[An intracranial haemorrhage in a febrile newborn]. / L'image du mois. Une hémorragie intracrânienne chez un nouveau-né fébrile.

A 15 days old newborn was admitted to the emergency room for a recent fever onset. In newborns, the priority is to rule out any bacterial infection and initiate broad spectrum antibiotics. The hemorrhagic appearance of the cerebrospinal fluid after lumbar puncture can sometimes be the only sign to suspect, other than obvious infectious aetiology, an intracranial haemorrhage.

: Un nouveau-né de 15 jours est admis en salle d'urgence pour de la fièvre. Au vu de l'immaturité immunitaire des nouveau-nés et selon les recommandations internationales, la priorité est d'exclure une infection d'origine bactérienne et d'administrer une antibiothérapie intraveineuse empirique. Lors de la réalisation du bilan étiologique, l'aspect hémorragique du liquide céphalo-rachidien peut être le témoin d'un syndrome méningé d'étiologie autre qu'infectieuse, et notamment d'une hémorragie intracérébrale.

[Food protein-induced enterocolitis syndrome (FPIES) : a poorly known type of food allergy]. / Cas clinique. Le syndrome d'entérocolite induite par les protéines alimentaires (SEIPA) : une forme peu connue d'allergie alimentaire.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. Its pathophysiology is still poorly understood. FPIES mainly affects infant and young children, although cases have been reported in adults. Its symptomatology is restricted to gastrointestinal manifestations and the onset of allergic reaction subsequent to exposure is delayed. The most common culprit for children is cow's milk. Initial clinical presentation of FPIES is oftentimes acute, though it can also be chronic. Diagnosis relies on clinical criteria, which have been recently redefined and subject to international consensus. Through two clinical cases, this report aims to describe the characteristics of this emerging disease as well as delineate the treatment thereof.

Le syndrome d'entérocolite induite par les protéines alimentaires (SEIPA) est une allergie alimentaire non IgE-médiée dont la physiopathologie est encore mal connue. Elle touche principalement le jeune enfant, bien que des cas chez l'adulte soient décrits. Elle se caractérise par des symptômes uniquement digestifs et d'apparition retardée lors de l'exposition à l'allergène. L'aliment le plus fréquemment incriminé chez l'enfant est le lait de vache. Le SEIPA peut se présenter sous deux formes, aiguë ou chronique, la forme aiguë étant la plus fréquente. Son diagnostic repose, essentiellement, sur des critères cliniques qui ont été redéfinis, récemment, lors d'un consensus international. Ce travail, à travers deux cas cliniques, a pour objectif de décrire les caractéristiques de cette maladie émergente et de discuter des grandes lignes de son traitement.

[Coexistence of sickle cell disease and systemic lupus erythematosus]. / Co-existence d'une drépanocytose et d'un lupus érythémateux disséminé.

Sickle cell disease and systemic lupus erythematosus (SLE) are two distinct chronic conditions sharing many clinical manifestations. Coexisting of these two diseases is rare, but it is important to make the diagnosis of SLE in sickle cell patients to initiate appropriate treatment and limit the risk of complications. High titers of autoantibodies have been reported in sickle cell patients as well as a higher risk of immune deficiency. These patients present a defective activation of the alternative pathway of the complement that increases the risk of infection with encapsulated bacteria and a difficulty in eliminating antigenes that could predispose to autoimmune diseases. We report three case of children with sickle cell disease. They developed symptoms initially attributed to sickle cell disease, but after investigations revealed an underlying SLE.

La drépanocytose et le lupus érythémateux disséminé (LED) sont deux pathologies chroniques distinctes partageant certaines manifestations cliniques communes. La coexistence de ces deux pathologies est rare. Cependant, il est important de faire le diagnostic de LED chez ces patients drépanocytaires afin de pouvoir instaurer un traitement adéquat et limiter le risque de complications. Des hauts titres d'anticorps ont été décrits chez les patients drépanocytaires ainsi qu'un risque plus élevé de déficits immunitaires. Ces patients présentent un défaut dans l'activation de la voie alterne du complément qui augmente le risque d'infection à bactéries encapsulées et un défaut d'élimination d'antigènes qui pourrait prédisposer aux maladies auto-immunes. Nous décrivons le cas de trois patientes drépanocytaires majeures. Elles ont développé des symptômes attribués initialement à la drépanocytose, mais qui se sont par la suite révélés être un LED.

