Genetic and phenotypic spectrum associated with IFIH1 gain-of-function.

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.

Methotrexate-induced Acute Myelopathy in a Teenager With High-risk Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is one of the most frequent malignancies in childhood whose long-term survival has increased up to 80% thanks to modern therapy enhancements. Nevertheless, methotrexate (MTX) remains a mainstay of ALL therapy, but also represents one of the major causes of neurotoxicity in patients with ALL. MTX-induced toxicity occurs in about 9% of patients treated for ALL. It usually affects deep white matter region leading to leukoencephalopathy, which has varying clinical manifestations ranging from acute neurologic disturbances to seizures or chronic permanent encephalopathy. Here we describe a 13-year-old girl affected with ALL who developed lower limbs hypesthesia and static ataxia due to transverse myelopathy after intrathec administration of MTX therapy. A high-dose corticotherapy combined to vitamin supplementation and rehabilitation was tested. Neurological evolution was characterized by slow and partial recovery.

Phenotype-Genotype Correlation in Children with Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with an incidence of ∼1 in 4,000 live births. Neurofibromin, the gene product, is ubiquitously expressed at high levels in the nervous system and functions as a tumor suppressor. Haploinsufficiency of neurofibromin through mutation leads to an increased risk of developing benign and malignant tumors in affected individuals. Although NF1 has complete penetrance, it displays considerable inter- and intrafamilial variability in phenotypic expression which poses disease prediction and management problems. Some NF1 genotype-phenotype correlations have been described. To evaluate the genetic component of variable expressivity in NF1, we examined the phenotypic correlations between affected relatives in 52 NF1 patients from 45 families.

Horner Syndrome in Children: A Clinical Condition with Serious Underlying Disease.

Aim Horner syndrome corresponds to the clinical triad of miosis, ptosis, and facial anhidrosis. These symptoms are related to injury of the oculosympathetic chain. In children, Horner syndrome is classified as congenital or acquired. While the diagnosis is made through clinical examination, there is some debate regarding the use of imaging modalities and the extent of anatomical coverage required. Methods Here, we describe two cases of children with acute Horner syndrome. We then review the literature about the different etiology and discuss the interest of some investigations. Results Case 1: An 8-month-old girl without personal or familial history, has presented a right acquired Horner syndrome without additional signs. Frontal chest radiography and ultrasonography of the neck and the abdomen was first achieved and returned normal. The cerebral and cervical magnetic resonance imaging (MRI) with angiographic sequences performed in a second time was also normal. Finally, an enhanced thoracic computed tomography (CT)-scan demonstrated a mass at the right pulmonary apex. Case 2: A 9-year-old boy without personal or familial history has presented an acute headache with loss of consciousness during a basketball competition. Upon waking up, the child has right hemiplegia, aphasia, and left Horner syndrome. The cerebral CT scan realized in the first line was normal. The MRI with angiographic sequences demonstrated M1 left carotid dissection with homolateral white matter infarction. Conclusion Imaging studies seem critical in delineating the nature and extent of any underlying pathology along the oculosympathetic pathway in children presenting a Horner syndrome. In these patients, a history of trauma or surgery may reduce the need for extensive systemic evaluation. Without such anamnesis, a decision to proceed with further evaluation is made with consideration of the relative incidence of tumor, especially neuroblastoma, or other treatable lesions. In this condition, MRI is the more sensitive and recommended investigation.

Impact of antenatal exposure to a mixture of persistent organic pollutants on intellectual development.

OBJECTIVE: Strong experimental evidence exists that several endocrine disrupting chemicals (EDCs) have neurobehavioral toxicity. However, evidence of associations between prenatal exposure and child's cognitive development is inconsistent. Moreover, toxicants are generally analyzed one by one without considering aggregate effects. We examined here the impact of a prenatal exposure to a mixture of persistent organic pollutants (POPs) on intellectual abilities in preschool children, and compared their effects to those described in the literature. METHODS: Sixty-two children were included in a longitudinal cohort. Four organochlorine pesticides, four polychlorinated biphenyls (PCBs) and seven perfluorinated compounds (PFCs) were measured in cord blood. Intellectual abilities were assessed at 6 years of age using the Wechsler Preschool and Primary Scale of Intelligence 4th ed. (WPPSI-IV). We examined the associations between a mixture of POPs and cognitive performances using principal components approach (PCA) and weighted quantile sum (WQS) regression taking sex difference into account. RESULTS: No negative correlation was found when analyses were performed on boys and girls together. In sex-stratified analyses, lower scores in full scale intelligence quotient (FSIQ) and fluid reasoning index (FRI) were observed in boys most exposed to a mixture of POPs. Increase of the WQS index was also associated with lower verbal comprehension index (VCI) scores in girls only. No other negative correlation was found using both WQS and PCA models. CONCLUSION: Our study suggests deleterious associations between antenatal exposure to a mixture of POPs and sex-specific cognitive level, clarifying some trends described in the literature.

Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review.

BACKGROUND: Stuve-Wiedemann syndrome (SWS) is a rare and severe genetic disease characterized by skeletal anomalies and dysautonomic disturbances requiring appropriate care. Peer support is mandatory to fill the lack of clinical recommendations in such rare diseases. We report a new case and provide the first systematic review of all previous published cases. OBJECTIVE: To better describe the timeline of SWS and to improve paediatric management. DATA SOURCES: SWS English publications available on Pubmed until 31/03/2021. STUDY SELECTION: Case description combining typical osteo-articular and dysautonomic involvement (with 2 items by categories required for children < 2 years and 3 items > 2 years). DATA EXTRACTION: Demographic, clinical, genetics and outcome data. RESULTS: In our cohort of 69 patients, the median age at report was 32 months. Only 46% presented antenatal signs. Mortality rate is higher during the first 2 years (42% < 2 years; 10% > 2 years) mainly due to respiratory failure, pulmonary arterial hypertension appearing to be a poor prognosis factor (mortality rate 63%). After 2 years, orthopaedic symptoms significantly increase including joint mobility restriction (81%), spinal deformations (77%) and fractures (61%). CONCLUSIONS: Natural history of SWS is marked by a high mortality rate before 2 years due to dysautonomic disturbances. A specialized multidisciplinary approach is needed to address these early mortality risks and then adapt to the specific, mainly orthopaedic, needs of patients after 2 years of age. Further research is required to provide clinical guidelines and improve pre-natal counselling.