Nervous System Malformations Research Articles

Tolvaptan for Treatment of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in a Child with Corpus Callosum Agenesis.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the common causes of euvolemic hyponatremia (serum Na+ < 135 mEq/L) in hospitalized children. It is characterized by increased serum ADH, leading to water retention via its action on V2 receptors in the distal renal tubules.Various conditions such as pain, the postoperative state, drugs, central nervous system infections, tumors, malformations, and pneumonia can predispose a person to SIADH. The conventional treatment of SIADH includes fluid restriction and salt supplementation. Occasionally, this may fail to control hyponatremia, mandating pharmacological therapy. V2-receptor antagonists are an FDA-approved therapy for adults with euvolemic and hypervolemic hyponatremia. However, there is limited experience with their use in the pediatric population. Here, the authors present a girl with corpus callosum agenesis with severe symptomatic hyponatremia due to SIADH who was successfully managed with the V2-receptor antagonist tolvaptan.

Fetal agenesis of the septum pellucidum: Ultrasonic diagnosis and clinical significance.

To describe the prenatal ultrasound (US) findings, genetic results, and clinical outcomes of fetuses with suspected agenesis of the septum pellucidum (ASP) in the Chinese population. This retrospective, single-center study included a cohort of fetuses with ASP diagnosed by prenatal imaging over a 10-year period. We evaluated US findings, associated anomalies, genetic results, and clinical outcomes. Prenatal and postnatal imaging findings were compared as well as the clinical outcome of delivery. Ninety patients were included, with a median follow-up time of 36months (1-96months). Thirty-six fetuses (40%) with isolated ASP were diagnosed by prenatal US or magnetic resonance imaging (MRI); 39 cases (43.3%) had ASP with central nervous system malformations and 15 cases (16.6%) had ASP with non-CNS abnormalities. Additional imaging findings were supplemented with prenatal MRI in 13 cases. Genetic tests were performed on 32 patients, of whom six had abnormalities. Prenatal US results of 40 patients (40/70) diagnosed by referral hospitals did not correspond to our findings. Of the 38 patients with postnatal records, 11 had abnormal neurological development. The outcome of an isolated ASP is usually favorable; however, neurological developmental delay is commonly observed if it is combined with other malformations.

My Journey.

This is the life story of Dr. Lucy B. Rorke-Adams, who was raised in the rural Midwest of the United States by Armenian immigrant parents during the Depression. The youngest in a family of five girls, she was lovingly nurtured by her parents and sisters. She was encouraged to become educated in order to lead a worthwhile life and contribute to society. She chose medicine, specifically the specialty of pediatric neuropathology, and over her long career succeeded in advancing the field. In particular, she made major contributions to understanding childhood brain tumors, central nervous system (CNS) malformations, and pathophysiology of abusive CNS injury in infants and children.

Clinical features and genetic analysis of Dandy-Walker syndrome

BackgroundDandy-Walker syndrome (DWS) is a rare congenital malformation of the central nervous system (CNS), characterized by underdevelopment or dysplasia of the cerebellar vermis, expansion of the fourth ventricle and posterior fossa cistern. The incidence is aboutapproximately 1/25000–1/35000. At present, the etiology and pathogenesis of DWS are not completely clear. It is mostly considered to be a multifactorial genetic disease that is related to both genetic factors and environmental factors. There is no large sample size analysis of the chromosomal profile of DWS up to now. This study aims to provide clinical reference for prenatal diagnosis via summarizing the clinical features and pregnancy outcomes of Dandy-Walker syndrome.MethodsA total of 76 cases of foetal Dandy-Walker syndrome out of 19,506 pregnant women underwent cordocentesis or amniocentesis for genetic detection. Rapid prenatal karyotyping, single nucleotide polymorphism array (SNP-array) and BACs-on-Beads™ (BoBs) were performed for prenatal genetic diagnosis. The results of ultrasonography, genetic analysis and pregnancy outcome were recorded.ResultsOf the 76 cases, 19 were isolated DWS, while 57 cases were accompanied by other ultrasound-visible abnormalities. Ultrasound abnormalities of the CNS were most frequently observed, accompanied by DWS. Twenty-five out of 76 cases had chromosomal abnormalities, and the rate of chromosomal abnormalities increased in pregnant women of advanced maternal age or in combination with other ultrasound abnormalities. Of the 19 cases in the isolated DWS group, nine pregnant women chose to terminate the pregnancy, while seven cases continued the pregnancy and all infants were normal. Among the 57 pregnant women with pathological ultrasound manifestations other than foetal DWS, 44 chose to terminate the pregnancy, while 12 cases continued the pregnancy. Further follow-up revealed one newborn with postnatal neurodevelopmental delay. A female term neonate presented with very severe sensorineural deafness, and an infant died 7 days after birth with abnormal development of multiple organs.ConclusionsPregnant women with DWS in foetal ultrasonic examination should be offered a careful and comprehensive foetal ultrasound scan and further prenatal genetic testing including karyotype analysis and SNP-array. The prognosis of the foetus without chromosomal aberration is good in isolated DWS pregnancies but poor in nonisolated DWS pregnancies.

