The association of severe encephalopathy and question mark ear is highly suggestive of loss of MEF2C function.

Auriculocondylar syndrome and isolated question mark ear result from dysregulation of the endothelin 1-endothelin receptor type A signaling pathway. Animal models have highlighted the role of the transcription factor MEF2C as an effector of this pathway. We report heterozygous MEF2C loss-of-function as a possible cause of question mark ear associated with intellectual deficiency.

French National Diagnostic and Care Protocol for antiphospholipid syndrome in adults and children.

Antiphospholipid syndrome (APS) is a chronic autoimmune disease involving vascular thrombosis and/or obstetric morbidity and persistent antibodies to phospholipids or certain phospholipid-associated proteins. It is a rare condition in adults and even rarer in children. The diagnosis of APS can be facilitated by the use of classification criteria based on a combination of clinical and biological features. APS may be rapidly progressive with multiple, often synchronous thromboses, resulting in life-threatening multiple organ failure. This form is known as "catastrophic antiphospholipid syndrome" (CAPS). It may be primary or associated with systemic lupus erythematosus (associated APS) and in very rare cases with other systemic autoimmune diseases. General practitioners and paediatricians may encounter APS in patients with one or more vascular thromboses. Because APS is so rare and difficult to diagnosis (risk of overdiagnosis) any suspected case should be confirmed rapidly and sometimes urgently by an APS specialist. First-line treatment of thrombotic events in APS includes heparin followed by long-term anticoagulation with a VKA, usually warfarin. Except in the specific case of stroke, anticoagulants should be started as early as possible. Any temporary discontinuation of anticoagulants is associated with a high risk of thrombosis in APS. A reference/competence centre specialised in autoimmune diseases must be urgently consulted for the therapeutic management of CAPS.

Strengths and limitations of a policy for handling and following up suspected pediatric cases of SARS-CoV-2 infection.

To compensate for the poor initial knowledge about pediatric SARS-CoV-2 infections and the limited access to non-urgent medical care during lockdown, a local telephone follow-up program was set up to remotely monitor children with confirmed or suspected SARS-CoV-2 infection at the pediatric emergency department of a French tertiary hospital. We retrospectively assessed 131 children. A total of 488 phone call attempts resulted in 293 (60%) teleconsultations. This telephone follow-up program was simple and appeared necessary in the first stage of the pandemic with an emergent pathogen. However, it was time-consuming and should be improved for further use.

Hirschsprung disease, associated syndromes and genetics: a review.

Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.

Klebsiella pneumoniae and Klebsiella oxytoca meningitis in infants. Epidemiological and clinical features.

BACKGROUND: The incidence of meningitis caused by Klebsiella pneumoniae (Kp) and Klebsiella oxytoca (Ko) in high-income countries is unknown, and no series have been published to date. METHODS: We conducted a nationwide multicenter observational study in France between 2006 and 2016. All children from the French national registry for paediatric bacterial meningitis under the age of 1 year and hospitalized for Kp or Ko meningitis were included. Virulence factors of four Klebsiella spp. strains were explored by whole genome sequencing. RESULTS: Of 1859 cases of meningitis in children under the age of 1 year, 13 cases (0.7%) of Klebsiella spp. meningitis (nine for Kp meningitis and four for Ko meningitis) were registered in the French national registry. Three of the patients died and 50% of the survivors had developmental delays. CONCLUSIONS: Prematurity, low birth weight, and congenital anomalies of the urinary tract appear to be risk factors for Klebsiella spp. meningitis as well as virulence factors of the strain.

[Distribution of neutralizing measles serum antibodies according to age in women of childbearing age in France in 2005-2006]. / Distribution en fonction de l'âge de la concentration sérique des anticorps neutralisants antirougeole chez les femmes en âge de procréer en France en 2005-2006.

