Facuté de Medecine

The development in therapeutic strategies has increased survival of children affected by inborn errors of metabolism with restricted diet (IEMRD). These diseases have mild-and long-term consequences on the health. Little is known about the impact on the quality of life (QoL) of children and their families. The aims of this study were: to compare the QoL of the children and parents affected by IEMRD with the QoL of the general population and one pathology associated with long-term consequences. Patients and methods: This cross-sectional study was performed at the French Reference Center for inborn metabolic disorders (Marseille, France). Inclusion criteria were: a child with a diagnosis of organic aciduria, urea cycle defect, or maple syrups urine disease (MSUD). Socio-demographics, clinical data, and QoL were recorded. Results: Twenty-one of 32 eligible families were included during a planned routine visit. Ten (47%, 95% CI 27-69%) children were affected by organic aciduria, six (29%, 95% CI 10-48%) by urea cycle defects, and five (24%, 95% CI 6-42%) by MSUD. Among the younger children, the general well-being was significantly lower in the children with IEMRD than in the leukemia children (58 ± 16 versus 76 ± 15, p = 0.012), and among the older children, the leisure activities were significantly lower in the children with IEMRD than in the leukemia children (29 ± 18 versus 62 ± 22, p < 10 -3 ), while the relationships with teachers were better (76 ± 23 versus 60 ± 23, p = 0.01). The physical QoL score was lower in the parents than in the French norms (66 ± 21 versus 75 ± 1, p = 0.05). Factors modulating QoL were: eating and neurologic disorders, enteral nutrition, and feeding modalities. Conclusion: The children and the parents of children affected presented altered 'physical' and 'social' QoL scores compared with the norms and patients with leukemia and their families. Future studies based on larger cohort studies should determine the different weights of potential predictive factors of QoL.

Syndromic diarrhea/Tricho-hepato-enteric syndrome (SD/THE) is a rare and severe bowel disorder caused by mutation in SKIV2L or in TTC37, 2 genes encoding subunits of the putative human SKI complex. The estimated prevalence is 1/1,000,000 births and the transmission is autosomal recessive. The classical form is characterized by 5 clinical signs: intractable diarrhea of infancy beginning in the first month of life, usually leading to failure to thrive and requiring parenteral nutrition; facial dysmorphism characterised by prominent forehead and cheeks, broad nasal root and hypertelorism; hair abnormalities described as woolly and easily removable; immune disorders resulting from defective antibody production; intrauterine growth restriction. The aetiology is a defect in TTC37, a TPR containing protein, or in the RNA helicase SKIV2L, both constituting the putative human ski complex. The ski complex is a heterotetrameric cofactor of the cytoplasmic RNA exosome which ensures aberrants mRNAs decay. The diagnosis SD/THE is initially based on clinical findings and confirmed by direct sequencing of TTC37 and SKIV2L. Differential diagnosis with the other causes of intractable diarrhea is easily performed by pathologic investigations. During their clinical course, most of the children require parenteral nutrition and often immunoglobulin supplementation. With time, some of them can be weaned off parenteral nutrition and immunoglobulin supplementation. The prognosis depends on the management and is largely related to the occurrence of parenteral nutrition complications or infections. Even with optimal management, most of the children seem to experience failure to thrive and final short stature. Mild mental retardation is observed in half of the cases.

An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases (VEO-IBD). The present study aimed at defining how next-generation sequencing (NGS) methods can be used to improve identification of known molecular diagnosis and adapt treatment. 207 children were recruited in 45 Paediatric centres through an international collaborative network (ESPGHAN GENIUS working group) with a clinical presentation of severe VEO-IBD (n=185) or an anamnesis suggestive of a monogenic disorder (n=22). Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing (WES) of parents-child trios. Genetic findings were validated clinically and/or functionally. Molecular...