[Recurrence of congenital diaphragmatic hernia]. / Une récidive de hernie diaphragmatique congénitale.

Through the case report of a child who had had a congenital diaphragmatic hernia (cdh) and then relapsed 8 months after initial surgery, the various risk factors related to a cdh, its pre- and postnatal management as well as some long-term complications are discussed.

Par le biais du cas clinique d'un enfant qui a été opéré d'une hernie diaphragmatique congénitale (HDC) et qui a récidivé 8 mois plus tard, les différents facteurs de risques liés à la HDC, sa prise en charge ante et post-natale ainsi que quelques possibles complications à long terme sont discutés.

[How I treat a neonatal Herpes simplex virus infection]. / Comment je traite l'infection néonatale à Herpès simplex.

Neonatal herpes simplex virus infection is rare but important to recognize because of the major risk of sequelae or death. The diagnosis is mainly based on specific clinical and biological analyses. Aciclovir is the treatment of choice, duration of administration depending on the severity of the disease. A six-month treatment with suppressive-dose oral aciclovir is recommended to improve the child's prognosis. From a clinical case, we reviewed the literature to improve the management.

L'infection néonatale à Herpès est peu fréquente mais importante à reconnaître vu le risque important de séquelles ou de mortalité. Le diagnostic repose principalement sur des analyses cliniques et biologiques spécifiques. L'aciclovir est le traitement de choix, la durée d'administration varie en fonction de l'importance de l'atteinte. Un traitement de 6 mois par voie orale est conseillé pour améliorer le pronostic de l'enfant. A partir d'un cas clinique, nous avons revu la littérature pour connaître les dernières recommandations afin d'améliorer la prise en charge.

[Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations in children]. / Le cas clinique du mois. Maladie de Rendu-Osler et malformations artério-veineuses pulmonaires chez l'enfant.

Hereditary hemorrhagic telangiectasia is a constitutional vascular dysplasia characterized by chronic epistaxis, mucocutaneous and visceral telangiectasias and arteriovenous malformations. Apart from family screenings, the disease is rarely diagnosed during the pediatric age given the late advent of typical clinical symptoms. Nevertheless, arteriovenous malformations are sometimes already present at a young age with significant morbidity risk. Therefore, it is important to establish an early diagnosis. We describe two pediatric cases of hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations with divergent clinical presentation.

La maladie de Rendu-Osler, ou télangiectasies hémorragiques héréditaires, est une dysplasie vasculaire constitutionnelle. Elle se caractérise par des épistaxis spontanées et récidivantes, des télangiectasies cutanéo-muqueuses et viscérales et des malformations artério-veineuses. En dehors d'un dépistage familial, cette maladie est rarement diagnostiquée à l'âge pédiatrique étant donné l'apparition tardive des symptômes cliniques typiques. Cependant, les malformations artério-veineuses sont parfois présentes dès le plus jeune âge avec des risques importants de morbidité, d'où l'importance d'un diagnostic précoce. Nous décrivons deux cas pédiatriques de maladie de Rendu-Osler et de malformations artério- veineuses pulmonaires avec des présentations cliniques très différentes.

[Prostaglandins and the immune response at the intestinal submucosal level. A potential site for interference with the repeated use of paracetamol and ibuprofen at a young age?]. / Les prostaglandines et l'immunité du chorion sous-muqueux intestinal. Questions à propos de l'usage répété du paracétamol et de l'ibuprofène en bas âge.

