Clinical, functional and genetic characterization of 16 patients suffering from chronic granulomatous disease variants - identification of 11 novel mutations in CYBB.

Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The most common form is the X-linked CGD (X91-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were performed. We classified them as suffering from different variants of CGD (X910 , X91- or X91+ ), according to NADPH oxidase 2 (NOX2) expression and NADPH oxidase activity in neutrophils. Eleven mutations were novel (nine X910 -CGD and two X91- -CGD). One X910 -CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single mutation using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91- -CGD were also novel; one deletion, c.-67delT, was localized in the promoter region of CYBB; the second c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91- -CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new three-dimensional model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91- -CGD patients correlates with mild clinical forms of CGD, whereas X910 -CGD and X91+ -CGD cases remain the most clinically severe forms.

Short-course antibiotic treatment of bone and joint infections in children: a retrospective study at Montpellier University Hospital from 2009 to 2013.

BACKGROUND: Acute haematogenous bone and joint infections (AHBJI) represent a diagnostic and therapeutic emergency in children, with significant potential sequelae in the case of delayed treatment. Although historically the recommendations for treatment have been based on surgery and prolonged antibiotic therapy, recent studies have demonstrated that short-course antibiotic therapy is also effective. OBJECTIVES: We evaluated a short-term antibiotic protocol for both osteomyelitis and septic arthritis in a 6 year retrospective study at the University Hospital of Montpellier. METHODS: This protocol was based on an initial intravenous treatment with a re-evaluation after 48 h and an early switch to oral therapy in the case of a favourable clinical course for a minimum total duration of 15 days. Antibiotics were selected based on local microbiological epidemiology and systematically adapted to bacteriological results. RESULTS: One hundred and seventy-six cases of AHBJI were included, comprising 56 patients with osteomyelitis, 95 with septic arthritis and 25 who had both of these. The aetiological agent was identified in 42% of the cases, with the main pathogens being Staphylococcus aureus (39%) and Kingella kingae (27%). The mean intravenous treatment duration was 4 days, while the total treatment duration was 15 days. There were no treatment failures, mild sequelae occurred in 1% of the cases and the secondary surgical revision rate was 7%. CONCLUSIONS: The results of this study are comparable to those reported for evaluations of prolonged antibiotic therapy protocols, thus indicating that a common short-term antimicrobial therapy for the management of both osteomyelitis and septic arthritis (minimum of 15 days) is a viable option for treating AHBJI in children. Further prospective studies to confirm these findings are hence warranted.

Thrombosis in the perforasome in idiopathic purpura fulminans with anti-protein S antibodies: Anatomical and clinical evidence to improve management.

Idiopathic purpura fulminans (IPF) is a rare and severe form of purpura fulminans caused by acquired protein S deficiency. It can lead to severe thrombotic complications, such as large skin necrosis and amputation. The lesions almost exclusively affect the lower limbs, and their distribution is similar among patients with IPF, unlike classical purpura fulminans lesions. Our hypothesis is that vascular structures called perforasomes may be involved in IPF, possibly caused by protein S deficiency. We analyzed all case reports and case series published in the literature that provided sufficient data for an anatomical study of limb injuries. For precise localization of areas of necrosis, we examined each case using descriptions and images to determine whether they overlapped with vascular territories that include perforasomes. We analyzed twelve cases from the literature and identified six vascular territories: the anterolateral, anteromedial, and posterior territories of the upper leg, as well as the anterolateral, anteromedial, and posterolateral territories of the lower leg. For each territory, we described the most probable vascular damage and the corresponding perforasome. IPF is a complex multifactorial disease in which a direct involvement of perforating arteries may be suspected and taken into account in the surgical of lesions.

Post-viral idiopathic purpura fulminans is associated with inherited thrombophilia and anti-cardiolipin antibodies.