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. Cell transplantation is in clinical development for the treatment of various ailments including acquired and inborn hepatic diseases. Detection and quantification of the donor cells after infusion remain difficult. Traditional methods (sex-based FISH, HLA mismatch, and Short Tandem Repeat PCR) can only achieve low levels of sensitivity (1%) and therefore are seldom used. The use of a droplet digital PCR (ddPCR) assay based on mismatch of null alleles is a promising alternative. Methods. We selected genes with a high frequency of null genotype in the general population (SRY, RHD, TRY6, LEC3C, GSTM1, and GSTT1) and investigated their expression by liver progenitor cell donors and liver cell therapy recipients, in order to identify genes of interest for each donor/recipient couple. We first validated the detection of microchimerism by ddPCR and then used these assays to detect and quantify microchimerism in pre- and postinfusion liver biopsies. Results. We validated the ddP...

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with hitherto unknown syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing and bone fragility, a clinical entity we have termed O2HE (Osteo-Oto-Hepato-enteric) syndrome. 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.

In the end of April nearly 100 cases of children aged between 6 month and 9 years with Kawasaki like disease have been reported (mostly in Europe) probably linked to COVID-19. We aim to sum up the known data about this new entity based on published data (in a case report, a serie of 8 cases and in newspapers and society statement) and using our knowledge of classical Kawasaki disease. It seems to be a post infectious disease with an onset between 2-4 weeks after the infection, probably in genetically predisposed children aged between 6 month to 17 years. A very rough estimation of incidence based on data from Bergamo, Italy, and New York State and a lot assumption is between 0.011% (95% CI:0.009-0.014%) - 0.31% (95% CI: 0.2-0.47%) of infected children. Clinical signs overlaps with Kawasaki disease in some children, but another feature is prominent gastrointestinal manifestations. For the 9 detailed patients most had incomplete presentation for Kawasaki disease (with a mean 1.7 (+/-1...

OBJECTIVES To understand how children perceive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in relation to public representations and to evaluate their interpretations. METHODS Children’s perceptions of SARS-CoV-2 were evaluated by asking 103 French children, aged 5 to 17 years old, first to draw a coronavirus and then to identify SARS-CoV-2 in a series of 16 images during summer 2020. RESULTS One hundred three children were included in the study, either during outpatient visits at the hospital (in Marseille and Paris) or through the authors’ social network, and were grouped in terms of age, parents’ occupation, mode of recruitment, and recollection of having previously seen a representation of a coronavirus. Half of the children drew the coronavirus as circular in shape, and almost all included a crownlike feature. One-third of the drawings had anthropomorphic features. Although the pictorial representations of the virus were fairly accurate overall, the children’s ...

Background.Transplantation is a saving therapeutic that has heavy consequences. The quality of life (QoL) of transplanted children and their parents has been little studied and should help physicians better manage these patients. The objectives of the study were to assess: i) the QoL of transplanted children and parents and compare it with that of children with other chronic conditions associated with long-term consequences, and ii) potential variables modulating the QoL.Methods.This cross-sectional study was performed in a multidisciplinary paediatric unit (Timone Hospital, Marseille, France). Children were less than 18 years old; had a liver, kidney or heart transplant; and had a time since transplantation of 1 to 10 years. Socio-demographics and clinical data were recorded from medical forms. The QoL was assessed using the VSP-A (Vécu et Santé Perçue de l’Adolescent et de l’Enfant) and the WhoQoL self-reported questionnaires. Results.Forty-five families were included (response ra...

