Prenatal Diagnosis of Hemimegalencephaly Using Radiological Methods: A Case Report.

Hemimegalencephaly is a rare congenital anomaly characterized by an increase in the size and dysplastic involvement of one cerebral hemisphere, which can be partial or complete. It may also be associated with anomalies in the cerebellum and brainstem and, in some cases, be a part of different syndromes. The result of these abnormalities leads to intractable epilepsy and developmental delay. Diagnosis is typically made through imaging studies in the postnatal period, but it can also be done before birth. We present the case of a 23-week pregnant patient in whom a prenatal diagnosis of hemimegalencephaly was made, highlighting the need for fetal magnetic resonance imaging (MRI) to confirm the diagnosis.

Allelic heterogeneity in a patient with postzygotic MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

A case of mosaic MTOR-associated hemimegalencephaly and hypomelanosis of Ito, died at 33 probably because of sudden unexpected death in epilepsy. Assessment of the variant allele fraction (VAF) in different tissues postmortem showed high variability not correlated with clinical features, representing the most detailed assessment of VAFs in different tissues to date.

Clinical characteristics and surgical management of facial infiltrating lipomatosis: a single center experience.

BACKGROUND: Facial infiltrating lipomatosis (FIL) is a rare condition characterized by congenital facial enlargement. Beyond its impact on physical appearance, FIL can also impair essential facial functions such as swallowing, chewing, vision, and breathing, imposing a substantial physiological and psychological burden. Currently, fewer than 80 cases of FIL have been reported, and the characteristics and management strategies for FIL remain unclear. METHODS: We reviewed the clinical, surgical, and radiological records of 39 FIL patients who were treated at our center. Of these, genetic testing was performed for 21 patients. RESULTS: Aberrant overgrowth involves subcutaneous fat, bones, muscles, glands, tongue, lips, and teeth. Epidermal nevi could be observed in the dermatomes innervated by the three branches of the trigeminal nerve, with the highest frequency seen in the dermatome of the mandibular branch. Four patients exhibited concurrent hemimegalencephaly (HMEG), with one case presenting HMEG on the opposite side of the FIL. Nineteen patients were confirmed to harbor the PIK3CA mutation. Thirty-three patients underwent surgical procedures, with a post resection recurrence rate of approximately 25%. CONCLUSIONS: A variety of maxillofacial structures may be involved in FIL. PIK3CA mutations are important pathogenic factors. Emerging targeted therapies could present an additional treatment avenue in the future. However, surgery currently remains the predominant treatment choice for FIL. The timing and modality of surgery should be individually customized, taking into account each patient's unique circumstances. Notably, there is a significant possibility of postoperative recurrence during childhood and adolescence, necessitating early strategic planning of disease management.

Predicting seizure outcomes and functional outcomes after hemispherotomy: are we any better?

INTRODUCTION: Present study attempted to analyze seizure freedom and detailed functional outcomes after functional hemispherotomy and utility of hemispherotomy outcome prediction scale (HOPS) scores in predicting outcomes. METHODS: Patients who underwent functional hemispherotomy were analyzed for clinical presentation, neuroimaging, seizure outcomes, and functional outcomes. RESULTS: A total of 76 procedures were performed on 69 patients. Mean age at the surgery was 8 ± 6.1 years. Fourteen patients were < 2 years. Age of onset epilepsy of the cohort was 2.0 ± 3.3 years. All had severe catastrophic epilepsy with multiple daily seizures. All patients had motor deficits with 36 (52%) patients had contralateral dysfunctional hand. Perinatal stroke (49%) was most common substrate followed by cortical malformations (21.7%). Eight patients had contralateral imaging abnormalities. Fifty-nine (86.76%) patients remained seizure free (Engle 1a) at 41 + -20.9 months. HOPS scores were available for 53 patients and lowest seizure outcome was 71% for HOPS score of 4. Lower HOPS scores predicted better seizure outcomes. Cortical malformations operated earlier than 2 years predicted poor seizure outcomes (66.6%). Positive functional outcomes are recorded in 80% of patients with 78% reporting improvement from the pre-surgical level. Five (7.2%) patients underwent shunt surgery. One mortality recorded. CONCLUSIONS: Hemispherotomy has excellent seizure outcomes. Early surgery in cortical malformations appears to be predictor of poorer seizure outcomes. HOPS score is a good tool to predict the seizure outcomes. Hemispherotomy is perceived to improve the Cognitive and functional performance.