UNLABELLED: Measles-vaccine coverage (MVC) increased significantly only beginning in 1983 based on the official recommendations. The majority of women born after 1983 should have vaccine-acquired rather than naturally derived immunity. Passively transferred measles antibodies (Mab) are expected to provide protection to offsprings during their 1st few months of life. OBJECTIVE: Compare neutralizing Mab titers according to age in women aged 12-40 years, i.e., born before and after 1983. METHODS: A multicenter seroepidemiological study was conducted in France in 2005-2006; 210 outpatient or hospitalized women were enrolled and classified into 4 age groups (12-18, 19-22, 23-30, and 31-40 years). Mab titers were assessed using a reference plaque reduction neutralization assay (protection threshold > 120 mIU/ml). RESULTS: Ninety-four percent of subjects had a Mabs titer greater than 120 mIU/ml. Women born before 1983 had significantly higher geometric mean titers (GMTs) of Mabs than those born after 1983(1358 mIU/ml vs. 731 mIU/ml [p<0.001]). The comparison of the 4 cohorts showed a significant decrease (p<0.001) in GMTs of Mab in the female population with increasing age (670, 771, 1173, and 1821 mUI/ml, respectively, in the 12-18, 19-22, 23-30, and 31-40 years age groups). For the 1st time in France, we show in women of childbearing age that in 2005-2006 neutralizing Mab GMTs were far above protective threshold for all age groups. Women in younger age groups (with high MVC) have significantly lower Mab titers. A lower passive transfer of Mab to their offsprings could result in a shorter period of measles protection and question the measles vaccine 1st dose at 1 year.

Impact of social deprivation on length of stay for common infectious diseases in two French university-affiliated general pediatric departments.

BACKGROUND: Adult deprived patients consume more healthcare resources than others, particularly in terms of increased length of stay (LOS) and costs. Very few pediatric studies have focused on LOS, although the effect of deprivation could be greater in children due to the vulnerability of this population. Our objective was to compare LOS between deprived and nondeprived children hospitalized for acute infectious diseases in two university-affiliated pediatric departments located in a low-income area of northern Paris. METHODS: We performed a prospective observational multicenter study in two university-affiliated hospitals, Hôpital Robert-Debré and Hôpital Jean-Verdier. All the patients under 15 years of age admitted to the general pediatric department for pneumonia, bronchiolitis, gastroenteritis, or pyelonephritis between 20 October 2016 and 20 March 2017 were included. Deprivation was assessed with an individual questionnaire and score (EPICES). Endpoints included length of stay, costs, and readmission rates at 15 days in each quintile of deprivation. Multivariate regression assessed the association between deprivation and each endpoint. RESULTS: A total of 556 patients were included in the study and 540 were analyzed. Sixty percent were boys and the mean age was 9 months±18. Bronchiolitis was the most frequent diagnosis (67.8%). Fifty-six percent of patients were considered to be deprived based on the EPICES questionnaire. Mean LOS was 4.6±3.5 days and we found no significant difference in LOS between the different deprivation quintiles (P=0.83). Multivariate regression did not show an association between LOS and deprivation. CONCLUSION: There was no difference between deprived and nondeprived patients in terms of LOS. Deprivation may therefore impact hospitals in other ways such as admission rates. The impact of deprivation during hospitalization for chronic diseases should also be investigated.

Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease.

Hirschsprung disease (HSCR) stands as a model for genetic dissection of complex diseases. In this model, a major gene, RET, is involved in most if not all cases of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal susceptibility loci under a multiplicative model. HSCR susceptibility alleles can harbor either heterozygous coding sequence mutations or, more frequently, a polymorphism within intron 1, leading to a hypomorphic RET allele. On the other hand, about 30% of HSCR are syndromic. Hitherto, the disease causing gene has been identified for eight Mendelian syndromes with HSCR: congenital central hypoventilation (CCHS), Mowat-Wilson (MWS), Bardet-Biedl (BBS), Shah-Waardenburg (WS4), cartilage-hair-hypoplasia (CHH), Smith-Lemli-Opitz (SLO), Goldberg-Sprintzsen (GSS), and hydrocephalus due to congenital stenosis of the aqueduct of sylvius (HSAS). According to the HSCR syndrome, the penetrance of HSCR trait varies from 5 to 70%. Trisomy 21 (T21) also predisposes to HSCR. We were able to collect a series of 393 patients affected by CCHS (n = 173), WS4 (n = 24), BBS (n = 51), MWS (n = 71), T21 (n = 46), and mental retardation (MR) with HSCR (n = 28). For each syndrome, we studied the RET locus in two subgroups of patients; i.e., with or without HSCR. We genotyped the RET locus in 393 patients among whom 195 had HSCR, and compared the distribution of alleles and genotypes within the two groups for each syndrome. RET acts as a modifier gene for the HSCR phenotype in patients with CCHS, BBS, and Down syndrome, but not in patients with MWS and WS4. The frequent, low penetrant, predisposing allele of the RET gene can be regarded as a risk factor for the HSCR phenotype in CCHS, BBS, and Down syndrome, while its role is not significant in MWS and WS4. These data highlight the pivotal role of the RET gene in both isolated and syndromic HSCR.