Immune deviations have been shown to exponentially increase in young children. As a consequence, research investigating possible environmental reasons for this increase is considered a public health priority. An improved understanding of the immunity of the intestinal submucosal lamina propria has demonstrated the importance of prostaglandins (PGE2s) on its local development with general immune consequences further on. PGE2s appear at this intestinal submucosal level from the metabolism of arachidonic acid mediated by type-2 cyclooxygenases (COX2s) situated in the membranes of many immune cells. The potential risk of repeated inhibition of PGE2 synthesis at a young age has been demonstrated in experiments with animals systemically exposed to a non-steroidal anti-inflammatory drug (NSAID). The repeatedly exposed animal cannot develop tolerance to food antigens and exhibits autoimmune deviations. Acetaminophen (paracetamol) and ibuprofen are analgesic and antipyretic medications given to children either alone or in combination, most often without medical prescription. Recently, it has been demonstrated that paracetamol, like ibuprofen, also carries, besides its central action, a non-selective inhibitory action on peripheral COXs. However, this inhibitory action only relates to physiological concentrations of arachidonic acid and explains the difference in their respective anti-inflammatory effects. Since recently published data have repeatedly reported an increase of immune deviations associated with paracetamol exposure at a young age, it appears important to better understand the possible negative impact of excessive and repetitive inhibitions of the physiological synthesis of prostaglandins by COX2s in childhood during which all immune mechanisms are built up at the intestinal submucosal level. Therefore, a well-designed prospective strategy for pharmacovigilance of these COX inhibitors repeatedly given during childhood is urgently needed.

[Implementation of the intestinal micro flora in the early stage and adequate immunity later on]. / Etablissement du microbiote intestinal en bas âge et qualité de l'immunité ultérieure.

The pre and postnatal development of human immunity are remarkably continuous. The feto-placental unit builds up to promote a climate of immune tolerance specifically driven in this way by the maternal immunity. The process of birth triggers the development of the infant's postnatal immunity, in first place through the bacterial colonisation of a sterile intestinal mucosa. The progressive immune response stabilisation at the sub-mucosa level during the first year of life will arise from the interface between the host and its microflora. It will take place progressively and will occur thanks to a variety of successive and complementary very complex immune mechanisms, under the influence of a rich and diversified intestinal microbiotia. Solid scientific arguments allow hypothesising that immune deviances later in life could be the consequence of an inadequate bacterial pressure on the intestinal mucosa at the early stage. A variety of epigenetic modifications taking place in this early stage could account for the deviant programming of later immunity. Each health care provider should acknowledge that some therapeutic and nutritional interventions during the first year of life may interfere with this complex immune development, giving rise to a risk of increasing immune deviancies later on.

Value of intravenous 6-mercaptopurine during continuation treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG.

Between November 1990 and November 1996, EORTC Children Leukemia Group conducted a randomized trial in de novo acute lymphoblastic leukemia and lymphoblastic non-Hodgkin's lymphoma patients using a Berlin-Frankfurt-Munster protocol to evaluate the monthly addition of intravenous 6-mercaptopurine (i.v. 6-MP) (1 g/m(2)) to conventional continuation therapy comprising per oral MTX weekly and 6-MP daily. Only during the first 18 months of the randomization period, 6-MP p.o. was interrupted for 1 week after each i.v. 6-MP. A total of 877 patients was randomized to either no i.v. 6-MP (Arm A) or additional i.v. 6-MP (Arm B). A total of 217 relapses (91 in Group A vs 128 in Group B) and 13 deaths in CR (5 vs 8) were reported; a total of 134 patients (55 vs 79) died. The median follow-up was 7.6 years. At 8 years, the disease-free survival rate was lower (P=0.005) in Arm B (69.1% (s.e.=2.2%)) than in Arm A (77.9% (s.e.=2.0%)), and the hazard ratio was 1.45 (95% CI 1.12-1.89). In conclusion, as delivered in this study, i.v. 6-MP was detrimental to event-free survival.

Treatment of childhood autoimmune haemolytic anaemia with rituximab.

