Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency.

Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) RIPK3 variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection. The patient's fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient's cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-ß and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient's human pluripotent stem cell (hPSC)-derived cortical neurons displayed impaired cell death and enhanced viral growth after HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE by impairing the cell death-dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs.

Perinatal inflammation is associated with social and motor impairments in preterm children without severe neonatal brain injury.

OBJECTIVE: To test the association between exposure to perinatal inflammation - i.e. clinical chorioamnionitis or early-onset neonatal infection - in preterm children without severe neonatal brain injury and neurodevelopmental outcome at 30 months of corrected age (CA). DESIGN: Cross-sectional study from a French regional cohort of clinical follow-up (SEVE Network). PATIENTS: One hundred sixty-four surviving neonates without severe brain injury - namely, grade III and IV cerebral hemorrhage and cystic periventricular leukomalacia - and without late-onset neonatal inflammation exposure - namely, late-onset neonatal infection and necrotizing enterocolitis -, born at less than 33 weeks of gestational age from November 2011 to June 2015 and enrolled in the SEVE Network. MAIN OUTCOME MEASURE: Global developmental quotient (DQ) score of the revised Brunet-Lézine scale and its four indices measured by the same neuropsychologist at 30 months of CA. RESULTS: After multivariate analysis, exposure to perinatal inflammation was not found significantly associated with a modification of the global DQ score (coefficient -1.7, 95% CI -4.8 to 1.3; p = 0.26). Exposure to perinatal inflammation was associated with a decrease of the gross motor function DQ score (coefficient -6.0, 95% CI -9.9 to -2.1; p < 0.01) and a decrease of the sociability DQ score (coefficient -5.1, 95% CI -9.2 to -0.9; p = 0.02). Language and visuospatial coordination DQ scores were not affected by exposure to perinatal inflammation. CONCLUSION: Exposure to perinatal inflammation in preterm children without severe neonatal brain injury is independently associated with decreased motor and social abilities at 30 months of CA.

PNPLA2 mutation: a paediatric case with early onset but indolent course.

Neutral lipid storage disease (NLSD) due to PNPLA2 mutation is a rare disorder with a severe muscular and cardiac outcome. All but one reported cases have been diagnosed during adulthood. It is thus ordinarily distinguished from Chanarin-Dorfman syndrome, a paediatric NLSD with a more widespread symptomatology. We report the case of a young child incidentally diagnosed with significant and persistent hyperCKemia. At 3 years, muscle biopsy showed marked lipid storage. A homozygous mutation in PNPLA2 was found. Fourteen years later, the noticeable outcome is the absence of muscle weakness at rest, a normal muscular MRI, and no cardiac involvement. Yet the patient exhibits some systemic features, notably hearing loss. This paediatric case of NLSD with myopathy indicates that important lipid accumulation may occur very early in the absence of patent clinical and imaging muscle involvement. Furthermore, PNPLA2 mutations may be associated with multisystem features more frequently encountered in Chanarin-Dorfman syndrome.

Obstetrical and neonatal characteristics vary with birthweight in a cohort of 100 term newborns with symptomatic arterial ischemic stroke.

OBJECTIVES: Many questions remain regarding the mechanism of perinatal stroke. METHODS: In a series of 100 prospectively enrolled term neonates with symptomatic arterial ischemic stroke, we explored family antecedents, pregnancy and delivery conditions and clinical presenting features and distinguished features of the 50 larger infants with the remainder. Cardiac and cervical arterial imaging were performed in 70 and 51 cases. RESULTS: Previous fetal loss, first pregnancy, primiparity, twin-gestation, cesarean and traumatic delivery, neonatal distress, male sex and premature rupture of membranes were statistically more common than in the general population. Normal pregnancy proportion and mean birthweight were in the normal range, arguing against a vasculo-placental origin in the majority. Furthermore, there was an excess of large babies. The larger infants were more subject to suffer from acute perinatal events, with a trend for an excess of neonatal distress (p=0.065) and for more severe presenting features (p=0.027), while the lighter were more likely to have experienced longstanding obstetrical risk factors such as complicated pregnancy (p=0.047) and tobacco exposure (p=0.028). Cervical MR angiography showed an internal carotid occlusion in two babies, whereas echo-Doppler was always normal; in one case the two methods were discordant. Echocardiography was non-informative. INTERPRETATION: The data from this prospective cohort of neonates with stroke confirm that many obstetrical and perinatal factors are risk determinants. They also suggest that birthweight and gender may be biomarkers of two populations of neonates with different pathological mechanisms. MR angiography appears more sensitive than echo-Doppler for the exploration of the neonatal cervical vasculature.

Primary leptomeningeal ALK+ lymphoma in a 13-year-old child.

A distinct pathologic entity characterized by expression of the anaplastic lymphoma kinase (ALK) protein (hence described as ALK lymphoma) has emerged within the heterogeneous group of CD30 anaplastic large-cell lymphomas. Central nervous system (CNS) involvement is extremely rare in anaplastic large-cell lymphoma. In children, only isolated cases have been reported, mainly as secondary CNS involvement. We report on a 13-year-old boy presenting with headaches and diplopia. Cerebrospinal fluid was infiltrated with atypical large granular lymphocytes. Magnetic resonance imaging of the brain revealed leptomeningeal enhancement. A frontal lobe biopsy showed a pleomorphic neoplasm diffusely infiltrating the meninges composed of large cells with bizarre nuclei similar to those evidenced in cerebrospinal fluid. Immunohistochemical stains showed diffuse strong positivity for CD8, CD30, anaplastic lymphoma kinase protein: p80 and negative monocyte-macrophage and B cell markers. TCR gamma was clonally rearranged. This finding was confirmed by reverse transcription-polymerase chain reaction analysis of the NPM/ALK fusion protein. Epstein-Barr virus was not detected. No evidence of extra-CNS disease was found by imaging study, cytologic examination, or molecular studies. The patient underwent complete remission with polychemotherapy followed by a CNS irradiation. At +10 months from onset, he suffered a full relapse. After a short-term remission with vinblastine, he underwent nonmyeloablative allogeneic bone marrow transplantation, but unfortunately died from multiple organ failure. This case is the first reported occurrence of a primary meningeal ALK lymphoma in a child.