A case of acrocallosal syndrome in a neonate with congenital heart abnormality

The usual features of the acrocallosal syndrome (ACLS) are agenesis of the corpus callosum, mental retardation, prominent craniofacial deformities, and specific digital abnormalities. ACLS is a rare genetic disorder which may be autosomal recessive, however it usually occurs sporadically. A 20-day-old newborn was admitted to the pediatric clinic due to the discovery of corpus callosum agenesis during pregnancy. The fetal echocardiography revealed an ASD and moderate tricuspid regurgitation (TR). During limb assessment, right foot pre-axial polydactyly was noted, and skull exam revealed anterior fontanelle enlargement. The brain MRI showed agenesis of the corpus callosum and enlarged lateral ventricles. The parents had no consanguinity and their genetic test had shown no anomalies.The neurologist decided to monitor the neurological development of the child. The current case provides additional evidence that ACLS can be associated with pre-axial polydactyly and craniofacial symptoms including enlargement of the anterior fontanelle. Second-trimester ultrasonography can detect central nervous system malformations such as ventricular enlargement and corpus callosum anomalies. Moreover, Echocardiography is recommended to check for heart abnormalities in these children.

Actual epidemiological profile and management of central nervous system (CNS) malformations in a neurosurgery department in sub-Saharan Africa

Introduction: Central Nervous System (CNS) malformations usually leave the family in disarray and doctors’ staff powerless. In developed countries, the rigorous application of preventive measures has contributed to a significant reduction incidence of these malformations. In African societies, mystical-religious considerations and low socio-economic level contribute to the increased occurrence of these malformations. The purpose of this work was to evaluate the prevalence and management of CNS malformations in our neurosurgical department. Methods: This was a retrospective study conducted in the neurosurgery department of Yalgado Ouedraogo Teaching Hospital, in Ouagadougou, from 2016 to 2019. All cases of CNS malformations managed in the department with a workable medical record were reviewed. Results: Five hundred and twenty-four cases were selected. The prevalence of malformations was 7.05%. The mean age of patients was 1.48 years (1 day and 76 years). Thirty-one (5.9%) cases of CNS malformations were diagnosed antenatally. One hundred and twenty-four (23.6%) ultrasounds (including 51 antenatal), 418 CT scans (79.7%) and 9 MRIs (1.7%) were performed. Hydrocephalus [(n = 219 (41.7%)] and spina bifida [(n = 213 (40.6%)] were the most common pathologies. Surgical treatment was indicated in 435 cases (83%) of which 179 (41.1%) could be operated. After a follow-up of 15.8 months, there were 46.3% sequelae identified. Conclusion: CNS malformations are common in our context. They are not always prone to be treated surgically and are at the origin of many neurological sequelae and lifelong disability. Hence there is an urgent need to focus on improving preventive measures in Sub-Saharan Africa.