Hemispherotomy in an infant with hemimegalencephaly and Ohtahara syndrome.

We represent the case of a premature twin neonate born from uncomplicated pregnancy who developed seizures at the age of 24 h. Two-dimensional ultrasound and magnetic resonance imaging revealed left-sided hemimegalencephaly. Further extensive diagnostic evaluation revealed a diagnosis of Ohtahara syndrome. Resistance of the seizures to antiepileptic therapy led to hemispherotomy that was performed at the age of 10 months. Our patient is now a 4-year-old child, walking, eating without a nasogastric tube, still with right hemiparesis and lateral strabismus but without seizures.

Neuroimaging Findings in Fetal Hemimegalencephaly: Case Study and Review.

BACKGROUND: Limited information exists in the prenatal literature regarding the neuroimaging features of fetal hemimegalencephaly. SUMMARY: This report describes ultrasound and magnetic resonance imaging (MRI) findings in a second-trimester fetus with an isolated, severe form of hemimegalencephaly. The most prominent imaging findings included unilateral enlarged cerebral hemisphere and ipsilateral ventriculomegaly causing cerebral asymmetry, midline shift, and macrocephaly. Abnormal cortical development imaging signs were also evident. A literature review encompassing 23 reports describing 36 cases, including ours, is presented. KEY MESSAGES: Characteristic ultrasound findings for the diagnosis of hemimegalencephaly are not always apparent prenatally. Asymmetric ventriculomegaly emerges as the most common but nonspecific presenting feature during routine second- or third-trimester ultrasound scans. Subsequent high-resolution prenatal neurosonography and fetal MRI facilitate definitive prenatal diagnosis, showcasting associated features primarily related to cortical migration, differentiation, and maturation. Postnatally, the prognosis is poor due to intractable seizures, hemiplegia, and progressive neurodevelopmental delay.

Contralateral hippocampal sclerosis following functional hemispherectomy in children: A report of three cases.

PURPOSE: Hippocampal Sclerosis (HS) may co-exist with temporal or extratemporal lesions (dual pathology) in children and is usually ipsilateral to the radiological lesion. Here were report three cases with extensive hemispheric cortical malformation and drug resistant epilepsy who had persistent seizures after functional hemispherectomy (FH) and developed contralateral HS after the surgery. METHODS: This retrospective study enrolled children who underwent FH and developed contralateral HS after surgery. Their clinical, EEG, radiological and pathological data were reviewed and summarized. RESULTS: Ninety-five children underwent FH during the study period; Three cases (3.2%) were eligible. They all had unilateral extensive hemispheric cortical malformation who underwent FH between 3 and 5 months of age with no clinical, EEG or radiological suggestion for involvement of contralateral hemisphere prior to FH. All three patients had persisting seizures after FH. Contralateral HS was detected between 2.2 to 3.7 years after FH in all three cases. Two of the patients showed pathogenic variants in GATOR1 pathway genes. CONCLUSIONS: The genesis of contralateral HS in the reported patients remains unexplained. The presence and distribution of "second-hit" somatic mutations may play an important role in governing the seizure outcomes of epilepsy surgery in patients with apparently unilateral malformations of cortical development.

Neuroectodermal Diseases: A Comparative Case Report Study.

Neuroectodermal disease involves abnormalities that arise from the ectodermal origin, such as the nervous system, eyeball, retina, and skin. Due to the rarity of the disease, it is often underdiagnosed or misdiagnosed. In this study, the researcher presents two cases of pediatric patients with no fetomaternal complications who presented with focal seizures as their initial complaint. During the examination, varying skin color pigmentation and an abnormal neurophysical examination were observed. Cranial imaging showed hemimegalencephaly and voltage asymmetry on EEG. Skin biopsy was performed on both cases, which revealed basketweave orthokeratosis. The combination of a triad of intractable epilepsy, developmental delay, and cutaneous lesion prompted the consideration of a neuroectodermal disease. The study shows two cases of hypomelanosis of Ito and nevus syndrome, both of which may be due to mTOR and RAS pathways, respectively.

The somatic p.T81dup variant in AKT3 gene underlies a mild cerebral phenotype and expands the spectrum including capillary malformation and lateralized overgrowth.