Mendelian inheritance, pLI, gnomAD, ExAC Genetic constraint metrics such as the gnomAD probability of being loss-of-function (LoF) intolerant (pLI) are used to prioritize candidate genes but the mode of inheritance of highly constrained genes has never specifically been studied. We compared 605 genes with a pLI of 1 (pLI1 group) with a random sample of 635 genes from gnomAD (the random group) in terms of genetic constraint metrics, associations with Mendelian disease, modes of inheritance, and two intragenic constraint scores: the percentage of constraint coding regions (CCR) in the 99 th percentile and the gene variation intolerance rank (GeVIR). The proportion of genes associated with a Mendelian disease was 35.9% (217/605) in the pLI1 group and 19.5% (124/635) in the random group (p < 0.0001). The modes of inheritance in the random group were autosomal dominant for 35 genes (28.2%), autosomal recessive for 69 (55.6%), mixed for 14 (11.3%) and X-linked for 6 genes (4.8%). The corresponding distribution in the pLI1 group was 150 (69.1%), 26 (12.0%), 14 (6.5%) and 27 (12.4%) (p < 0.0001). The percentage of CCRs in the 99th percentile was 0.3 in the random group versus 1.12 in the pLI1 group (p < 0.0001). The GeVIR score was 50.9 for the random group versus 15.1 for the pLI1 group (p < 0.0001). High genetic constraint does not seem to be associated with a particular mode of inheritance but does seem to be associated with the intragenic constraint scores considered here. Some highly constrained genes are associated with two different modes of inheritance.

Background Commercially available house dust mite components may improve routine testing of allergic patients. Objective To establish the prevalence and serum levels of IgE to commercial Der p 1, Der p 2, Der p 10 and the carbohydrate MUXF3 in house dust-mite allergic patients. To compare individual vs. allergen microarray methods. Methods Prevalence and serum levels of IgE to Dermatophagoides pteronyssinus extract and components Der p 1, Der p 2, Der p 10 and MUXF3, specific IgG 4 to D. pteronyssinus, total serum IgE levels, and clinical features (age, asthma, rhinitis and atopic dermatitis) were determined in 123 patients (64 children) with the ImmunoCAP ® method. Immuno-CAP ISAC ® was performed in 24 patients. Results All patients had serum IgE to D. pteronyssinus. Prevalences of serum IgE to commercial components were Der p 1 93%, Der p 2 77% (Der p 1 or Der p 2 94%), Der p 10 28% and MUXF3 25%. Levels of D. pteronyssinus IgE strongly correlated with Der p 1 and Der p 2 IgE (r = 0.89 and 0.85 respectively), but not Der p 10 and MUXF3. Immuno-CAP ® and ImmunoCAP ISAC ® were concordant, but the quantitative correlation was poor. No clinical implication for the prevalence, levels, or molecular IgE reactivity profile to house dust mite components was found. Conclusions and Clinical Relevance Commercially available Der p 1 and Der p 2 strongly correlate with IgE D. pteronyssinus. The lack of Der p 1 and Der p 2 IgE may help with differential diagnosis. Der p 10 serum IgE prevalence and levels suggest different patterns in food and mite-related tropomyosin sensitization. Serum IgE to carbohydrate MUXF3, although unexpectedly prevalent, were low and did not modify D. pteronyssinus IgE levels. Follow-up may be best carried out with individual rather than microarrayed components.

Objective: To study the relationship between child psychiatric disorders and quality of life (QoL). Method: In a sample of 310 children (ages 6-18 years) referred for psychiatric problems, children, parents, and clinicians reported on psychopathology and subjective and objective QoL indicators. Results: Six diagnostic categories were distinguished: attention-deficit and disruptive behavior disorders, anxiety disorders, pervasive developmental disorders, mood disorders, other disorders, and no diagnosis. In overall QoL, no differences were found between the diagnostic categories, except in clinician's ratings, who rated children with pervasive developmental disorder as having a poorer QoL than children with other diagnoses. In each diagnostic category specific QoL subdomains were affected: for children with attention-deficit and disruptive behavior disorder, school functioning and social functioning; for children with anxiety disorder, emotional functioning; for children with pervasive developmental disorder, social functioning; and for children with mood disorder, emotional functioning. Conclusions: Across multiple raters, the distinguished child psychiatric disorders had a different impact on QoL. Knowledge about domains of QoL that are affected in specific child psychiatric disorders can help clinicians to focus on particular QoL domains during the diagnostic process and to define adequate treatment goals.