.5 x N and total bilirubin < or =66 micromol/L were associated with normalization of liver test results in 90% of children. CONCLUSIONS UDCA may significantly improve clinical status and liver test results in some children with liver disease associated with ZZ AAT deficiency. No beneficial effect of UDCA was shown in children with the most severe liver involvement. Initial levels of GGT and total bilirubin may be of prognostic value for therapy effectiveness.

Resume L’evolution du syndrome nephrotique idiopathique de l’enfant tient a la chronicite de la maladie et aux sequelles irreversibles des traitements. La cyclosporine permet une epargne cortisonique, au prix d’une dependance exposant les patients au risque de nephrotoxicite. Le mycophenolate mofetil est efficace en transplantation d’organe et dans la prise en charge de certaines glomerulopathies, mais les donnees a long terme concernant son utilisation en pediatrie restent limitees. Nous rapportons les resultats d’une cohorte de 12 patients traites par mycophenolate mofetil pour un syndrome nephrotique corticodependant, en raison d’une nephrotoxicite de la cyclosporine. Nous presentons les resultats du suivi de l’activite de leur maladie, de l’efficacite du nouveau traitement, de leur fonction renale et de leur indice de masse corporelle. Au terme d’un suivi moyen de 31,25 mois (17–59 mois), huit patients etaient en remission, traites uniquement par mycophenolate mofetil, sans effets secondaires notables. Leur fonction renale s’est amelioree et leur indice de masse corporelle a diminue. Trois patients ont rechute a l’arret du mycophenolate mofetil. Ce travail suggere la place du mycophenolate mofetil dans le traitement au long cours des syndromes nephrotiques corticodependants non seulement en montrant une maitrise de la maladie, mais aussi en ameliorant la fonction renale et l’indice de masse corporelle des patients.

Objectives To evaluate the performance of a strategy in which, after immunoreactive trypsinogen (IRT) determination, genetic analysis is replaced by a biological test, the pancreatitis-associated protein (PAP) enzyme-linked immunosorbent assay (ELISA). Study design The French newborn screening program includes cystic fibrosis (CF) screening by the IRT/CFTR mutation strategy. PAP was assayed on screening cards, in parallel with IRT, in all newborns from 5 French regions (n = 204,749). Analysis of PAP values in CF and non-CF newborns with elevated IRT allowed direct comparison between the current strategy and the proposed IRT/PAP strategy. Results A protocol in which newborns with IRT >50 ng/mL and PAP >1.8 ng/mL and those with IRT >100 ng/mL and PAP >1.0 ng/mL are directly recalled for sweat testing would have the same performance as the IRT/CFTR mutation strategy. Conclusions The IRT/PAP strategy is an alternative for CF newborn screening, which avoids the drawbacks of genetic analysis and is cheaper and easier to implement than the current IRT/CFTR mutation strategy.

In this report, we present updated spectrum and frequency of mutations of the CFTR gene that are responsible for cystic fibrosis (CF) in Languedoc-Roussillon (L-R), the southwestern part of France. A total of 75 different mutations were identified by DGGE in 215 families, accounting for 97.6% of CF genes and generating 88 different mutational genotypes. The frequency of p.F508del was 60.23% in L-R versus 67.18% in the whole country and only five other mutations (p.G542X, p.N1303K, p.R334W, c.1717-1G>A, c.711+1G>T) had a frequency higher than 1%. The mutations were scattered over 20 exons or their border. This sample representing only 5.7% of French CF patients contributed to 24% of CFTR mutations reported in France. This is one of the highest molecular allelic heterogeneity reported so far in CF. We also present the result of a neonatal screening program based on a two-tiered approach “IRT/20 mutations/IRT” analysis on blood spots, implemented in France with the aim to improve survival and quality of life of patients diagnosed before clinical onset. This 18-month pilot project showed an unexpected low incidence of CF (1/8885) in South of France, with only six CF children detected among 43,489 neonates born in L-R, and 13 among 125,339 neonates born in Provence-Alpes-Côte-d'Azur (PACA).

International audience; Evaluation of serum lipase as predictor of severity of acute pancreatitis in children. [J Pediatr Gastroenterol Nutr. 2014]Serum lipase as an early predictor of severity in pediatric acute pancreatitis.