Heterozygous germline or somatic variants in AKT3 gene can cause isolated malformations of cortical development (MCDs) such as focal cortical dysplasia, megalencephaly (MEG), Hemimegalencephaly (HME), dysplastic megalencephaly, and syndromic forms like megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, and megalencephaly-capillary malformation syndrome. This report describes a new case of HME and capillary malformation caused by a somatic AKT3 variant that differs from the common p.E17K variant described in literature. The patient's skin biopsy from the angiomatous region revealed an heterozygous likely pathogenic variant AKT3:c.241_243dup, p.(T81dup) that may affect the binding domain and downstream pathways. Compared to previously reported cases with a common E17K mosaic variant, the phenotype is milder and patients showed segmental overgrowth, an uncommon characteristic in AKT3 variant cases. These findings suggest that the severity of the disease may be influenced not only by the level of mosaicism but also by the type of variant. This report expands the phenotypic spectrum associated with AKT3 variants and highlights the importance of genomic analysis in patients with capillary malformation and MCDs.

Technological and computational approaches to detect somatic mosaicism in epilepsy.

Lesional epilepsy is a common and severe disease commonly associated with malformations of cortical development, including focal cortical dysplasia and hemimegalencephaly. Recent advances in sequencing and variant calling technologies have identified several genetic causes, including both short/single nucleotide and structural somatic variation. In this review, we aim to provide a comprehensive overview of the methodological advancements in this field while highlighting the unresolved technological and computational challenges that persist, including ultra-low variant allele fractions in bulk tissue, low availability of paired control samples, spatial variability of mutational burden within the lesion, and the issue of false-positive calls and validation procedures. Information from genetic testing in focal epilepsy may be integrated into clinical care to inform histopathological diagnosis, postoperative prognosis, and candidate precision therapies.

Facial infiltrating lipomatosis with hemimegalencephaly and lymphatic malformations caused by nonhotspot phosphatidylinositol 3-kinase catalytic subunit alpha mutation.

We report an unusual case of facial infiltrating lipomatosis with hemimegalencephaly and lymphatic malformations. In addition to the clinical data and imaging findings, detection of a heterozygous PIK3CA nonhotspot known pathogenic variant C420R in a facial epidermal nevus provided novel insight into the pathogenic effect of somatic PIK3CA mutations.

mTOR pathway: Insights into an established pathway for brain mosaicism in epilepsy.

The mechanistic target of rapamycin (mTOR) signaling pathway is an essential regulator of numerous cellular activities such as metabolism, growth, proliferation, and survival. The mTOR cascade recently emerged as a critical player in the pathogenesis of focal epilepsies and cortical malformations. The 'mTORopathies' comprise a spectrum of cortical malformations that range from whole brain (megalencephaly) and hemispheric (hemimegalencephaly) abnormalities to focal abnormalities, such as focal cortical dysplasia type II (FCDII), which manifest with drug-resistant epilepsies. The spectrum of cortical dysplasia results from somatic brain mutations in the mTOR pathway activators AKT3, MTOR, PIK3CA, and RHEB and from germline and somatic mutations in mTOR pathway repressors, DEPDC5, NPRL2, NPRL3, TSC1 and TSC2. The mTORopathies are characterized by excessive mTOR pathway activation, leading to a broad range of structural and functional impairments. Here, we provide a comprehensive literature review of somatic mTOR-activating mutations linked to epilepsy and cortical malformations in 292 patients and discuss the perspectives of targeted therapeutics for personalized medicine.

Somatic mosaicism of the PI3K-AKT-MTOR pathway is associated with hemimegalencephaly in fetal brains.

It is known that somatic activation of PI3K-AKT-MTOR signaling causes malformations of cortical development varying from hemimegalencephaly to focal cortical dysplasia. However, there have been few reports of fetal cases. Here we report two fetal cases of hemimegalencephaly, one associated with mosaic mutations in PIK3CA and another in AKT1. Both brains showed polymicrogyria, multiple subarachnoidal, subcortical, and subventricular heterotopia resulting from abnormal proliferation of neural stem/progenitor cells, cell differentiation, and migration of neuroblasts. Scattered cell nests immunoreactive for phosphorylated-S6 ribosomal protein (P-RPS6) (Ser240/244) were observed in the polymicrogyria-like cortical plate, intermediate zone, and arachnoid space, suggesting that the PI3K-AKT-MTOR pathway was actually activated in these cells. Pathological analyses could shed light on the mechanisms involved in disrupted brain development in the somatic mosaicism of the PI3K-AKT-MTOR pathway.