Bone Defect of the Cranial Vault: Difficulty of the Diagnostic about a Case, and Revew of Literature

The bone defects of the cranial vault encompassed rare malformations including acalvaria, hypocalvaria, acrania, hypocrania, anencephaly and exencephaly. They are also described in some pathological entities such as aplasia cutis congenita of the scalp. We report an unusual case of cephalic malformation which combine defects of the skin, the dura mater, and the bones of the vault, with a malformation of the central nervous system. This unique case emphasizes a problem of nosological definition between the terms mentioned above. acalvaria, the acrania, the hypocalvaria and the aplasia cutis congenita. Thus, herein, we proceed to a literature review of bone defects of the skull and their differential diagnosis.

An Antenatal Diagnostic of Meckel Gruber Syndrome (Mks): Case Report

MKS, Meckel Gruber syndrome is a rare, lethal, genetic multiple congenital anomaly characterized by the following triad: cerebral malformation (primarily occipital encephalocele), polycystic kidneys, and polydactyly, as well as associated abnormalities that may include cleft lip/palate, cardiac and genital abnormalities, central nervous system (CNS) malformations, hepatic fibrosis, and bone dysplasia. The mode of transmission of MKS is autosomal recessive. Genetic counseling should be offered to couples at risk. MKS is lethal in utero or in the very early neonatal period, with pulmonary hypoplasia and renal failure being the main causes of early death. Our case illustrates the importance of prenatal diagnosis, essentially by ultrasound, in order to ensure adequate management.

Intraoral and maxillofacial abnormalities in patients with autosomal dominant hyper-IgE syndrome.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is an inborn error of immunity (IEI) caused by a dominant-negative mutation in the signal transducer and activator of transcription 3 (STAT 3). This disease is characterized by chronic eczematoid dermatitis, recurrent staphylococcal skin abscesses, pneumonia, pneumatoceles, and extremely high serum IgE levels. Loss-of-function STAT3 mutations may also result in distinct non-immunologic features such as dental, facial, skeletal, and vascular abnormalities, central nervous system malformations and an increased risk for bone fractures. Prophylactic treatment of Candida infections and prophylactic antimicrobial therapy for staphylococcal skin infections and sinopulmonary infections are essential. An awareness of the oral and maxillofacial features of HIES may facilitate early diagnosis with genetic counselling and may improve future patient care. This study describes oral, dental, and maxillofacial manifestations in 14 patients with genetically defined AD-HIES. We also review the literature and propose recommendations for the complex care of patients with this rare primary immunodeficiency.

Evaluating the Role of Perilesional Tissue in Pathobiology of Epileptogenesis of Vascular Malformations of the Central Nervous System.

Seizures are common presentation of cerebral vascular malformation (CVM). Topography and haemodynamic alterations are proposed as mechanisms for epileptogenesis, but the role of glial/neuronal alterations in perilesional tissue has not received much attention. Identification of the exact pathophysiologic basis could have therapeutic implications. To evaluate whether angioarchitectural factors of CVM or alterations in neuroglial/stroma of the adjacent cortex contribute to seizures. The clinical, imaging and histological characteristics of arteriovenous malformation (AVM) and cerebral cavernous malformation (CCM) with and without seizures was evaluated using neuroimaging imaging and digital subtraction angiography parameters and histopathology by morphology and immunohistochemistry. Fifty-six cases of CVM were diagnosed over a 2-year study period. Of these, 32 had adequate perilesional tissue for evaluation (AVM, 24; CCM, 8). Seizures at presentation was seen in 12/24 (50%) of AVM and 5/8 (62.5%) CCM. In AVM, hemosiderin deposition and gliosis in parenchyma (p=0.01) had significant association with seizure. Siderotic vessels in the adjacent cortex was exclusively seen only in CCM with seizures (p=0.018). Angioarchitectural features of CVM on imaging and neuronal alterations in adjacent cortex on histology failed to show any statistically significant difference between the two groups (p>0.05). We propose that changes in adjacent cortex appear to be epileptogenic rather than the malformation per se. Reactive gliosis and hemosiderin deposits in perilesional tissue in AVM and siderotic vessels in CCM were associated with seizure. This explains the better outcomes following extended lesionectomy that includes epileptogenic perilesional tissues.