International audience; OBJECTIVES: Syndromic diarrhoea/tricho-hepato-enteric syndrome (SD/THE) is a rare congenital syndrome. The main features are intractable diarrhoea of infancy, hair abnormalities, facial dysmorphism, intrauterine growth restriction and immune system abnormalities. It has been linked to abnormalities in two components of the putative human ski complex: SKIV2L and TTC37. The long-term outcome of this syndrome is still unknown. We aim to describe the long-term outcome, in the French cohort of patients born since 1992. DESIGN: Review of the clinical and biological features of the 15 patients with SD/THE, followed in France and born between 1992 and 2010. RESULTS: All patients presented typical SD/THE syndrome features, of intractable diarrhoea in infancy requiring parenteral nutrition, a facial dysmorphism with hair abnormalities, and immunological disorders. Half of them also had liver and skin abnormalities. Five children died, among which 3 died due to infections. Probabilities of survival according to the Kaplan-Meier method were 93.3%, 86.7%, 74.3 and 61.9%, respectively at 1 year, 5 years, 10 years and 15 years of age. 3/15 were weaned from parenteral nutrition (PN) with likelihood of weaning being 10% at 5 years and 40% at 10 years. At birth 80% were small for gestational age and the short stature persisted in 60%. Haemophagocytic syndrome was noted in 60% and mild mental retardation was present in 60%. CONCLUSIONS: SD/THE is a rare disease with high morbidity and mortality. Management should be focused on nutrition and immunological defects.

Background Familial defective apolipoprotein B-100, a dominantly inherited form of hypercholesterolemia caused by a single Arg3500Gln mutation, is silent in childhood but may confer a high risk of cardiovascular disease in adulthood. The objective was to determine the prevalence of familial defective apolipoprotein B-100 in hypercholesterolemic French children and to provide a basis for targeting screening efforts in this population. Methods One hundred ninety children attending 13 pediatric clinics distributed throughout France were included based on the presence of type IIa hypercholesterolemia with a plasma low-density lipoprotein-cholesterol level of more than 130 mg/dL. The Arg3500Gln mutation was detected in dried blood spots using a polymerase chain reaction assay combined with enzymatic restriction. Results Three hyperlipidemia phenotypes were found: monogenic dominant pure hypercholesterolemia (n = 117), polygenic hypercholesterolemia (n = 43), and combined hyperlipidemia (n = 11). Three unrelated children were heterozygous for the Arg3500Gln mutation; all three had monogenic dominant pure hypercholesterolemia (3/94 families; 3.2%), yielding a prevalence of 1.83% (3/164) in hypercholesterolemic children, which is similar to prevalences reported in European adults. Conclusions The familial defective apolipoprotein B-100 mutation was common (1/31) in children with a phenotype of familial hypercholesterolemia, supporting screening in this population with the goal of preventing premature cardiovascular events.

Interferon-alpha (IFN) has been approved as treatment for children with chronic hepatitis B (CHB). The aims of this study were to assess the impact on children's growth of the disease itself and of IFN treatment. The growth of 142 children with CHB (70 IFN-treated, 72 untreated) was monitored for a minimum of one year. Regression analysis models were used to determine which of the variables most affected children's growth. After adjusting for racial differences, the population of 142 children with CHB had a mean baseline height for age percentile of 39 and a mean baseline weight for age percentile of 38, which were significantly different (P < 0.0001) from the 50th percentiles of their respective reference populations. The height for age Z score of untreated children was inversely correlated with serum hepatitis B virus DNA and aspartate aminotransferase levels, and the weight for age Z score was inversely correlated with serum hepatitis B virus DNA levels. While undergoing IFN therapy, children displayed a "U-shaped" growth pattern, such that height for age and weight for age Z scores at 3 or 6 months were lower than scores at baseline or 12 months. In this study the average child with CHB showed compromised growth even in the absence of IFN therapy. During IFN therapy, children's growth was temporarily disrupted.