Mutations of the RET gene in isolated and syndromic Hirschsprung's disease in human disclose major and modifier alleles at a single locus.

BACKGROUND: In Hirschsprung's disease (HSCR), a hypomorphic allele of a major gene, RET, accounts for most isolated (non-syndromic) cases, along with other autosomal susceptibility loci under a multiplicative model. However, some syndromic forms of HSCR are monogenic entities, for which the disease causing gene is known. OBJECTIVE: To determine whether RET could be considered a modifier gene for the enteric phenotype on the background of a monogenic trait. METHODS: The syndromic HSCR entities studied were congenital central hypoventilation (CCHS) and Mowat-Wilson syndrome (MWS), caused by PHOX2B and ZFHX1B gene mutations, respectively. The RET locus was genotyped in 143 CCHS patients, among whom 44 had HSCR, and in 30 MWS patients, among whom 20 had HSCR. The distribution of alleles, genotypes, and haplotypes was compared within the different groups. To test the interaction in vivo, heterozygous mice were bred for a null allele of Phox2b and Ret genes. RESULTS: RET was shown to act as a modifier gene for the HSCR phenotype in patients with CCHS but not with MWS. The intestine of double heterozygote mice was indistinguishable from their littermates. A loss of over 50% of each gene function seemed necessary in the mouse model for an enteric phenotype to occur. CONCLUSIONS: In CCHS patients, the weak predisposing haplotype of the RET gene can be regarded as a quantitative trait, being a risk factor for the HSCR phenotype, while in MWS, for which the HSCR penetrance is high, the role of the RET predisposing haplotype is not significant. It seems likely that there are both RET dependent and RET independent HSCR cases.

[Iron and susceptibility to infections]. / Fer et prédisposition aux infections.

Iron is essential for proper functioning of the host immune system as well as an essential nutrient for growth of various pathogens. Iron deficiency increases infection susceptibility, specially those due to intracellular pathogens. At the opposite, excess iron stores could increase the virulence of some pathogens. Hepcidin synthesis is increased during the acute inflammation phase; leading to decreased iron intestinal absorption and retention of the metal within macrophages. This is considered to result from a defense mechanism of the child to limit the availability of iron for extracellular pathogens. On the other hand, iron affect innate immune responses by influencing IFN-γ or NF-kB pathways in macrophages. Consequently, iron enhances host resistance to intracellular pathogens but excess iron may alter immune system.

Antimicrobial treatment of infrequent bacterial species isolated in children.

This section summarizes the empirical antimicrobial treatment according to the less frequent bacterial species responsible for infection whether community-acquired or nosocomial. It specifies their role in diseases and the recommended antibiotics, taking into account their natural and most common acquired resistance and the pharmacokinetic-pharmacodynamic parameters. The advice of an infectious disease specialist or bacteriologist is recommended.

[Kikuchi-Fujimoto disease mimicking malignant lymphoma in adolescents]. / La maladie de Kikuchi-Fujimoto ; un diagnostic différentiel méconnu du lymphome chez l'adolescent.

Kikuchi-Fujimoto disease, also known as histiocytic necrotizing lymphadenitis, is a rare cause of lymphadenopathy in children. This benign disease can mimic lymphoma and misleads doctors. It was first described in Asia, where it occurred especially in young women. Recent publications show that it can also affect teenagers and young adults in Caucasian populations. The pathophysiology remains unknown. Three hypotheses have been raised for this disease: the role of viruses (in particular HHV-8), genetic predisposition (two alleles in HLA class II genes were found more frequently in patients with Kikuchi disease), and an autoimmune cause because of the correlation with lupus erythematosus. Few cases have been reported in Europe so far. In this article, we report three cases of Kikuchi disease observed in less than 2 months in a single hospital in France. All three patients were teenagers who presented with lymphadenopathy, either isolated or combined with fever, weakness, and weight loss. In all of them, the hypermetabolic activity of the lymph node on the PET scanner misled us to suspect lymphoma. The diagnosis of Kikuchi disease was finally made, for all patients, after 2 weeks in the hospital based on lymph node biopsy. Based on this report, we highlight that early biopsy in presence of lymphadenopathy can avoid unnecessary extensive investigations. Moreover, in this rare disease, it is very surprising to come across three cases that are not family-related, in such a short period of time. This strengthens the hypothesis of the possible implication of an environmental factor in the pathophysiology of Kikuchi disease.