Evaluating the Role of Perilesional Tissue in Pathobiology of Epileptogenesis of Vascular Malformations of the Central Nervous System

Background and Purpose: Seizures are common presentation of cerebral vascular malformation (CVM). Topography and haemodynamic alterations are proposed as mechanisms for epileptogenesis, but the role of glial/neuronal alterations in perilesional tissue has not received much attention. Identification of the exact pathophysiologic basis could have therapeutic implications. To evaluate whether angioarchitectural factors of CVM or alterations in neuroglial/stroma of the adjacent cortex contribute to seizures.Method: The clinical, imaging and histological characteristics of arteriovenous malformation (AVM) and cerebral cavernous malformation (CCM) with and without seizures was evaluated using neuroimaging imaging and digital subtraction angiography parameters and histopathology by morphology and immunohistochemistry.Results: Fifty-six cases of CVM were diagnosed over a 2-year study period. Of these, 32 had adequate perilesional tissue for evaluation (AVM, 24; CCM, 8). Seizures at presentation was seen in 12/24 (50%) of AVM and 5/8 (62.5%) CCM. In AVM, hemosiderin deposition and gliosis in parenchyma (&lt;i&gt;p&lt;/i&gt;=0.01) had significant association with seizure. Siderotic vessels in the adjacent cortex was exclusively seen only in CCM with seizures (&lt;i&gt;p&lt;/i&gt;=0.018). Angioarchitectural features of CVM on imaging and neuronal alterations in adjacent cortex on histology failed to show any statistically significant difference between the two groups (&lt;i&gt;p&lt;/i&gt;&gt;0.05).Conclusions: We propose that changes in adjacent cortex appear to be epileptogenic rather than the malformation per se. Reactive gliosis and hemosiderin deposits in perilesional tissue in AVM and siderotic vessels in CCM were associated with seizure. This explains the better outcomes following extended lesionectomy that includes epileptogenic perilesional tissues.

Postnatal Edward’s syndrome

Edward's syndrome or trisomy 18 syndrome is due to meiotic nondisjunction with multisystemic involvement. It is characterized by craniofacial, skeletal, cardiovascular, central nervous system and genitourinary malformations. Developmental delay is common in all children. Most cases are diagnosed before birth based on the mother's age and the detection of ultrasound abnormalities in the second and third trimesters. A careful examination is therefore very important to confirm the diagnosis and to help identify unexpected abnormalities. There is very little data on Edward's syndrome. This case report can contribute to the literature and compare it to other known genetic disorders. Keywords : Trisomy 18 syndrome, Edwards syndrome, diagnosis, genetic disorders.

Potential therapeutic targets and medications for arteriovenous malformations of the central nervous system

Arteriovenous malformations (AVMs) of the central nervous system are high-flow arteriovenous shunts that lead to considerable risks of hemorrhagic stroke and neurological deficits in young patients. Due to the complex angioarchitecture and their close anatomical relationship with the brain and spinal cord, the management of brain and spinal AVMs is challenging. Conventional invasive treatments, including microsurgery, endovascular embolization, and stereotactic radiosurgery, are associated with considerable risks and unsatisfactory efficacy. In addition, the lack of medications for AVMs represents an unmet clinical need. In recent years, the pathogenesis of AVMs has been progressively explored. The increased understanding of the mechanisms of the formation, progression, and rupture of AVMs has opened up several potential directions for AVM pharmacotherapy. In recent years, some promising drugs targeting angiogenesis, inflammation, vessel wall integrity, and the mitogen-activated protein kinase (MAPK)-extracellular receptor kinase (ERK) signaling pathway have been tested in a series of clinical investigations. In this review, we summarize the potential mechanisms, preliminary efficacy, and side effects of the candidate medications, including bevacizumab, minocycline or doxycycline, thalidomide, and trametinib, in the treatment of brain and spinal AVMs.

Prenatal Diagnosis of Chromosome 16p11.2 Microdeletion.