Background Liver-kidney microsome type 1 (LKM1) antibodies are specific markers of autoimmune hepatitis (AIH) type 2. Antibodies to LKM1 have been found in 2% to 3% of adults infected with hepatitis C virus (HCV) without AIH. Thirty percent of these antibodies are directed against linear sequences of CYP2D6 protein. LKM1 antibodies in HCV+/LKM1+ sera and in sera of AIH patients do not recognize the same CYP2D6 epitopes. The current study was conducted to determine whether LKM1 antibodies in HCV+/LKM1+ children's sera are the result of the same immune response as the antibodies described in AIH type 2 and in HCV+/LKM1+ adult patients. Methods Sera from 10 HCV+/LKM1+ children were tested against human liver microsomal and cytosolic proteins by Western blot analysis and against synthetic peptides of the CYP2D6 sequence between amino acids 200 and 429 by dot blot. The same sera were tested against radiolabeled CYP2D6 by immunoprecipitation. Results Four of 10 sera tested by Western blot analysis showed immunoglobulin (Ig) G-type antibodies against CYP2D6, and 2 had antibodies against proteins of 58, 66, and 84 kDa. One of the sera also contained IgM-type anti-66-kDa and 84-kDa proteins. The radioligand test detected anti-CYP2D6 antibodies in 9 of 10 patients. Five of the anti-CYP2D6-positive sera recognized a peptide between amino acids 200 and 429 including amino acids 254-271. Conclusions Most HCV+/LKM1+ sera from children recognize conformational epitopes of the CYP2D6 antigen, and half recognize linear epitopes. Some HCV+/LKM1+ sera demonstrated antibodies against the AIH type 2 main antigenic site of the CYP2D6. Screening of HCV RNA should be performed before starting treatment of presumed autoimmune hepatitis associated with LKM1.

Except for cystic fibrosis, which is the most frequent genetic disorder in the Caucasian population, diseases of the exocrine pancreas are relatively uncommon in children. However, they are many and varied in terms of their pathogenesis and clinical manifestation. They can be classified as: (1) congenital anatomical abnormalities, (2) congenital secretory insufficiencies, and (3) pancreatitis. In all of these diseases, when pancreatic insufficiency (whether partial or complete) is present, the nutritional status of the patients must be investigated regularly, and pancreatic enzymes as well as nutritional supplementations must be prescribed as soon as malnutrition is present, or even prophylactically. The preservation of good nutritional status is the guarantee of a better prognosis.

BACKGROUND & AIMS: Treatment of chronic hepatitis B with interferon alfa is not approved in children. The aim of this study was to evaluate the safety and efficacy of interferon alfa (IFN-alpha) in children with chronic hepatitis B and increased transaminase levels. METHODS: Children were given either IFN-alpha2b (6 megaunits/m2 thrice weekly for 24 weeks) or no treatment. Clearance of markers of viral replication was evaluated 24 weeks after therapy and after 48 weeks of observation in controls. RESULTS: Of 149 children enrolled, 144 were evaluable (70 treated and 74 controls). Serum hepatitis B e antigen and viral DNA became negative in 26% of treated children and 11% of controls (P < 0.05). Serum aminotransferase levels normalized and liver histology improved among responders. Hepatitis B surface antigen became undetectable in 10% of treated patients and 1% of controls. Female gender and interferon treatment were the only significant predictors of response. Ethnic origin, baseline aminotransferase level, initial DNA levels, and histology did not correlate with response. Most adverse reactions were mild or moderate, and dose was reduced in 24% of children. CONCLUSIONS: In children with chronic hepatitis B, INF-alpha promotes loss of viral replication markers and surface antigen and improves aminotransferases and histology.

Resume Sur la base d'etudesepidemiologiques demontrant son efficacitedans la prevention de la mort subite du nourrisson (MSN), la position dorsale ou laterale pendant le sommeil est recommandee pour tous les nourrissons en dehors de situations medicales particulieres. Le reflux gastroœsophagien (RGO) constitue une situation particuliere oula position proclive ventraleâ30° a fait la preuve de son efficacitetherapeutique. La conference de consensus considere que ce traitement positionnel du RGO ne doiteˆtre envisageque dans les circonstances oule benefice attendu apparait superieur au risque de MSN qu'il induit. La position en proclive ventral avec orthostatisme de 30° ne doit paseˆtre un traitement de premiere intention du RGO non compliquedu nourrisson et du nouveau-neaˆterme, mais elle reste un deselements du traitement dans les cas resistants aux prescriptions dietetiques et medicamenteuses.