Neonatal Smith-Kingsmore syndrome: case report and literature review / 中国新生儿科杂志

Objective:To study the clinical and genetic features of neonatal Smith-Kingsmore syndrome (SKS).Methods:The clinical data of a newborn with SKS admitted to our hospital in November 2021 were reviewed. Using "Smith-Kingsmore", "rapamycin gene", "newborn", "premature infant", "the mammalian target of rapamycin", "MTOR", "mTOR", "Smith-Kingsmore syndrome", "megalencephaly", "macrocephaly" and "hemimegalencephaly" as keywords, databases including CNKI, Wanfang Database, VIP database, PubMed, Embase, Web of Science and the Cochrane Library were searched from the date of establishment to January 1, 2022. The clinical and genetic features of neonatal SKS from published literature were summarized.Results:The case admitted to our hospital was a male preterm infant. The presenting symptoms were groan and hypotonia. The facial abnormalities included macrocrania, ocular hypertelorism, depressed nasal bridge and low-set ears. Brain MRI showed lateral ventricle enlargement. Whole-genome sequencing (WGS) showed mTOR gene nonsense heterozygous mutation (NM_004958.4:c.7255G>A:p.Glu2419Lys). Neither father nor mother had any pathogenic gene mutations. The infant had seizure at 2-month and phenobarbital was effective reducing seizure. Gross motor delay was present at 3-month. Sixteen related articles were retrieved, including eight articles with 10 neonatal cases. Among them, 6 cases were male. The main clinical features were megalencephaly or hemimegalencephaly (9/10), facial developmental malformation (8/10), hypotonia (6/10), large-for-gestational age (LGA) infants (5/10), cerebral ventricle dilation (4/10) and abnormal corpus callosum (4/10). All the gene mutations were missense mutations, including c.5395G>A(p.Glu1799Lys) mutation in 5 cases, c.4448G>T(p.Cys1483Phe) mutation in 1 case, c.4448G>T(p.Cys1483Tyr) mutation in 1 case, c.7235A>T(p.Asp2412Val) mutation in 1 case, c.5663T>G(p.Phe1888Cys) mutation in 1 case, c.5390C>T(p.Thr1799IIe) mutation in 1 case.Conclusions:The clinical phenotypes of neonatal SKS are diverse, including megalencephaly, facial malformation, LGA and hypotonia. The brain MR findings included (hemi) megalencephaly, cerebral ventricle dilation and corpus callosum hypoplasia. Most of the gene mutations are missense mutations and c.5395G>A(p.Glu1799Lys) is the hotspot.

Neuroimaging features of genetic syndromes associated with CNS overgrowth.

Overgrowth syndromes can manifest with enlargement of the brain and other body parts and are associated with malignancy. Much of the current literature focuses on the imaging findings of the somatic overgrowth, while there is relatively little describing the overgrowth of the central nervous system. In this pictorial essay, we discuss common syndromes with central nervous system overgrowth, highlight key imaging features, and review the underlying genetics, including the PI3K-AKT-mTOR pathway as well as other syndromes from various genes.

Hemimegalencephaly: Evolution From an Atypical Focal Early Appearance on Fetal MRI to More Conventional MR Findings.

Hemimegalencephaly, or unilateral megalencephaly, is a sporadic congenital brain malformation characterized by enlargement of a cerebral hemisphere due to an abnormal proliferation of neurons or glial cells. Hemimegalencephaly is part of a spectrum of disorders, increasingly referred to as mTORopathies, which arise as a result of dysregulation or hyperactivation of the mammalian target of rapamycin (mTOR)-signaling cascade resulting in less restricted cell growth and survival. The resultant cortical disorganization and enhanced neuronal excitability often manifest clinically in the form of seizures. Ultrasound and magnetic resonance imaging (MRI) are often used to characterize hemimegalencephaly. Typical imaging findings seen include diffuse unilateral enlargement of a cerebral hemisphere with overlying cortical malformation and ipsilateral dilation of the lateral ventricle. This paper will review an unusual case of focal hemimegalencephaly diagnosed on prenatal imaging. Initial in utero MRI revealed a mass-like lesion in the frontal lobe without associated perilesional cerebral edema. Keying in on abnormalities within the overlying cortex was crucial in suggesting focal hemimegalencephaly as a leading diagnosis and distinguishing it from alternative diagnoses such as a neoplasm. Follow-up fetal MRI demonstrated the evolution of the cerebral abnormality and confirmed the diagnosis. Early diagnosis facilitated appropriate counseling of the parents and guided postnatal imaging and management.