Introduction: Idiopathic purpura fulminans (IPF) is a rare and severe coagulation disorder, associated with transient anti-protein S (anti-PS) antibodies in the context of post-viral infection such as varicella. Anti-protein S antibodies are frequently found in the context of varicella, in contrast with the rarity of IPF. Other factors such as anti-phospholipid antibodies (APL) and inherited thrombophilia may be associated with severe vascular complication. Method: This is an ancillary study of a French multicenter retrospective series and systematic review of literature. We analyzed patients who were tested for inherited thrombophilia, namely antithrombin, protein C, protein S deficiency; prothrombin gene G20210A polymorphism (FII:G20210A),Factor V R506Q polymorphism (FV:R506Q); and/or for APL (lupus anticoagulant (LA), anti-cardiolipin antibodies (ACL), or anti-beta 2-GPI antibodies (Aß2GP1). Results: Among the 25 patients tested for inherited thrombophilia, 7 (28%) had positive results. Three had FV R506Q, two FII:G20210A, one compound heterozygote FV:R506Q associated to FII:G20210A, and one protein C deficiency. APL testing was performed in 32 patients. It was positive in 19 patients (59%): 17 ACL (53%), 5 LA (16%), 4 Aß2GP1 (13%). The risk of severe complications was not associated with presence of inherited thrombophilia or APL presence, with RR: 0.8 [95% CI: 0.37-1.71], p = 1 and RR: 0.7 [95% CI: 0.33-1.51], p = 0.39, respectively. We found a high prevalence of inherited thrombophilia or APL in a population of patients with IPF. However, we do not find an association with the occurrence of severe vascular complications or venous thromboembolism.

Pediatric deep neck infections: Clinical description and analysis of therapeutic management.

OBJECTIVES: The aim of our study was to describe clinical presentations, bacteriological results, and therapeutic management in a pediatric population presenting with acute pharyngeal suppuration. A further aim was to identify clinical, bacteriological, and radiological predictors of success associated with exclusive medical treatment. METHOD: A retrospective study was carried out including patients under 18 years of age hospitalized between January 1, 2015 and December 31, 2017 in our center for acute pharyngeal suppuration. We identified three groups of patients: group A, treated with exclusive intravenous antibiotics; group B, surgically treated after 48 h of appropriate antibiotic therapy, due to persistent fever and/or clinical worsening and/or persistence of a collection on follow-up imaging; group C, surgically treated as first-line therapy in association with intravenous antibiotics. A total of 83 patients were included: 36 in group A, 12 in group B, and 35 in group C. These three groups were compared for several variables: age of the patients, polynuclear neutrophil counts, diameter of the collections (the largest diameter found on imaging), duration of antibiotic therapy, delay before return to apyrexia, and hospitalization duration. RESULTS: A neck mass and torticollis were present, respectively, in 48.8 and 47.6% of cases. No breathing difficulties were reported. Streptococcus pyogenes was the most frequently identified microorganism. The average diameter of the collections from patients treated surgically as first-line therapy (group C) was significantly larger than that of the patients treated with antibiotics (group A) (27.89 mm vs. 18.73 mm, respectively, p = 0.0006). All the patients who required surgery despite 48 h of appropriate antibiotic therapy (group B) had collections with diameters greater than or equal to 15 mm. There was no significant difference between the groups concerning hospitalization duration. CONCLUSION: Exclusive medical treatment is associated with a high cure rate, mainly for collections with small diameter. We recommend special attention to patients treated with first-line exclusive intravenous antibiotic therapy and with a collection diameter greater than or equal to 15 mm.

Intrafamilial cluster of pulmonary tuberculosis due to Mycobacterium bovis of the African 1 clonal complex.

A new clonal complex of Mycobacterium bovis present at high frequency in cattle from west central African countries has been described as the African 1 (Af1) clonal complex. Here, the first intrafamilial cluster of human tuberculosis cases due to M. bovis Af1 clonal complex strains is reported. We discuss hypotheses regarding modes of transmission.

[Turicella otitidis infection: otitis media complicated by mastoiditis]. / Infections àTuricella otitidis: à propos d'un cas d'otite moyenne compliquée de mastoïdite.