The 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 article, 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 themrecurrent. 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 that is not consistently affected in THE syndrome. Last, we suggested a model for the putative structure of the unknown Thespin protein. Hum Mutat 32:277-281, 2011. (C) 2011 Wiley-Liss, Inc.

BACKGROUND. Increased age at surgery has a negative impact on results of the Kasai operation for biliary atresia in infancy and early childhood. It remained unclear if an age threshold exists and if this effect persists with extended follow-up. In this study we examined the relationship between increased age at surgery and its results in adolescence. METHODS. All patients with biliary atresia who were living in France and born between 1986 and 2002 were included. Median follow-up in survivors was 7 years. RESULTS. Included in the study were 743 patients with biliary atresia, 695 of whom underwent a Kasai operation; 2-, 5-, 10-, and 15-year survival rates with native liver were 57.1%, 37.9%, 32.4%, and 28.5%, respectively. Median age at Kasai operation was 60 days and was stable over the study period. Whatever the follow-up (2, 5, 10, or 15 years), survival rates with native liver decreased when age at surgery increased (≤30, 31–45, 46–60, 61–75, and 76–90 days). Accordingly, we estimated that if every patient with biliary atresia underwent the Kasai operation before 46 days of age, 5.7% of all liver transplantations performed annually in France in patients younger than 16 years could be spared. CONCLUSIONS. Increased age at surgery had a progressive and sustained deleterious effect on the results of the Kasai operation until adolescence. These findings indicate a rational basis for biliary atresia screening to reduce the need for liver transplantations in infancy and childhood.

AIM: This study aimed to test the efficacy of mesalazine in maintaining remission in pediatric Crohn's disease (CD) following successful flare-up treatment. METHODS: In this double-blind, randomized, placebo-controlled trial, 122 patients received either mesalazine 50mg/kg per day (n=60) or placebo (n=62) for one year. Treatment allocation was stratified according to flare-up treatment (nutrition or medication alone). Recruitment was carried out over two periods, as the first period's results showed a trend favoring mesalazine. Relapse was defined as a Harvey-Bradshaw score more than or equal to 5. Time to relapse was analyzed using the Cox model. RESULTS: The one-year relapse rate was 57% (n=29) and 63% (n=35) in the mesalazine and placebo groups, respectively. We demonstrated a twofold lower relapse risk (P

