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Composite panel of six neuroimages showing the brain MRI study in the girl, at the age of 3.5 years: FLAIR-axial scan (A), T2-weighted coronal (B), and sagittal (C) sections; and coronal T1 3D scan (D), as well as reconstructions (reformat) derived from this last study both in axial (E) and sagittal (F) planes. A complex picture of microcephaly, partial agenesis of the corpus callosum with remnants of the genu (white arrow), simplified gyral pattern especially in the parietal and occipital regions of both hemispheres; enlarged and flattened ventricles (grey arrows), with colpocephaly and ectasia of temporal horns were also present. Apparently, no changes in myelin composition and cortical thickness were noticed (black arrows), even if the image protocol shown in this figure is of low quality due to partial panel reformatting. No signs or stigmata of TSC were detected within the brain (e.g., cortical tubers).
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Mutations of TSC1 and TSC2 genes cause classical Tuberous Sclerosis Complex (TSC), a neurocutaneous disorder characterized by a tendency to develop hamartias, hamartomas, and other tumors. We herein report on a girl, now aged 5 years, who presented a previously unreported, distinct clinical phenotype consisting of primary microcephaly (head circumf...
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Midbrain and hindbrain (MBHB) malformations are a rare group of congenital abnormalities that involve the neural structure of the posterior cranial fossa, leading to significant causes of neurodevelopmental dysfunction. Recent advancements in genetic and neuroimaging technologies have significantly enhanced our understanding of these disorders. The integration of these advances has facilitated a systematic classification of these conditions. A basic understanding of MBHB embryology is fundamental in order to understand the malformations occurring in their structures: MBHB neurons are mainly generated in the neuroepithelium, lining the walls of the fourth ventricle. Moreover, the regional specificity of the neural tube is determined by a combination of transcription factors expressed, organizing the fate of the neighboring regions as well. Clinical features of MBHB malformations are typically nonspecific; some patients may be asymptomatic or may develop neurological symptoms including hypotonia, ataxia, abnormal eye movements, decreased visual attention, cranial nerve deficits, cognitive impairment, and psychiatric symptoms. Many malformations have been described. We proposed the description of some of them, reporting their main morphologic aspects, magnetic resonance imaging (MRI) peculiar signs and their clinical presentation. Midbrain clefts, for example, are malformations characterized by median separation in the ventral midbrain which involves a communication with the cerebral aqueduct giving a “keyhole” shape. Pontine tegmental cap dysplasia, instead, is a rare hindbrain malformation responsible for a nonprogressive neurological disorder and is described with hypoplastic flat ventral pons, hypoplasia of the middle cerebellar peduncles, and hypoplasia and malformation of the worm. Joubert syndrome, cerebellar nodular heterotopia, abnormal cerebellar foliation, and Lhermitte–Duclos disease, also called dysplastic cerebellar gangliocytoma, have been described as well in order to provide a general overview on this diagnostic challenge reporting the most recent findings.
Polymicrogyria, cobblestone malformations, and tubulinopathies constitute a group of neuronal migration abnormalities beyond the pial limiting membrane. Their etiopathogenesis remains unclear, with proposed environmental and genetic factors, including copy number variations and single-gene disorders, recently categorized.
Polymicrogyria features numerous small circumvolutions separated by large, shallow grooves, often affecting the perisylvian cortex with various presentations. Clinical manifestations vary depending on lesion degree, extent, and location, commonly including epilepsy, encephalopathies, spastic tetraparesis, mental retardation, and cortical function deficits.
Cobblestone malformations exhibit a Roman-like pavement cortex, affecting both hemispheres symmetrically due to disruption of the glia limitans, frequently linked to glycosyltransferase gene mutations. Classified separately from lissencephaly type II, they are associated with congenital muscular dystrophy syndromes such as Fukuyama congenital muscular dystrophy, Walker–Warburg syndrome, and muscle–eye–brain disease.