Autoimmune haemolytic anaemia commonly has a severe course in young children, thus requiring multiple immunosuppressive treatments. Five children with refractory idiopathic autoimmune haemolytic anaemia, and one child with the disease after bone-marrow transplantation, were treated with rituximab-a monoclonal antibody against CD20. Tolerance of the treatment was good. However, circulating Bcells were absent and hypogammaglobulinaemia was seen for 9 months after treatment. All patients remained in complete remission 15-22 months after the start of rituximab therapy. Corticosteroids and immunosuppressive drugs were stopped or their dose markedly reduced. We suggest that rituximab could be a valuable treatment for autoimmune haemolytic anaemia, although a long-lasting but transient B-cell deficiency develops.

[Immune deficiencies: diagnosis, management, some perspectives]. / Déficits immunitaires primaires: diagnostic, prise en charge, quelques perspectives.

Severe primary immunodeficiencies (PID) are rare; their global incidence is comparable to that of childhood leukemia; they include more than 100 different entities. Clinical manifestations are: unusually severe or frequent infections or infections that do not respond to adequate treatment; an increased risk of certain malignancies; sometimes auto-immune manifestations. Delayed diagnosis and management of PID can lead to severe and irreversible complications or to death. PID can become manifest only in the adult; in common variable immune deficiency, the median age at diagnosis is between the 2nd and the 3rd decade of life. PID are often transmitted genetically; recent progresses in molecular biology have allowed more precise and earlier, including antenatal, diagnosis. Molecular treatment of 3 infants with a severe immunodeficiency has recently been achieved in April 2000. Those progresses were mostly based on the study of immunodeficiency databases. We present here the work of a Belgian group specialized in PID; meetings have started in June 1997. This group establishes guidelines for the diagnosis and treatment of PID, adapted to the local situation. The elaboration of a national register of PID is also underway; this has to provide all guaranties of anonymity to patients and families. Such a register already exists at the European level; it has provided the basis for new diagnostic and therapeutic possibilities. The inclusion of Belgian data in this register should allow essential progresses essential for our patients.

Five years of experience with hydroxyurea in children and young adults with sickle cell disease.

The short-term beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) has been proven by randomized studies in children and adults. The Belgian registry of HU-treated SCD patients was created to evaluate its long-term efficacy and toxicity. The median follow-up of the 93 patients registered is 3.5 years; clinical and laboratory data have been obtained for 82 patients at 1 year, 61 at 2 years, 44 at 3 years, 33 at 4 years, and 22 after 5 years. On HU, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirm a significant difference in the number of hospitalizations (P =.0002) and days in the hospital (P <.01), throughout the treatment when compared to prior to HU therapy. The probabilities of not experiencing any event or any vaso-occlusive crisis requiring hospitalization during the 5 years of treatment were, respectively, 47% and 55%. On HU, the rate per 100 patient-years of severe events was estimated to be 3.5% for acute chest syndrome, 1.2% for aplastic crisis, 0.4% for splenic sequestration; it was 0% for the 9 patients with a history of stroke or transient ischemic attack followed for an average of 4 years. No important adverse effect occurred. Long-term chronic treatment with HU for patients with SCD appears feasible, effective, and devoid of any major toxicity; in patients with a history of stroke, HU may be a valid alternative to chronic transfusion support. (Blood. 2001;97:3628-3632)

Value of high-dose cytarabine during interval therapy of a Berlin-Frankfurt-Munster-based protocol in increased-risk children with acute lymphoblastic leukemia and lymphoblastic lymphoma: results of the European Organization for Research and Treatment of Cancer 58881 randomized phase III trial.