Functional hemispherotomy for epilepsy in the very young.

OBJECTIVE: Epilepsy is one of the most common neurological disorders in children. Among very young children, one-third are resistant to medical treatment, and lack of effective treatment may result in adverse outcomes. Although functional hemispherotomy is an established treatment for epilepsy, its outcome in the very young child has not been widely reported. In this study the authors investigated seizure and developmental results after hemispherotomy in children younger than 3 years. METHODS: The authors reviewed a prospective database of all children younger than 3 years with medically intractable epilepsy who underwent functional hemispherotomy at the authors' institution during the period between 2012 and 2020. Demographic data, epilepsy history, underlying etiology, operative and transfusion details, and seizure and developmental outcomes were analyzed. RESULTS: Twelve patients were included in this study. The mean age (± SD) at seizure onset was 3 ± 2.6 months and at surgery was 1.3 ± 0.77 years, with a mean follow-up of 4 years. Diagnoses included hemimegalencephaly (n = 5), hemidysplasia (n = 2), hypoxic/hemorrhagic (n = 2), traumatic (n = 1), Sturge-Weber syndrome (n = 1), and mild hemispheric structural abnormality with EEG/PET correlates (n = 1). Eleven patients achieved an Engel class I outcome, and 1 patient achieved Engel class IV at last follow-up. No deaths, infections, cerebrovascular events, or unexpected long-term neurological deficits were recorded. All children progressed neurodevelopmentally following surgery, but their developmental levels remained behind their chronological age, with an overall mean composite Vineland Adaptive Behavior Scale score of 58 (normal: 86-114, low: < 70). One patient required insertion of a subdural peritoneal shunt, 1 patient required dural repair for a CSF fluid leak, and 1 patient required aspiration of a pseudomeningocele. In 2 patients, both of whom weighed less than 5.7 kg, the first operation was incomplete due to blood loss. CONCLUSIONS: Hemispherotomy in children younger than 3 years offers excellent seizure control and an acceptable risk-to-benefit ratio in well-selected patients. Families of children weighing less than 6 kg should be counseled regarding the possibility of staged surgery. Postoperatively, children continue to make appropriate, despite delayed, developmental progress.

A rare case of hemimegalencephaly diagnosed prenatally.

Hemimegalencephaly (HME), or unilateral megalencephaly, is a rare congenital brain malformation defined as overgrowth of one cerebral hemisphere or part of it resulting from abnormal cortical development and neuronal migration. However, cortical developmental abnormalities are rarely diagnosed prenatally. This is the reason for our study, in which we describe and compare ultrasound and MRI findings in a fetus with HME.

Postmortem Diagnosis of the Proteus Syndrome by Next Generation Sequencing of Affected Brain Tissue.

We report a case of a somatic overgrowth syndrome diagnosed at forensic autopsy with the aid of next generation sequencing as Proteus syndrome. Somatic overgrowth syndromes result from spontaneous somatic mutations that arise early in development and display a mosaic pattern of expression in patient tissues. Due to the temporal and anatomic heterogeneity of these syndromes, phenotypes vary widely, resulting in clinical overlap. Furthermore, the variable ratio of mutated to nonmutated cells in patient tissue can result in low-level mutations that could be missed using Sanger sequencing. Due to these factors, recent literature points to next generation sequencing (NGS) as an adjunct to diagnosis of these rare entities. A male in his fourth decade of life presented to our forensic autopsy service with physical features suggestive of a somatic overgrowth syndrome. Due to the paucity of clinical information accompanying the individual, a definitive diagnosis based on physical characteristics, alone, was not possible. Next generation sequencing of affected formalin-fixed and paraffin-embedded brain tissue confirmed the presence of the variant in AKT1 (c.49G>A, p.Glu17Lys, in 14.13% of reads) found in Proteus syndrome. To our knowledge, this is the first report of the mosaic variant of AKT1 detected in brain tissue and the first reported case of a postmortem diagnosis of Proteus syndrome with the aid of NGS. We conclude that NGS can be used as an adjunctive method to support a specific diagnosis among the somatic overgrowth syndromes postmortem in the absence of sufficient clinical history.