Tubulinopathies encompass diverse cerebral malformations resulting from α-tubulin isotype gene variants, exhibiting a wide clinical spectrum including motor/cognitive impairment, facial diplegia, strabismus, and epilepsy.
Diagnosis relies on magnetic resonance imaging (MRI) with age-specific protocols, highlighting the gray–white junction as a polymicrogyria marker, though neonatal diagnosis may be challenging due to technical and brain maturity issues.
To date, no effective treatments are available and management include physiotherapy, speech and language therapy, and vision training program for oculomotor disabilities; antiepileptic drugs are commonly necessary, and most severe forms usually require specific nutritional support.
Recent progress in developmental biology, molecular genetics, and neuroimaging has enabled a more profound comprehension of developmental disorders affecting the embryonic midbrain and hindbrain, which manifest clinically. The purpose of this review is to describe anomalies of the midbrain/hindbrain such as pontocerebellar hypoplasia (PCH), congenital disorders of glycosylation (CDG), cerebellar hemisphere hypoplasia. PCH is a group of disorders that is both clinically and genetically diverse. These disorders are identified by the hypoplasia and degeneration of the cerebellum and ventral pons. A total of 18 distinct clinical subtypes of PCH, each linked to pathogenic variants in 19 different genes, have been documented, like mutations in TSEN54 (coding a subunit of tRNA splicing endonucleases complex) and TBC1D23 which display moderate-to-severe intellectual disability (ID) and microcephaly. CDG represent a set of inherited conditions marked by impaired glycosylation of proteins and lipids. The most prevalent subtype among CDG is PMM2-CDG, inherited in a recessive manner, causing reduced activity of phosphomannomutase. Its phenotype varies from mild to severe, involving the central nervous system and affecting many other organs as well. Patients who are severely affected also exhibit visceral symptoms alongside severe ID and other neurological manifestations. Cerebellar hypoplasia (CH) is characterized by a cerebellum of diminished volume while maintaining its shape. CH exhibits a diverse range of neuroradiologic features, etiologies, clinical characteristics, and neurodevelopmental involvement. Cerebello–oculo–facio–genital syndrome is linked to a recessive MAB21L1 mutation. Jubert's syndrome, associated with a rare autosomal recessive mutation, is identified on magnetic resonance imaging by cerebellar worm hypoplasia and midbrain malformations. The rhombencephalosynapsis, characterized by vermian agenesis or hypogenesis with the fusion of the cerebellar hemispheres, emerges during embryogenesis. It can manifest alone or in conjunction with other and/or extracerebral abnormalities.
The knowledge regarding the midbrain and the hindbrain (MBHB) malformations has been progressively increased in recent years, thanks to the advent of neuroimaging and genetic technologies. Many classifications have been proposed in order to well describe all of these patterns. The most complete and detailed one is based on the genetic and embryologic features that allow an easier and effective knowledge of these disturbs. It categorizes them into four primary groups: (1) Malformations resulting from early anteroposterior and dorsoventral patterning defects or the misspecification of MBHB germinal zones.(2) Malformations linked to later generalized developmental disorders that notably impact the brain stem and cerebellum, with a pathogenesis that is at least partially comprehended.(3) Localized brain malformations significantly affecting the brain stem and cerebellum, with a pathogenesis that is partly or largely understood, encompassing local proliferation, migration, and axonal guidance.(4) Combined hypoplasia and atrophy observed in presumed prenatal-onset degenerative disorders. Regarding diagnosis, brain stem malformations are typically identified during prenatal assessments, particularly when they are linked with anomalies in the cerebellum and cerebrum. Magnetic resonance imaging is the primary neuroimaging method in the evaluation of these malformations. The clinical characteristics of individuals with malformations in the midbrain or hindbrain are generally nonspecific. Common findings at presentation are hypotonia, motor retardation, ataxia, variable degree of intellectual disability, and abnormal eye movement (e.g., nystagmus, abnormal saccades, oculomotor apraxia, strabismus, and abnormal smooth pursuit). The complexity and the number of these MBHB malformations are constantly increasing. We will provide an overview of MBHB disorders, focusing on embryology, genetic, clinical, and neuroradiology features that could be helpful for clinicians and neuroscientist to understand process of these conditions.
