Megalencephaly Capillary Malformation Syndrome

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Holoprosencephaly (HPE), the most prevalent developmental anomaly affecting the forebrain in humans, occurs in ∼1 in 16,000 liveborn neonates, with an incidence reaching 1 in 250 in conceptuses. This condition is distributed worldwide. HPE is etiologically heterogeneous, and its pathogenesis is variable. Environmental, teratogenic, genetic, or metabolic factors can contribute to the development of HPE. Notably, maternal insulin-dependent diabetes mellitus and maternal alcoholism are among the primary causative factors. HPE may be linked to various well-defined multiple malformation syndromes characterized by a normal karyotype, such as Smith–Lemli–Opitz's, Pallister–Hall's, or velocardiofacial syndrome. Alternatively, it can be associated with chromosomal abnormalities. (i.e., Patau's syndrome and, less frequently, Edwards' syndrome or Down's syndrome). The major genes implicated in HPE are SHH, ZIC2, SIX3, and TGIF. The range of HPE is extensive, covering diverse neuropathological phenotypes of varying severity. Three classical types of HPE can be distinguished in increasing order of severity: lobar HPE, characterized by separated right and left ventricles with some continuity across the frontal cortex; semilobar HPE, featuring a partial separation; and the most severe form, alobar HPE, where there is a single brain ventricle and the absence of an interhemispheric fissure. Additionally, there are other variations of HPE, ranging in severity, including the less severe interhemispheric median HPE (also known as middle interhemispheric variant). The phenotypic spectrum of HPE is highly extensive, encompassing severe cerebral malformations to microforms. Children with HPE often encounter numerous medical challenges; among them neurological disorders, craniofacial malformations, endocrine disorders, oral and motor dysfunction, and dysfunction of the autonomic nervous system. Neurologic problems, such as cerebral palsy and seizures, are common. The diagnosis of HPE is typically made prenatally, relying primarily on ultrasound and magnetic resonance imaging examinations. The prognosis for individuals with HPE is largely dependent on its underlying causes. Those with cytogenetic abnormalities, in particular, face a significantly poorer prognosis, with only 2% surviving beyond 1 year.

Section: Epidemiologymentioning

confidence: 99%

Holoprosencephaly: The Disease and Its Related Disabilities

Balconara,

La Cognata,

Zanghì

et al. 2024

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“…Rare causes of postnatal hydrocephalus include malformations, midline tumors, choroid plexus papilloma and Galen's vein malformation. [25][26][27] In the newborn with hydrocephalus, the skull tends to grow rapidly causing macrocephaly already in the first month of life. The forehead is disproportionately wide, the sutures are diastased, the anterior fontanel is tense and dilation of the veins on the scalp is observed.…”

Section: Postnatal Hydrocephalusmentioning

confidence: 99%

Congenital/Primitive Hydrocephalus: Classification, Clinical Aspects, and Rehabilitation Approach

Caltabiano,

La Cognata,

Zanghì

et al. 2024

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Hydrocephalus is a heterogeneous disorder of cerebrospinal fluid (CSF) flow that leads to abnormal enlargement of the brain ventricles. The prevalence of infant hydrocephalus is approximately one case per 1,000 births. Hydrocephalus occurs due to an imbalance between the production and the absorption of CSF. The causes of hydrocephalus secondary to CSF overproduction are papilloma of the choroid plexus and rarely diffuse hyperplasia of the villi. All the other hydrocephalus forms are secondary to obstruction to normal CSF reabsorption and are also known as obstructive hydrocephalus. According to the location of obstruction, obstructive hydrocephalus can be defined as communicating, when caused by extraventricular obstruction of the CSF flow or decreased resorption of CSF distal to the fourth ventricle in the cisterns of the base or in the subarachnoid spaces, or as not communicating, in case of intraventricular obstruction to fluid flow. There is a third category, common in preterm infants, called external hydrocephalus which is secondary to delayed development of arachnoid function. Hydrocephalus leads to an increase in intraventricular pressure because of the lack of the mechanism regulating the homeostasis of the CSF flow. Increased intraventricular pressure is responsible for the clinical symptoms in affected child. Clinical presentation varies with age. In the neonatal period, prolonged or frequent apneic or bradycardic events, increasing head circumference, presence of sunsetting eyes or upward gaze palsy, evidence of full or tense anterior/posterior fontanelle, and splayed cranial sutures are signs of increased intracranial pressure. In infants, the most common signs are progressive macrocephaly, irritability, nausea/vomiting, headache, gait changes, and regression of developmental milestones. The extent of brain damage depends on the cause that led to hydrocephalus, the patient's age, and the rapidity of onset. The surgical treatment modalities consist of endoscopic ventriculostomy of the third ventricle and ventriculoperitoneal or ventriculoatrial CSF shunt.

“…2). [28][29][30] All these genes encode proteins associated with the centrosome and play a regulatory role in the mitosis of progenitor cells within the neuroepithelium lining the cerebral ventricles. This evidence emphasizes the correlation between brain size and heightened mitotic activity in neuronal precursors.…”

Section: Microcephaly Primary Hereditarymentioning

confidence: 99%

Microcephaly and Its Related Syndromes: Classification, Genetic, Clinical, and Rehabilitative Considerations

Di Nora,

La Cognata,

Zanghì

et al. 2024

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Microcephaly, a form of cortical cortex malformation, results from abnormal cellular production and proliferation, identified when the occipital frontal head circumference (OFC) falls two or more standard deviations (SDs) below the expected average for age, gender, and population. Severity is classified based on SD: mild (OFC < 2 SD) or severe (OFC < 3 SD). While microcephaly can lead to developmental delay, intellectual disability, epilepsy, and cerebral palsy, not all cases exhibit these issues. Classified as primary/congenital or secondary/postnatal, microcephaly can stem from genetic or acquired factors in both types. Congenital microcephaly origins vary, while secondary microcephaly is characterized by normal OFC at birth, followed by a decrease within the first year, often associated with progressive cognitive and motor impairments. Primary hereditary microcephaly (MCPH), or microcephaly vera, is genetically diverse, with 28 related genes (MCPH1 to MCPH28) encoding proteins linked to centrosomes and progenitor cell mitosis in the brain ventricle's neuroepithelium. Defects in deoxyribonucleic acid (DNA) repair pathways (e.g., NBN, FANCA, ATR, ATM genes) can lead to microcephaly by impairing DNA repair. Enzyme deficiencies in metabolic pathways may also contribute, causing toxic metabolite accumulation or essential metabolite loss (microcephaly of metabolic origin). Acquired congenital microcephaly may result from ischemic or infectious processes, drugs, radiation, maternal diseases during pregnancy, with damage influenced by fetal genetics, environmental interactions, developmental stage, and exposure intensity/duration. Diagnostic workup includes electroencephalogram, ophthalmological, auditory, magnetic resonance imaging, metabolic, echocardiogram, and infection screening tests, alongside genetic evaluations like cytogenetic studies, fluorescence in situ hybridization, comparative genomic microarray-hybridization, single-nucleotide microarray-polymorphism, and exome sequencing. Symptomatic treatment is available, and genetic counseling is crucial for affected families.