[Visceral leishmaniasis without splenomegaly. A pediatric case report]. / Leishmaniose viscérale sans splénomégalie. À propos d'un cas chez un nourrisson.

Pediatric visceral leishmaniasis is caused by Leishmania infantum, a dog parasite transmitted to humans by the bite of the female phlebotomine sand fly. The well-known clinical triad is fever, pallor, and splenomegaly. A secondary macrophage activation syndrome (MAS) can complicate this infection, which is lethal when not treated. When MAS is observed without any explanation, a visceral leishmaniasis is highly recommended. We report a case of visceral leishmaniasis in a 21-month-old child complicated by a macrophage activation syndrome without splenomegaly. No immunodeficiency was diagnosed that could explain this unusual clinical condition. To our knowledge, this is the first case of visceral leishmaniasis without splenomegaly reported to date.

Outcomes of bacterial meningitis in children.

OBJECTIVE: Pediatricians are well aware of the immediate risks of bacterial meningitis in children. However, the long-term outcome of the disease has not been extensively studied. We aimed: (i) to evaluate the duration and quality of the long-term follow-up of children diagnosed with bacterial meningitis in a general pediatric department, (ii) to estimate the incidence of sequelae at the various stages of follow-up, and (iii) to compare our data with that of other studies. METHODS: We conducted a retrospective study and included 34 children (3 months-15 years) who had been hospitalized for bacterial meningitis in the pediatric department of a University Hospital between January 1st, 2001 and December 31st, 2013. RESULTS: Overall, 32% of patients presented with sequelae and 15% with seizures. Only one patient presented with hearing loss, but 23.5% of patients did not have any hearing test performed. Seven patients had a neuropsychological assessment performed and no severe neuropsychological sequela was observed in this group. The average follow-up duration increased during the study period (from 23 to 49months). The long-term follow-up modalities observed in other studies were highly variable. Assessing the incidence and severity of sequelae was therefore difficult. CONCLUSION: A standardized follow-up should be implemented by way of a national surveillance network of children presenting with bacterial meningitis.

[Epidemiology of tuberculosis in France]. / Epidémiologie de la tuberculose en France.

Tuberculosis remains one of the leading cause of death from infectious disease in the world. Tuberculosis control is one of the Word Health Organisation priority. One third of the population was estimated to be bacillus tuberculosis carrier responsible for 8 million of new tuberculosis cases occurring each year and nearly 2 million deaths. In Europe near 400,000 cases have been declared in 2001 with a west-east gradient in the incidence rate: 11 cases for 100,000 in west european countries, 41 per 100,000 in central european countries and 92 per 100,000 in east european countries. The number of tuberculosis cases decreased in France with an average annual decline of 7.5% between 1972 and 1988. This trend discontinued in 1989. Between 1991 and 1993 the number of reported tuberculosis increased. This excess of cases is attributable partly to HIV infection, but also to worsening in socio-economic conditions. From 1993 to 1997 the number of cases decreases again and the incidence rate is about 11 p. 100,000 and remains stable. In 2002, 6322 cases have been declared in France. There are important geographic differences. The Ile de France region has the highest incidence rate: 27.1 per 100,000. The rates of the other regions are much lower. The infection risk is different according to age, sex and nationality. People over 75 are one of the most affected age group. Children under 15 years of age represent 4.3% of cases with half of these cases before 5 years of age. As in adult, incidence rate of tuberculosis is 11 fold higher in migrants children than in french children. Less than 10 cases of tuberculous meningitis are reported annually under 15 years of age. Since 2003, mandatory notification includes tuberculous infection for children under 15 years of age. Data recorded in mandatory notification might be useful to improve tuberculosis control in France.

[Meningococcal vulvovaginitis in a prepubertal girl]. / Vulvite à méningocoque chez une fillette impubère.

Neisseria meningitidis is an uncommon cause of vulvovaginitis in the prepubertal girl. The microorganism must not be mistaken for Neisseria gonorrhoeae, as the consequences of such an error may be serious. Colonization or infection by Neisseria meningitis is not uncommon in adolescents and adults. Vulvitis, even when it is recurrent, is not per se a good indicator of sexual abuse, but some microorganisms found by vaginal swab can make it possible, likely or certain. Sexual transmission of N. meningitidis has not been described in the prepubertal child.