UNLABELLED: Turicella otitidis is a nonfermentative, Gram-positive bacillus, which is almost exclusively isolated from the ear. Few cases of infection caused by T. otitidis have been reported in the literature, but the pathogenic potential of this little-known bacterium remains controversial, particularly in acute and chronic otitis media. CLINICAL OBSERVATIONS: A retrospective study of T. otitidis isolated in the University Hospital of Montpellier in 2004 found T. otitidis in 13 patients. Among them, a 3-year-old girl had presented with acute and perforated otitis media and mastoiditis caused by T. otitidis, thereby confirming the pathogenic effect of this bacterium. CONCLUSION: T. otitidis is relatively frequently isolated from middle ear samples in healthy patients. However, T. otitidis has been implicated in serious cases of infection and should be considered an opportunistic pathogen. Its clinical significance can be difficult to establish and each case should be carefully interpreted. From a bacteriological point of view, T. otitidis should be precisely identified to obtain more information regarding its role in clinical pathology.

Epidemiological survey in a day care center following toddler sudden death due to human metapneumovirus infection.

We report the sudden death of a 33-month-old child owing to acute respiratory distress syndrome due to human metapneumovirus (hMPV) infection. Of 30 children attending the same day care centre, 26% and 59% had hMPV and multiple infections, respectively; three of six children with pneumonia had a diagnosis of hMPV. hMPV infection is common in childhood viral co-infections but it can cause sudden death.

Pediatric angiostrongyliasis.

Angiostrongyliasis, the leading cause worldwide of eosinophilic meningitis, is an emergent disease due to Angiostrongylus cantonensis larvae, transmitted accidentally to humans. Contamination of children usually occurs by direct contact with an infected mollusk. Eosinophilic meningoencephalitis is the major clinical feature of this parasitic infection in humans. It is usually benign for adults, but more severe for children. Clinical symptoms usually combine fever, meningitis, and neurological signs (somnolence, moaning, hypotonia, convulsions, and increased intracranial pressure). Presumptive diagnosis of human angiostrongyliasis is based on epidemiologic characteristics, clinical symptoms, medical history, and laboratory findings, in particular, hypereosinophilia in blood and cerebrospinal fluid. Treatment is based on corticosteroids associated with anthelmintics. This work reviews the diagnosis and treatment of this life-threatening (especially in children) parasitic disease and the need for preventive action.

[Thromboembolic disease in pediatric oncology]. / La maladie thrombo-embolique veineuse en oncologie pédiatrique.

The survival rate of children with cancer is now close to 80 %, as a result of continuous improvement in diagnostic and treatment procedures. Prevention and treatment of treatment-associated complications is now a major challenge. Thromboembolic venous disease, due to multifactorial pathogenesis, is a frequent complication (up to 40 % asymptomatic thrombosis in children with cancer), responsible for significant morbidity. Predominantly in children with acute lymphoblastic leukemia, lymphoma, or sarcoma, thromboembolic disease justifies primary prophylaxis in certain populations at risk, whether genetic or environmental. The curative treatment, well codified, is based on the administration of low-molecular-weight heparin. In the absence of robust pediatric prospective studies, this article proposes a concise decision tree summarizing the preventive and curative strategy.

[DRESS syndrome]. / Le syndrome DRESS: une toxidermie à connaître.

DRESS syndrome (drug reaction eosinophilia and systemic symptoms) is a rare and serious drug toxidermia with potentially multiple organ dysfunctions. This report relates the case of a 9-year-old girl who presented a right cervical and mediastinal adenopathy with a mediastinal lump, fever, and deterioration of the general condition. The hospital assessment concluded in an abscess due to Staphylococcus aureus secreting a Panton-Valentine toxin with nonsevere pleuritis and pericarditis. The outcome was favorable with antibiotic treatment consisting of amoxicillin-acid clavulanic, amikacin, and clindamycin followed by oxacillin, rifampicin, and colchicine. On the 25th day of treatment, she presented recurrence of fever with a generalized rash, moderate hepatic cytolysis, hypereosinophilia, with the presence of activated lymphocytes that were further suggestive of visceral DRESS syndrome. A skin biopsy was performed that confirmed the diagnosis. The outcome was favorable after stopping all ongoing treatments even though none of the administered treatments were classically responsible for the syndrome. Symptomatic treatments (antihistaminic and topical steroids) were also administered. Patch tests, performed secondarily, were positive to penicillins; amoxicillin-clavulanic acid or oxacillin were then suspected of being responsible for the DRESS syndrome. Potentially serious, the DRESS syndrome should be considered together with atoxic epidermal necrolysis or Stevens-Johnson syndromes in the case of any rash appearing after drug administration, especially in the presence of face and eyelid edema.