Periventricular nodular heterotopia (PVNH) is a group of malformation of cortical development characterized by ectopic neuronal nodules, located along the lateral ventricles. Magnetic resonance imaging can identify gray matter nodules located in wall of ventricles, which appear as island having the same signal of gray matter within white matter. The symptomatological spectrum is various, but the most common clinical presentation is with epileptic seizures, often a drug-resistant type. Features as severity, age of presentation, and associated malformations depend on the underlying etiology. From a genetic point of view, FLNA1 and ERMARD are acknowledged to be the main target of mutations that cause PVNH, although recently many other genes have shown a clear pathogenetic involvement. PVNH may manifest as a solitary discovery in brain imaging or present in conjunction with various other brain or systemic abnormalities. The diagnosis of PVNH is mainly carried out with electroneurophysiological and neuroimaging examinations, while the etiological diagnosis is made with genetic investigations. Treatment consists of use of anticonvulsant drugs, but no significant difference exists among them. In addition, frequently, PVNH-related seizures show poor response to drug, leading to requirement for surgical treatment, performed taking advantages from stereotactic ablative techniques that have a meaningful impact on surgical outcome.
Arnold Chiari malformations include a combination of posterior fossa, hindbrain, and cervical occipital junction abnormalities, sometimes associated with spinal cord abnormalities such as spina bifida, syringomyelia, and syringobulbia. The most frequent form is Chiari I syndrome but two other variants, progressively more severe, have been described. Chiari malformations are the result of defective development of posterior fossa and can be due to genetic mutations, skeletal malformations, and intrautero factors. Clinical manifestations depend on the compression of the nerve structures within the foramen magnum and the spinal canal and mainly consist in headache or neck pain, gait disturbances, sensory or motor abnormalities, and autonomic signs. However, a high number of cases of Chiari I is asymptomatic and the diagnosis is occasional. Diagnosis is performed through nuclear magnetic resonance imaging of the brain and cervical tract, although other investigations may support the diagnosis. First-line treatment for candidate patients is a surgical procedure that involves decompression of the posterior cranial fossa and the craniocervical junction, as well as correction of associated malformations with techniques that depend on the severity of the case. Anyhow, some symptomatic patients benefit from conservative medical treatment with nonsteroidal anti-inflammatory drugs.
Development of the central nervous system is a time-ordered and multistepped process that begins in the third week of development and continues after birth. Understanding of its normal embryologic development is fundamental to understand how specific malformations develop. This article provides a summary of human brain development and serves as a base to introduce the various malformations presented in this issue.
The pandemic of severe-acute-respiratory-syndrome-related coronavirus (SARS-Cov-2) has shown a wide spectrum of possible consequences in children, ranging from asymptomatic patients to the development of severe conditions, such as multisystem inflammatory syndrome in children and encephalopathies related to cytokine storm. Specifically, neurological and neuroimaging abnormalities, ranging from mild-to-the severe ones, have been documented in children as well, such as postinfectious immune-mediated acute disseminated encephalomyelitis, myelitis, neural enhancement, cranial nerve enhancement, and cortical injury, also without neurological symptoms. Considering the neurotropism of coronaviruses and SARS-Cov-2, which has been well described in the literature, we reviewed the literature reporting possible cerebral malformation in neonates due to the infection of SARS-Cov-2 in pregnancy. Coronavirus disease 2019 (COVID-19) during pregnancy might develop cerebral disorders in several ways. Articles in English in the literature were screened using the following search terms: (1) “brain malformations” AND “COVID-19”; (2) “cerebral malformations” AND “COVID-19”; (3) brain malformations AND “Sars-Cov-2”; (4) “cerebral malformations “AND “Sars-Cov-2.” Considering the congenital brain malformation found in newborns exposed to infection of SARS-Cov-2 pre- or neonatally, we identified one paper which reported three neonates with cerebral malformation. Although sporadic, cerebral malformations like atypical signals in white matter with delayed myelination, brain dysplasia/hypoplasia with delayed myelination, and unusual signals in the periventricular regions have been documented.