(1) Objective: To investigate the prenatal diagnosis and genetic counseling for 16p11.2 microdeletion syndrome and to evaluate its pregnancy outcome. (2) Methods: This study included 4968 pregnant women who selected invasive prenatal diagnoses from 1 January 2017 to 1 August 2022. These 4698 pregnancies underwent chromosomal microarray analysis (CMA), data on 81 fetuses diagnosed with 16p11.2 microdeletion syndrome based on prenatal ultrasound features and genetic test results were recorded, and their pregnancy outcome was evaluated. (3) Results: 1.63% of fetuses (81/4968) were diagnosed with 16p11.2 microdeletion syndrome. Among these, there were skeletal malformations in 48.15% of the 81 fetuses, cardiovascular malformations in 30.86%, central nervous system malformations (CNS) in 11.11%, digestive system structural abnormalities in 6.17%, and isolated ultrasonography markers in 3.70%. (4) Conclusions: 16p11.2 microdeletion syndrome can display various systemic ultrasound abnormalities in the perinatal period but vertebral malformations are the most common. Our study is the first to report that TBX1 and CJA5 are associated with 16p11.2 microdeletion syndrome, expanding the disease spectrum of 16p11.2 microdeletion syndrome. In our study, the ventricular septal defect is the main feature of cardiac structural abnormalities caused by 16p11.2 microdeletion syndrome. In addition, our study highlights the use of CMA in 16p11.2 microdeletion syndrome, analyzed their genetic results, and evaluated the follow-up prognosis, which can be useful for prenatal diagnosis and genetic counseling.

Pathogenic/likely pathogenic copy number variations and regions of homozygosity in fetal central nervous system malformations.

To explore pathogenic/likely pathogenic copy number variations (P/LP CNVs) and regions of homozygosity (ROHs) in fetal central nervous system (CNS) malformations. A cohort of 539 fetuses with CNS malformations diagnosed by ultrasound/MRI was retrospectively analyzed between January 2016 and December 2019. All fetuses were analyzed by chromosomal microarray analysis (CMA). Three cases with ROHs detected by CMA were subjected to whole-exome sequencing (WES). The fetuses were divided into two groups according to whether they had other structural abnormalities. The CNS phenotypes of the two groups were further classified as simple (one type) or complicated (≥ 2 types). (1) A total of 35 cases with P/LP CNVs were found. The incidence of P/LP CNVs was higher in the extra-CNS group [18.00% (9/50)] than in the isolated group [5.32% (26/489)] (P < 0.01), while there was no significant difference between the simpletype and complicated-type groups. (2) In the simple-type group, the three most common P/LP CNV phenotypes were holoprosencephaly, Dandy-Walker syndrome, and exencephaly. There were no P/LP CNVs associated with anencephaly, microcephaly, arachnoid cysts, ependymal cysts, or intracranial hemorrhage. (3) Only four cases with ROHs were found, and there were no cases of uniparental disomy or autosomal diseases. The P/LP CNV detection rates varied significantly among the different phenotypes of CNS malformations, although simple CNS abnormalities may also be associated with genetic abnormalities.

Macrotrombocitopenia, dismorfismi facciali e ritardo dello sviluppo psicomotorio: il gene CDC42

Cell Division Control 42 (CDC42) gene encodes for a small GTPase with a fundamental role in controlling intracellular signaling pathway. Gene mutations can cause different phenotypic manifestations, which reflect the variety of the role of this mediator, namely growth failure, facial dysmorphism, intellectual disability, cardiac and nervous system malformations, immunologic and hematologic alterations. The paper describes the case of a 9-year-old female patient presenting with a CDC42 mutation with complex clinical features.

A CASE REPORT OF RARE LOCALİZATİON FOR CAVERNOMA İN MİDBRAİN

Cavernous malformations are classified as a group of vascular malformations of the central nervous system. It usually occurs in the supratentorial region, rarely in the brainstem. When they are symptomatic, headache, brain stem signs, sensory and motor changes can usually occur. But it can be confused with a stroke in the case of acute developing lateralizing sensory-motor symptoms, especially in the absence of brainstem signs. It can be distinguished from hematoma by its well-circumscribed and nodular appearance. Although the prognosis is generally good, it can lead to serious deficits in patients with malformations in the brainstem. In our case report, it was found that it is worth presenting a case that started acutely without brain stem findings and had a good prognosis at 3-month follow-up with loss of strength on the right side and was treated conservatively.