Mucosal relapse of visceral leishmaniasis in a child treated with anti-TNFα.

Visceral leishmaniasis is an enzootic parasitosis present across the Mediterranean Basin. Some consider it an opportunistic parasite. We report the case of a girl treated with anti-tumour necrosis factor alpha (anti-TNFα) for juvenile idiopathic arthritis who had previously presented with visceral leishmaniasis. Two and a half years later, she presented a tumour-like mass in the nasal mucous membrane caused by Leishmania parasites. Leishmania infantum is classically responsible for visceral leishmaniasis, but pure mucocutaneous leishmaniasis has also been described. To our knowledge, this is the first observation of a recurrence of visceral leishmaniasis in the mucocutaneous form. The occurrence of atypical forms and presentations in those on anti-TNF therapy should be considered.

[Deep venous thrombosis complications during infections in pediatric patients: analysis of a series of 24 cases]. / Infections et thromboses veineuses en pédiatrie : analyse d'une série de 24 cas.

Venous thromboembolism disease (VTE) is rare in children (5.3 of 10,000 hospitalized children). However, morbidity and mortality are high, especially when the child is already suffering from severe sepsis. We report an analytical study of 24 cases of deep venous thrombosis occurring in children during infection, recorded at the Montpellier University Hospital between 1999 and 2009. Many parameters were studied in each population (age, sex, familial and personal history of thrombosis, history of thrombophilia, the presence of a venous catheter, a causative organism, time to onset of thrombus, topography of lesions, acquired abnormalities of hemostasis, and thrombosis prophylaxis). The children were aged from 1 day of life to 16 years. Thromboses occurred in two clinical contexts: "contact" thrombosis (which appeared near the infection) and disseminated thrombosis. This is an early complication because in most of the cases, it appeared in the first 10 days of sepsis. Infection and coagulation appear to be closely related and the states of latent or decompensated disseminated intravascular coagulation are common. Nevertheless, it is not possible to predict the occurence of a thrombotic event. The presence of risk factors (venous catheters, acquired thrombophilia, or constitutional thrombophilia) may increase the thrombogenic potential of the infection. VTE should always be suspected and sought in case of an unfavorable clinical course, and routine prophylaxis of thrombosis during sepsis should be discussed.

[Mitochondrial neurogastrointestinal encephalopathy disease]. / L'encéphalomyopathie neuro-gastro-intestinale mitochondriale : un tableau d'anorexie mentale atypique.

Mitochondrial neurogastrointestinal encephalopathy disease (MNGIE) is a rare autosomal-recessive syndrome, resulting from mutations in the TYMP gene, located at 22q13. The mutation induces a thymidine phosphorylase (TP) deficit, which leads to a nucleotide pool imbalance and to instability of the mitochondrial DNA. The clinical picture regroups gastrointestinal dysmotility, cachexia, ptosis, ophthalmoplegia, peripheral neuropathy, and asymptomatic leukoencephalopathy. The prognosis is unfavorable. We present the case of a 14-year-old Caucasian female whose symptoms started in early childhood. The diagnosis was suspected after magnetic resonance imaging (MRI), performed given the atypical features of mental anorexia, which revealed white matter abnormalities. She presented chronic vomiting, postprandial abdominal pain, and problems gaining weight accompanied by cachexia. This diagnosis led to establishing proper care, in particular an enteral and parenteral nutrition program. There is no known specific effective treatment, but numerous studies are in progress. In this article, after reviewing the existing studies, we discuss the main diagnostic and therapeutic aspects of the disease. We argue for the necessity of performing a cerebral MRI given the atypical features of a patient with suspected mental anorexia (or when the clinical pattern of a patient with mental anorexia seems atypical), so that MNGIE can be ruled out.

[Bronchopulmonary squamous cell carcinoma associated with HPV 11 in a 15-year-old girl with a history of severe recurrent respiratory papillomatosis: a case report]. / Papillomatose laryngée sévère évoluant vers un carcinome bronchopulmonaire associé à HPV 11 chez une enfant de 15 ans : à propos d'un cas.