To the Editor: Inquilinus limosus, a new multidrug-resistant species, was reported in 1999 as an unidentified gram-negative bacterium in a lung transplant patient with cystic fibrosis (CF) (1). This species was later characterized by the description of 7 new isolates of I. limosus and 1 isolate of Inquilinus sp (2). Infections and colonizations by I. limosus have been documented mainly in adolescent or adult patients with CF. To date, 8 clinical cases have been described in Germany (3,4), 1 case in the United States (1), 5 cases in France (5), and 1 case in the United Kingdom (6) (Table). Only 1 isolate of Inquilinus sp. has been recovered from blood samples of a patient without CF who had prosthetic valve endocarditis (7). Table Clinical and epidemiologic features of cystic fibrosis (CF) patients with Inquilinus limosus* Because this bacterium is not recorded in all commercial identification system databases currently available, a longitudinal study for I. limosus detection with a new real-time PCR assay with a Taqman probe (Applied Biosystems, Foster City, CA, USA), that targets the 16S rRNA gene, has been developed and compared with the culture isolation. Primers il1d (5′-TAATACGAAGGGGGCAAGCGT-3′) and il1r (5′-CACCCTCTCTTGGATTCAAGC-3′) and probe ilProbe (6FAM-GGTTCGTTGCGTCAGATGTGAAAG-TAMRA), which were used in this study, were designed on the basis of multisequence alignment of all I. limosus 16S rDNA sequences available in the GenBank database. To confirm specificity, the primers and probe were checked by using the BLAST program (www.ncbi.nlm.nih.gov/blast/Blast.cgi) and also by using suspension of several bacteria recovered habitually in patients with CF. For sensitivity of the Taqman PCR assay (Applied Biosystems), the minimal CFU detectable was 2 CFU/PCR. From January 2006 through June 2007, 365 sputum samples recovered from 84 children and 61 adults with CF and 71 sputum samples recovered from 54 patients without CF were screened blindly for I. limosus. By using our real-time PCR, we detected 9 I. limosus-positive samples from 4 patients with CF (Table); 8 of these samples were also culture positive. However, all sputum samples from patients without CF were negative. In 1 patient (Table, case 17), I. limosus was detected by using real-time PCR 3 months before the culture was positive. Retrospectively, the patient’s medical file was rechecked and his clinical respiratory condition worsened briefly at that stage, which indicates an infection by this bacterium. Thus, in our study, the incidence of I. limosus was 2.8% (4.9% for adults with CF and 1.2% for children with CF). The incidence of Burkholderia cepacia complex during the same period and in the same patients was 2.1% (3 adults with CF were positive, data not shown). The genus Inquilinus belongs to the α-Proteobacteria; the genus Azospirillum is the most closely related bacteria (2). This cluster of bacteria contains several strains that are able to grow under saline conditions and in biofilms (8,9). The mucoid phenotype of I. limosus may contribute to its colonization and resistance to many antimicrobial drugs. Recently, the exopolysaccharides (EPS) produced by I. limosus were studied. The authors indicated that I. limosus produces mainly 2 EPSs that exhibit the same charge per sugar residue present in alginate, the EPS produced by Pseudomonas aeruginosa in patients with CF. This similarity may be related to common features of the EPS produced by these 2 opportunistic pathogens that are related to lung infections (10). Transmission of I. limosus between patients with CF is not known, but in the report from Chiron et al., 1 of the 5 patients with I. limosus had a brother who had never been colonized with this bacterium despite living in the same home (5). Schmoldt et al. reported that 3 patients were treated in the same outpatient CF clinic during overlapping time periods and each patient was infected/colonized by an individual I. limosus clone, which suggests that there was no transmission among these patients (4). This bacterium has been recovered mainly from sputum of adolescents (mean age 17 ± 6.47 years, range 8–35), except in our study with a 2-year-old boy, which suggests that this emerging bacterium may be hospital acquired, as recently suggested (7). Because this bacterium is multiresistant to several antimicrobial drugs, particularly colistin, which is widely used for treatment for P. aeruginosa colonization (as was the case for our 4 patients), we hypothesize that this bacterium is selected during the evolution of the disease. We have developed a real-time PCR molecular method that is faster and easier than amplification-sequencing for prompt detection and accurate identification of I. limosus with good specificity and sensitivity. By using this screening assay, we identified 4 additional cases of patients with CF who were also infected with this bacterium, including a 2-year-old child. In addition, by using this technique, we were able to detect I. limosus in a patient with deteriorated respiratory function 3 months before the culture-based isolation, indicating that a low bacterial load, insufficient for being isolated in culture, can be detected by PCR in the lower respiratory tract of patients with CF.

Introduction Le diagnostic de l’allergie a l’arachide (AA) evolue depuis l’introduction des allergenes moleculaires. La plupart des etudes publiees jusqu’a present rapportent des resultats provenant de zones continentales temperees voire nordiques. Notre objectif a ete de decrire le profil moleculaire de sensibilisation chez les enfants marseillais allergiques a l’arachide et d’evaluer l’utilite de la realisation de ce profil pour le diagnostic et le pronostic de l’AA. Methodes Etude retrospective de 181 patients ( Resultats Chez les 117 patients AA, plusieurs allergenes majeurs ont ete identifies, avec des prevalences relativement faibles : Ara h 6 (64 %), Ara h 2 (63 %), Ara h 1 (60 %) et Ara h 9 (52 %). Une AA etait predite au mieux par les IgE Ara h 6, suivies par les IgE Ara h 2. La forte prevalence des IgE Ara h 9 entravait la distinction entre sensibilisation et AA. L’AA persistante etait associee avec des profils moleculaires plus riches et avec la presence d’IgE Ara h 1 et Ara h 9. Discussion La detection d’IgE vis-a-vis de Ara h 6 ou de Ara h 2, meme a des niveaux tres faibles, est un argument en faveur du diagnostic d’AA chez l’enfant mediterraneen. Elle ne renseigne par sur le pronostic, qui est lie a la richesse du profil moleculaire. Conclusion La realisation du profil moleculaire de sensibilisation a l’arachide chez l’enfant suspect d’une AA est utile d’un point de vie diagnostique et pronostique. La place des IgE Ara h 2 et Ara h 6 est confirmee chez l’enfant mediterraneen.