PURPOSE: The European Organization for Research and Treatment of Cancer 58881 study was designed to test in a prospective multicentric randomized trial the value of high-dose (HD) intravenous (IV) cytarabine (Ara-C) added to HD IV methotrexate (MTX) to reduce the incidence of CNS and systemic relapses in children with increased-risk acute lymphoblastic leukemia (ALL) or stage III and IV lymphoblastic lymphoma treated with a Berlin-Frankfurt-Munster (BFM)-based regimen. PATIENTS AND METHODS: After completion of induction-consolidation phase, children with increased-risk (risk factor > 0.8 or T-lineage) ALL or stage III and IV lymphoblastic lymphoma were randomized to receive four courses of HD MTX (5 g/m(2) over 24 hours every 2 weeks) and four intrathecal administrations of MTX (Arm A) or the same treatment schedule with additional HD IV Ara-C (1 g/m(2) in bolus injection 12 and 24 hours after the start of each MTX infusion) (Arm B). RESULTS: Between January 1990 and January 1996, 653 patients with ALL (593 patients) or lymphoblastic lymphoma (60 patients) were randomized: 323 were assigned to Arm A (without Ara-C) and 330 to Arm B (with Ara-C). A total of 190 events (177 relapses and 13 deaths without relapse) were reported, and the median follow up was 6.5 years (range, 2 to 10 years). The incidence rates of CNS relapse were similar in both arms whether isolated (5.6% and 3.3%, respectively) or combined (5.3% and 4.6%, respectively). The estimated 6-year disease-free survival (DFS) rate was similar (log-rank P =.67) in the two treatment groups: 70.4% (SE = 2.6%) in Arm A and 71.0% (SE = 2.5%) in Arm B. The 6-year DFS rate was similar for ALL and LL patients: 70.2% (SE = 1.9%) versus 76.3% (SE = 5.6%). CONCLUSION: Prevention of CNS relapse was satisfactorily achieved with HD IV MTX and intrathecal injections of MTX in children with increased-risk ALL or stage III and IV lymphoblastic lymphoma treated with our BFM-based treatment protocol in which cranial irradiation was omitted. Disappointingly, with the dose schedule used in this protocol, HD Ara-C added to HD MTX, although well tolerated, failed to further decrease the incidence of CNS relapse or to improve the overall DFS.

Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome.

Omenn syndrome (OS) is an inherited disorder characterized by an absence of circulating B cells and an infiltration of the skin and the intestine by activated oligoclonal T lymphocytes, indicating that a profound defect in the lymphoid developmental program could be accountable for this condition. Inherited mutations in either the recombination activating genes RAG1 or RAG2, resulting in partial V(D)J recombinase activity, were shown to be responsible for OS. This study reports on the characterization of new RAG1/2 gene mutations in a series of 9 patients with OS. Given the occurrence of the same mutations in patients with T-B-severe combined immune deficiency or OS on 3 separate occasions, the proposal is made that an additional factor may be required in certain circumstances for the development of the Omenn phenotype. The nature of this factor is discussed.

New dysostosis showing multilevel absence of vertebral pedicles: unique developmental anomaly of vertebral arches?

We report on an apparently normal child who shows hypopaplasia of the vertebral pedicles and posterior arches of several cervical, thoracic, and lumbar vertebrae with normally fused spinous apophyses, hypoplastic sacrum, lumbar epidural lipomatosis, synostoses of some cervical vertebral disks, and sacral spina bifida. The most likely mechanism is an abnormal differentiation of the spinal processes, due most probably to an absence of differentiation in cartilage of the dense mesenchyme forming their most anterior part. Because the anomalies affect multiple levels, we highly suspect a genetic basis to this unusual dysostosis affecting the development of the posterior sclerotomes.

Stroke and cerebral infarcts in children infected with human immunodeficiency virus.

OBJECTIVE: To study the causes of stroke and cerebral infarcts in children infected with the human immunodeficiency virus (HIV)-type 1. DESIGN: Case series. PATIENTS: Four of 380 HIV-infected children followed up in a 10-year period in our department who had a stroke with evidence of cerebral infarcts on radiological imaging. RESULTS: The four patients were severely immunodepressed, but their clinical status and outcome were different. Aneurysmal dilation of major cerebral arteries and thrombosis of these arteries or of small cortical vessels were discovered in two patients. Both patients had a history of frequent infections and had suffered repeated neurological events that resulted in severe clinical deterioration or death. An infectious causative agent was strongly suspected but was not detected. The other two patients had a more favorable outcome. An isolated cerebrovascular thrombosis was found in one patient, while in the other, HIV-1-related focal necrosis was suggested by the lack of permanent cerebrovascular abnormalities or thrombosis and by signs of necrosis in biopsy specimens of the brain. CONCLUSION: Stroke and cerebral infarcts in HIV-1 infected children have different causes and different prognoses.