Whole exome screening of neurodevelopmental regression disorders in a cohort of Egyptian patients

Developmental regression describes a child who begins to lose his previously acquired milestones skills after he has reached a certain developmental stage and though affects his childhood development. It is associated with neurodegenerative diseases including leukodystrophy and neuronal ceroid lipofuscinosis diseases (NCLs), one of the most frequent childhood-onset neurodegenerative disorders. The current study focused on screening causative genes of developmental regression diseases comprising neurodegenerative disorders in Egyptian patients using next-generation sequencing (NGS)-based analyses as well as developing checklist to support clinicians who are not familiar with these diseases. A total of 763 Egyptian children (1 to 11 years), mainly diagnosed with developmental regression, seizures, or visual impairment, were studied using whole exome sequencing (WES). Among 763 Egyptian children, 726 cases were early clinically and molecularly diagnosed, including 482 cases that had pediatric stroke, congenital infection, and hepatic encephalopathy; meanwhile, 192 had clearly dysmorphic features, 31 showed central nervous system (CNS) malformation, 17 were diagnosed by leukodystrophy, 2 had ataxia telangiectasia, and 2 were diagnosed with tuberous sclerosis. The remained 37 out of 763 candidates were suspected with NCLs symptoms; however, 28 were confirmed to be NCLs patients, 1 was Kaya-Barakat-Masson syndrome, 1 was diagnosed as infantile neuroaxonal dystrophy, and 7 cases required further molecular diagnosis. This study provided an NGS-based approach of the genetic causes of developmental regression and neurodegenerative diseases as it comprised different variants and de novo mutations with complex phenotypes of these diseases which in turn help in early diagnoses and counseling for affected families.

Edward’s Syndrome-A Case Report

Edward’s syndrome is commonly known as the trisomy 18 syndrome. It is a devastating genetic disorder that can be characterized by multiple congenital anomalies. About 50% babies with this syndrome do not survive beyond one week of age and approximately 95% does not survive past the first year of life. The feature of Edward’s Syndrome involves in craniofacial, skeletal, cardiovascular, central nervous system and genitourinary malformations. The mortality rate among infants with trisomy 18 is high as a result of cardiac and renal malformations, feeding difficulty, sepsis and central nervous system defects. Here we report a neonate with Edward’s syndrome.&#x0D; BANGLADESH J CHILD HEALTH 2021; VOL 45 (3) : 178-181

Prenatal characteristics and management of pregnants with fetal cerebellar malformation: 4-year single center experience

Introduction: Fetal cerebellar malformations (FCM) are known as very rare central nervous system malformations that occur as hypoplasia or agenesis of the cerebellum or vermis. In this study, the characteristics, diagnostic methods, risk factors and management of pregnant women diagnosed with FCM in the prenatal period were investigated.&#x0D; Material and Method: The patients who diagnosed with prenatal FCM in the perinatology center between March 2017-February 2021 were included, retrospectively. The frequency of fetal magnetic resonance imaging (MRI), amniocentesis and/or karyotype analysis rates, and termination frequency were evaluated. In addition, the factors affecting the amniocentesis and the termination/follow-up decision were investigated. &#x0D; Results: A total of 42 pregnant with FCM were included. The median gestational age was 24.0 years, and the mean gestational week was 25+2 (SD±5+1) weeks. Nearly half (40.5%) of patients were diagnosed before 24 weeks of gestation and 45.2% were primiparous. Cerebellar hypoplasia was observed in 47.6%, while vermis agenesis was observed in almost one third (31.0%); and also 19.0% had multiple FCM. The fetal USG was used in all pregnant women, fetal MRI was performed in only 4.8% for diagnosis of FCM. The rate of amniocentesis and karyotype analysis were 11.9% and 7.1%, retrospectively. No any complications were observed after the amniocentesis. The termination rate was 30.9%. The mean gestational week of those who had live birth was higher than those who were terminated (24+4 vs 20+5) (p=0.019).&#x0D; Conclusion: The frequency of FCM diagnosis has increased with the development of modern medicine and technology. There is no relationship between demographic characteristics of pregnant women and FCM. Socio-economic levels and religious belief differences affect the termination and birth rates.