Renal function evolution during idiopathic nephrotic syndrome depends on treatment toxicity. Cyclosporin is effective as a steroid-sparing agent but patients are dependant on this drug, which can lead to renal toxicity. Mycophenolate mofetil, a widely used drug in organ transplantation, has short-term beneficial effects in glomerular diseases, including idiopathic nephrotic syndrome. Little is known about mycophenolate mofetil in children and long-term evolution. We analysed a cohort of 12 children with steroid-dependant nephrotic syndrome due to minimal change disease in remission with cyclosporine therapy. They were switched to mycophenolate mofetil, when renal toxicity was diagnosed. We evaluated the number of relapses, tolerance of this new treatment, renal function and body mass index under mycophenolate. After a follow-up of 31.25 months, mycophenolate mofetil alone was effective in preventing relapses in eight patients, without side effects. Renal function significantly improved and the final body mass index decreased. Three patients relapsed on discontinuation of mycophenolate mofetil. The results suggest that mycophenolate mofetil is effective and safe in preventing relapses in steroid-dependant nephrotic syndrome. Furthermore, switching from cyclosporine to mycophenolate mofetil restores renal function. Therefore, mycophenolate mofetil might be considered as an alternative to cyclosporine, to preserve renal function and spare steroids during idiopathic nephrotic syndrome in children.

This study analyzed the results of the decentralized management of biliary atresia (BA) in France, where an improved collaboration between centers has been promoted since 1997. Results were compared to those obtained in England and Wales, where BA patients have been centralized in three designated centers since 1999. According to their birth dates, BA patients were divided into two cohorts: cohort A, with patients born between 1986 and 1996, had 472 patients; and cohort B, with patients born between 1997 and 2002, had 271 patients. Survival rates were calculated according to the Kaplan-Meier method and compared by using the log rank test and the Cox model. Four-year overall BA patient survival was 73.6% (95% CI 69.5%-77.7%) and 87.1% (CI 82.6%-91.6%) in cohorts A and B, respectively (P < .001). Median age at time of the Kasai operation was 61 and 57 days in cohorts A and B, respectively (NS). Four-year survival with native liver after the Kasai operation was 40.1% and 42.7% in cohorts A and B, respectively (NS): 33.9% (cohort A) and 33.4% (cohort B) in the centers with two or fewer caseloads a year, 30.9% (cohort A) and 44.5% (cohort B) in the centers with 3-5 cases/year, 47.8% (cohort A) and 47.7% (cohort B) in the center with more than 20 caseloads a year. In cohorts A and B, 74 (15.7%) and 19 (7%) patients, respectively, died without liver transplantation (LT). Four-year survival after LT was 75.1% and 88.8% in cohorts A and B, respectively (P = .006). In conclusion, BA patients currently have the same chance of survival in France as in England and Wales. The early success rate of the Kasai operation remains inferior in the centers with limited caseloads in France, leading to a greater need for LTs in infancy and early childhood.