Extensive research has been conducted on the cerebellum, making it one of the most thoroughly investigated regions of the brain. It plays a fundamental role not only in motor control but also in motor learning and cognition. The development of the cerebellum is a lengthy process, beginning during the embryonic period up to the first years of life. This slow and protracted process makes it a vulnerable organ liable to different insults, responsible for many developmental disorders such as Dandy–Walker syndrome, medulloblastoma, dystroglicanopathy, pontocerebellar hypoplasia, thubulinopathies, and Jubert syndrome. Due to several factors, the true prevalence of cerebellar malformations is not known in most cases. The cerebellum undergoes development through following four fundamental stages:
(1) Identification of the cerebellar region at the boundary between the midbrain and hindbrain.
(2) Establishment of two cell proliferation compartments: firstly, Purkinje cells and deep cerebellar nuclei emerge from the ventricular zone of the metencephalic alar plate; secondly, granule cell precursors are generated from a separate proliferation compartment known as the upper rhombic lip.
(3) Migration of granule cells toward the interior: granule precursor cells constitute the external granular layer (EGL), and during the initial postnatal year, granule cells migrate inward to their final position in the internal granular layer.
(4) Formation of cerebellar circuitry and subsequent differentiation.
Based on different types of involvement of the structures detected in the brain magnetic resonance, the classification of brainstem and cerebellar anomalies is divided into three categories: (1) mainly the cerebellum, (2) mainly the brain stem, and (3) both involved. This review will outline the developmental processes of the cerebellum and delve into common developmental disorders associated with it, including the Dandy–Walker syndrome, cerebellar hypoplasia, rhomboencephalosynapsis, lissencephaly, and gray matter heterotopias.
Schizencephaly is an uncommon anomaly in neuronal migration characterized by complete clefts that extend from the pia mater to the ependymal surface of the ventricular system. These clefts are encompassed by displaced gray matter and filled with cerebrospinal fluid. Typically, they are found most often in the frontal lobe or the area around the lateral sulcus and can occur on one or both sides. The size, location, and type of these clefts carry significant clinical and prognostic implications. Moreover, they are frequently associated with other central nervous system malformations, including the absence of the septum pellucidum, septo-optic dysplasia, optic nerve hypoplasia, pachygyria, polymicrogyria, cortical dysplasia, heterotopia, and dysplasia of the corpus callosum. Occurrence of schizencephaly is almost always sporadic but its etiopathogenesis is yet to be fully understood. Most likely environmental factors, including exposure to teratogens, viral infections, and maternal factors, operate jointly with genetic defects. To date COL4A1, EMX2, SHH, and SIX3 are the genes identified as possible pathogenetic target. It is interesting to notice that schizencephaly is commonly seen in abandoned or adopted children, as proof of causative effect of intrautero insults. Clinical presentations widely vary and symptoms include a spectrum of cognitive impairment, limb paresis/tetraparesis, and epileptic seizures either with early or late onset; anyway, none of these symptoms is ever-present and patients with schizencephaly can also have normal neurocognitive and motor development. Diagnostic gold standard for schizencephaly is magnetic resonance imaging, which allows to identify and characterize typical clefts. Treatment of schizencephaly is symptomatic and supportive and depends on the severity of morbidity resulting from the malformation. Therapy includes antiepileptic drugs, psychomotor rehabilitation, and in selected cases surgical approach.
