-
Frontiers in Pediatrics 2021Macrocephaly affects up to 5% of the pediatric population and is defined as an abnormally large head with an occipitofrontal circumference (OFC) >2 standard deviations... (Review)
Review
Macrocephaly affects up to 5% of the pediatric population and is defined as an abnormally large head with an occipitofrontal circumference (OFC) >2 standard deviations (SD) above the mean for a given age and sex. Taking into account that about 2-3% of the healthy population has an OFC between 2 and 3 SD, macrocephaly is considered as "clinically relevant" when OFC is above 3 SD. This implies the urgent need for a diagnostic workflow to use in the clinical setting to dissect the several causes of increased OFC, from the benign form of familial macrocephaly and the Benign enlargement of subarachnoid spaces (BESS) to many pathological conditions, including genetic disorders. Moreover, macrocephaly should be differentiated by megalencephaly (MEG), which refers exclusively to brain overgrowth, exceeding twice the SD (3SD-"clinically relevant" megalencephaly). While macrocephaly can be isolated and benign or may be the first indication of an underlying congenital, genetic, or acquired disorder, megalencephaly is most likely due to a genetic cause. Apart from the head size evaluation, a detailed family and personal history, neuroimaging, and a careful clinical evaluation are crucial to reach the correct diagnosis. In this review, we seek to underline the clinical aspects of macrocephaly and megalencephaly, emphasizing the main differential diagnosis with a major focus on common genetic disorders. We thus provide a clinico-radiological algorithm to guide pediatricians in the assessment of children with macrocephaly.
PubMed: 35096710
DOI: 10.3389/fped.2021.794069 -
Cell May 2023Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model...
Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly.
Topics: Humans; Brain; Macrophages; Microglia; Organoids; Phenotype
PubMed: 37172564
DOI: 10.1016/j.cell.2023.04.022 -
World Journal of Clinical Pediatrics May 2021Medical comorbidities are more common in children with autism spectrum disorders (ASD) than in the general population. Some genetic disorders are more common in children...
Medical comorbidities are more common in children with autism spectrum disorders (ASD) than in the general population. Some genetic disorders are more common in children with ASD such as Fragile X syndrome, Down syndrome, Duchenne muscular dystrophy, neurofibromatosis type I, and tuberous sclerosis complex. Children with autism are also more prone to a variety of neurological disorders, including epilepsy, macrocephaly, hydrocephalus, cerebral palsy, migraine/headaches, and congenital abnormalities of the nervous system. Besides, sleep disorders are a significant problem in individuals with autism, occurring in about 80% of them. Gastrointestinal (GI) disorders are significantly more common in children with ASD; they occur in 46% to 84% of them. The most common GI problems observed in children with ASD are chronic constipation, chronic diarrhoea, gastroesophageal reflux and/or disease, nausea and/or vomiting, flatulence, chronic bloating, abdominal discomfort, ulcers, colitis, inflammatory bowel disease, food intolerance, and/or failure to thrive. Several categories of inborn-errors of metabolism have been observed in some patients with autism including mitochondrial disorders, disorders of creatine metabolism, selected amino acid disorders, disorders of folate or B12 metabolism, and selected lysosomal storage disorders. A significant proportion of children with ASD have evidence of persistent neuroinflammation, altered inflammatory responses, and immune abnormalities. Anti-brain antibodies may play an important pathoplastic mechanism in autism. Allergic disorders are significantly more common in individuals with ASD from all age groups. They influence the development and severity of symptoms. They could cause problematic behaviours in at least a significant subset of affected children. Therefore, it is important to consider the child with autism as a whole and not overlook possible symptoms as part of autism. The physician should rule out the presence of a medical condition before moving on to other interventions or therapies. Children who enjoy good health have a better chance of learning. This can apply to all children including those with autism.
PubMed: 33972922
DOI: 10.5409/wjcp.v10.i3.15 -
Cold Spring Harbor Perspectives in... Nov 2019Phosphatase and tensin homolog (PTEN) is a classical tumor suppressor that antagonizes phosphatidylinositol 3-phosphate kinase (PI3K)/AKT signaling. Although there is a... (Review)
Review
Phosphatase and tensin homolog (PTEN) is a classical tumor suppressor that antagonizes phosphatidylinositol 3-phosphate kinase (PI3K)/AKT signaling. Although there is a strong association of germline mutations with cancer syndromes, they have also been described in a subset of patients with autism spectrum disorders with macrocephaly characterized by impairments in social interactions and communication, repetitive behavior and, occasionally, epilepsy. To investigate PTEN's role during neurodevelopment and its implication for autism, several conditional knockout mouse models have been generated. These models are valuable tools to understand PTEN's spatiotemporal roles during neurodevelopment. In this review, we will highlight the anatomical and phenotypic results from animal studies and link them to cellular and molecular findings.
Topics: Animals; Autism Spectrum Disorder; Disease Models, Animal; Humans; Mice; Mice, Knockout; Neurodevelopmental Disorders; PTEN Phosphohydrolase; Phosphatidylinositol 3-Kinases; Signal Transduction
PubMed: 31427284
DOI: 10.1101/cshperspect.a036780