Infliximab, a monoclonal antibody against tumor necrosis factor-alpha, has been shown to be effective for the treatment of refractory Crohn's disease in adult patients, but experience in pediatrics is limited. This retrospective study included 88 children and adolescents, 39 girls and 49 boys, with a median age of 14 years (range 3.3-17.9). Infliximab was indicated for active disease (66%) and/or fistulas (42%) that were refractory to corticosteroids (70%), and/or other immunosuppressive (82%) agents, and/or parenteral nutrition (20%). Patients received 1 to 17 infusions (median 4) of 5 mg/kg (range 3.8-7.3) of infliximab during a median time period of 4 months (1-17 months). Infusion reaction was noted in 13 patients (15%), with a total of 16 reactions in 450 infusions (4%). At Day 90 after the first infusion of infliximab, symptoms improved in 49% of patients, whereas 29% of patients were in remission and 13% of patients relapsed. From Day 0 to Day 90, Harvey-Bradshaw score decreased from 7.5 to 2.8 (P < 0.001), C-reactive protein from 36 to 16 mg/L (P < 0.01), and 1-hour erythrocyte sedimentation rate from 35 to 17 mm (P < 0.01). Dosage of corticosteroids decreased from to 0.59 to 0.17 mg/kg/d (P < 0.001); 53% of patients could be weaned of corticosteroids and 92% of parenteral nutrition. Treatment with infliximab is well tolerated and effective in most children and adolescents with Crohn's disease that is refractory to conventional immunosuppressive therapy. Nevertheless, long-term efficacy remains to be shown, and further studies are urgently needed to precisely determine the best modality of continuing treatment.

Severity scores are used to predict the outcome of acute pancreatitis (AP). Several scores are used in adult patients, but none has been thoroughly validated for specific use in paediatric patients. We retrospectively collected data from 48 children with AP (13 severe and 35 mild). The main causes were trauma (23%), idiopathic (23%), lithiasis (12.5%), and virus (10.5%). We evaluated 3 clinical scores (Ranson, Glasgow modified, and DeBanto) and Balthazar computed tomography severity index. The clinical scores had a good specificity (approximately 85%) but a low sensitivity (approximately 55%) in predicting the severity of paediatric AP. The radiological score is better (sensitivity 80%, specificity 86%). The area under the receiver operator characteristic curve was 0.699 (95% CI 0.508%-0.891%, P = 0.054) for the DeBanto score, 0.846 (95% CI 0.69%-1%, P = 0.001) for the Ranson score, and 0.774 (95% CI 0.584%-0.964%, P = 0.008) for the Glasgow and 0.898 (95% CI 0.73%-1%, P = 0.011) for the Balthazar computed tomography severity index score. In our paediatric cohort, the severity of AP was best predicted by Balthazar computed tomography-based scoring scale. Our results confirm previously reported low sensitivity of adult-based clinical scoring scales.

Results Median age was 6 years (10 months to 17 years) when ISAC was first performed, and 8 years (22 months to 18 years) when the latest ISAC was performed. With respect to the number and intensity of IgE reactivities, ISAC follow-up results entered one of the following categories: progression (16), stability (12), attenuation (8). Two patients displayed complex alterations of their molecular profile over time. In most cases, ISAC followup provided aid for the management of food exclusion or reintroduction regimens. Storage protein reactivity was the most frequent setting, but transition from one molecular profile to another, which were not clinically distinguishable, such as lipid tranfer proteins versus thaumatin-like proteins, was als noted. Complex cross-reactivity patterns or allergy to components which are unavailable for individual testing (sesame Ses i 1, thaumatin-like Act d 2, 7S vicillins other than those from Fabaceae, wheat Tri a 14) gained better insight from repeated ISAC assays. Finally, sequential “allergen landscape views” improved the understanding of the patient’s biological and clinical evolution.

Background & Aims: Oral rehydration therapy is the only treatment recommended by the World Health Organization in acute diarrhea in children. Antisecretory drugs available could not be used because of their side effects, except for racecadotril, which is efficient in acute diarrhea in adults. Methods: The efficacy and tolerability of racecadotril (1.5 mg/kg administered orally 3 times daily) as adjuvant therapy to oral rehydration were compared with those of placebo in 172 infants aged 3 months to 4 years (mean age, 12.8 months) who had acute diarrhea. The treatment groups were comparable in terms of age, duration of diarrhea, number of stools, and causative microorganism at inclusion. Results: During the first 48 hours of treatment, patients receiving racecadotril had a significantly lower stool output (grams per hour) than those receiving placebo. The 95% confidence interval was 43%— 88% for the full data set (n 5 166; P 5 0.009) and 33%—75% for the per-protocol population (n 5 116; P 5 0.001). There was no difference between treatments depending on rotavirus status. Significant differences between treatment groups were also found after 24 hours of treatment: full data set (n 5 167; P 5 0.026) and per-protocol population (n 5 121; P 5 0.015). Tolerability was good in both groups of patients. Conclusions: This study demonstrates the efficacy (up to 50% reduction in stool output) and tolerability of racecadotril as adjuvant therapy to oral rehydration solution in the treatment of severe diarrhea in infants and children.