[Congenital malaria as a result of Plasmodium malariae in an infant born to a HIV-seropositive woman]. / Paludisme congénital à Plasmodium malariae chez un nouveau-né de mère séropostive pour le VIH.

Congenital malaria is uncommon in France. The purpose of this report is to describe a case involving a six-week-old infant who was hospitalized with fever, hepatosplenomegaly, anemia and thrombopenia. Thick and thin blood smears were positive for Plasmodium malariae. The infant responded favorably to chloroquine. Based on this experience, we performed a search of the literature to find case reports on congenital malaria in France and compare clinical and epidemiologic data with series reported in the United States and from endemic areas. The placenta appears to provide an effective barrier against Plasmodium since infection is much more common than disease. The delay for onset of clinical symptoms is longer in temperate zones than in endemic areas. The type of parasite could account for this difference since African congenital malaria are due to Plasmodium falciparum while most cases described in the United States are due to Plasmodium vivax. We also discuss the possible implications of coinfection by HIV in the mother.

[Acute transverse myelitis associated with Mycoplasma pneumoniae infection in an eight year old boy]. / Myélite aiguë transverse a Mycoplasma pneumoniae chez un enfant de huit ans.

Many Mycoplasma pneumoniae extra respiratory infections have already been reported. The authors report the case of an eight year old child, presenting with acute transverse myelitis, with a PCR proven involvement of M. pneumoniae in CSF as well as the presence of specific IgM in blood. Acute transverse myelitis may have many causes, most of the time viral. The mechanisms of neurological involvement in M. pneumoniae infections are still unclear, but several points indicate an immune reaction. Corticotherapy first i.v. then per os has proved to be an efficient treatment for acute myelitis. Antibiotherapy is discussed because of the undocumented mechanisms of neurological involvement related to the mycoplasma.

[Complement terminal fraction deficiency revealed at first invasive meningococcal infection]. / Déficit en fraction terminale du complément révélé dès le premier épisode d'infection invasive à méningocoque.

Prevalence of complement protein deficiency in the general population is rare and its association with an increased risk of meningococcal infection is well established. However, management of these patients with potentially serious infections and indications warranting a search for such a deficiency have not met with consensus. We report the case of a 3-year-old child with no significant medical history who consulted in an emergency department for a fever after a stay in Senegal. Medical explorations concluded in septicemia and meningococcal W meningitis with a favorable outcome. Secondarily, we highlighted a complete deficiency of complement component C6. We diagnosed the same deficit in his twin sister who presented no infection. A long-term prophylactic antibiotic therapy and a meningococcal conjugate vaccine A,C,Y,W were set up for the twins. Recurrent invasive meningococcal infections and highlighting certain meningococcal serogroups are currently indications for complement protein exploration. We suggest expanding the search criteria for a complement protein deficiency after a single event of invasive meningococcal infection. This is an easy, rapid, and cost-effective screening system by dosage of CH50, C3, C4, and AP50. The arrival of the new meningococcal B vaccine will contribute to improving these patients' care. Family screening is necessary for prophylactic therapy.

[Association between the presence of antiphospholipid antibodies and the occurrence of autism spectrum disorder in childhood]. / Lien entre trouble du spectre autistique de l'enfant et anticorps antiphospholipides : une étude cas-témoin.

OBJECTIVES: To evaluate the association between the presence of antiphospholipid (APL) antibodies and the occurrence of autism spectrum disorder (ASD) in childhood. METHODS: A prospective, monocentric case-control study from February 2012 to August 2014 comparing the APL antibodies of children with ASD (group 1) and children without ASD (group 2). RESULTS: Group 1 consisted of 44 children with ASD defined by clinical, genetic, metabolic, and morphological criteria. Group 2 consisted of 26 control children without ASD. One of children with ASD (2.3 %) had persistent anticardiolipin (ACL) antibodies, five of them (11.4 %) had persistent APL antibodies, one of them (2.3 %) had antiannexin V (AAV) antibodies, and two of them (4.5 %) had antiphosphatidylethanolamine (APE) antibodies. Two of the control children (7.7 %) had persistent APL antibodies. None of them had persistent ACL, AAV, or APE antibodies. Comparing group 1 and 2 children, no significant difference was found between the presence and the titers of conventional and non conventional antibodies (P<0.05). Furthermore, one mother of an autistic child (3 %) had persistent APL antibodies. CONCLUSION: ASD had no significant relation with the presence of APL antibodies.