Malignant transformation of juvenile-onset recurrent respiratory papillomatosis (RRP) is a rare event and the cases reported have been mainly observed in adults. We report the case of a 15-year-old girl with a history of severe RRP who died of a HPV 11-associated bronchopulmonary squamous cell carcinoma with pericardial invasion. HPV 11 was identified in nasopharyngeal and tracheal papillomas, as well as in the pericardial fluid. HPV 11 isolate was further analyzed by amplification and sequencing of the E1, E2, E4, E6, and E7 genes. Only one amino acid substitution in E4 due to natural polymorphism was observed. Exons 5-9 of the patient's tumor protein 53 (TP53) gene were sequenced and no mutations were identified. This observation confirms that malignant conversion of juvenile-onset RRP associated with HPV 11 to squamous cell carcinoma may arise in children. HPV 11-induced carcinogenesis needs to be further investigated.

[Childhood parvovirus B19 encephalitis]. / Encéphalite à parvovirus B19 de l'enfant.

INTRODUCTION: Human parvovirus B19 (PVB19) causes erythema infectiosum or 5(th) disease in childhood, which mainly affects children between 3 and 15 years of age. PVB19 infections have also been described in association with a variety of neurologic manifestations including encephalitis. CASE REPORT: This 3-year 8-month-old boy developed febrile encephalitis (mental status change with seizures and left limb hypertonia) associated with a rash. The electroencephalographs revealed focal slowing with some spikes in front of the left centro-temporo-occipital areas ; bacteriological and biochemical cerebrospinal fluid (CSF) analysis were normal, brain radiologic studies (tomography and magnetic resonance imaging) were normal. The diagnosis of encephalitis associated with PVB19 primo infection was based on viral DNA detection in the serum and CSF using PCR and on the specific immunoglobulin M (without immunoglobulin G) detection in the serum. DISCUSSION: In France, encephalitis etiology is unknown in 48% of the cases. PVB19 accounts for 4.3% of undiagnosed meningoencephalitis in children. Although there is no specific sign, seizures and rash are reported in about one-half and one-quarter of cases, respectively. CONCLUSION: Even if PVB19 research is not cited in the French or American infectious disease society recommendations on the diagnosis and management of infectious encephalitis, this virus may be responsible, especially in cases of child febrile rash. Therefore, PVB19 research seems reasonable if the clinical presentation is concordant in children due to its diagnostic simplicity and efficacy.

[Multifocal inflammatory syndrome after invasive infection due to an M1 strain of Streptococcus pyogenes]. / Manifestations inflammatoires réactionnelles multifocales après infection invasive à Streptococcus pyogenes de type M1.

We report on a case of Streptococcus pyogenes invasive disease with toxic shock syndrome due to an M1 strain producing SpeA and SmeZ superantigenic toxins. Post-streptococcal sequelae included several episodes of reactive arthritis and orchitis whose outcome was favorable with corticosteroid therapy. Invasive streptococcal infections are increasingly reported and may associate septic, toxinic, and immunological diseases. High-grade systemic inflammation may induce nonsuppurative complications and autoimmune diseases by molecular mimicry. Among them, reactive arthritis has been recognized as a separate entity from acute rheumatic fever and post-streptococcal orchitis has not been described before. Treatment should be quickly started and should be effective on the etiologic agent but also on its toxins due to the severity of the invasive infections associated with the spread of highly virulent bacterial clones and the potential development of multifocal nonsuppurative sequelae.

[Gut translocation septicemia in infant]. / Septicémie par translocation d'origine digestive chez l'enfant.

Intestinal microbiotype necessary for life is a source of complications in childhood. Bacterial translocation is responsible of endogenous septicaemia and invasive complications. We report five cases of severe invasive infections associated with diarrhoea, digestive bleeding or sepsis. Biological parameters for inflammation are highly positive, and blood cultures reveal bacterial identification: salmonella enteridis, enterobacter cloacae, campylobacter jejuni, escherichia coli or clostridium difficile. We describe the predisposing factors and susceptibility status to develop translocation: invasive diarrhoea, asplenia, gasto-intestinal disease… All invasive infections in children require etiological approach with the possibility of an endogenous septicaemia (bacterial translocation). This approach minimises the nosocomial features undercurrent in these invasive infections, and leads also to other alternative preventive measures: antibiotic association, maintaining an enteral nutrition, pre or probiotic use, specific digestive decontamination.