To develop prognostic models for identifying children with hepatitis B who are likely to respond to interferon-alpha (IFN-alpha) or to spontaneously seroconvert, we evaluated results of a multinational controlled trial comprising 70 children with chronic hepatitis B who received IFN-alpha and 74 children who did not receive therapy. Prognostic models were developed using SMILES (similarity of least squares), which is a data analysis network that incorporates multidimensional relationships in the clinical data of complex diseases. Commonly collected clinical data included age, gender, serum aminotransferase (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and hepatitis B virus (HBV) DNA levels, and IFN-alpha dose. Additional data included pretreatment directional information (e.g. increases or decreases in serum aminotransferase and HBV DNA levels), liver biopsy results, race and transmission mode. Using data available prior to initiation of treatment, the SMILES models achieved prospective predictions of 89% for responders, 96% for non-responders, 100% for seroconverters and 93% for non-seroconverters. Although not predictive by themselves, the variables that had the greatest impact on predictions for IFN-alpha response were HBV DNA pretreatment direction, baseline HBV DNA, IFN-alpha dose and gender. The variables that had the greatest impact on predictions for spontaneous seroconversion were ALT pretreatment direction, baseline HBV DNA level, age and AST pretreatment direction. Therefore, these models may be useful in determining, in children with hepatitis B, the likelihood of response to IFN-alpha and spontaneous seroconversion.

AIM To determine whether pancreatitis associated protein (PAP) is a marker for cystic fibrosis which could be used in neonatal screening for the disease. METHODS PAP was assayed on screening cards from 202 807 neonates. Babies with PAP ⩾ 15 ng/ml, or ⩾ 11.5 ng/ml and immunoreactive trypsinogen (IRT) ⩾ 700 ng/ml were recalled for clinical examination, sweat testing, and cystic fibrosis transmembrane regulator (CFTR) gene analysis. RESULTS Median PAP value was 2.8 ng/ml. Forty four cases of cystic fibrosis were recorded. Recalled neonates (n=398) included only 11 carriers. A receiver operating characteristic curve analysis showed that PAP above 8.0 ng/ml would select 0.76% of babies, including all those with cystic fibrosis, except for one with meconium ileus and two with mild CFTR mutations. Screening 27 146 babies with both PAP and IRT showed that only 0.12% had PAP > 8.0 ng/ml and IRT > 700 ng/ml, including all cases of cystic fibrosis. CONCLUSION PAP is increased in most neonates with cystic fibrosis and could be used for CF screening. Its combination with IRT looks promising. Key messages CF neonatal screening with PAP is technically feasible in the same environment as other neonatal screenings (PKU, hypothyroidism) CF neonatal screening with PAP alone performs similarly to screening with IRT alone, with less carrier detection Combining PAP with IRT for CF neonatal screening could be as efficient as the IRT/DNA strategy, but would be cheaper and incur limited carrier detection If a legal requirement for informed consent before DNA testing has expired, the PAP/IRT strategy would be an alternative to the IRT/DNA strategy

Delayed response to medical treatment sometimes leads to unnecessary liver transplantation in patients with severely decompensated Wilson disease. We report the course of five patients (mean age 13.4 years, range 11 to 15 years) with severely decompensated Wilson disease who were successfully treated medically. Prothrombin time improved after a minimum of 1 month and returned to normal within 3 months to 1 year or more.

Hyper-IgD and periodic fever syndrome (HIDS) is a hereditary autoinflammatory syndrome, characterized by recurrent inflammatory attacks. Treatment of HIDS is difficult. Recently, the IL-1ra analogue anakinra was reported to be successful in aborting the IgD inflammatory attacks in a vaccination model. We report a clinical case of spectacular reduction of febrile attacks in a severe HIDS patient.