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1.
Magn Reson Imaging Clin N Am ; 32(3): 395-412, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-38944430

RÉSUMÉ

This review article provides a comprehensive overview of fetal MR imaging in supratentorial cerebral malformations. It emphasizes the importance of fetal MR imaging as an adjunct diagnostic tool used alongside ultrasound, improving the detection and characterization of prenatal brain abnormalities. This article reviews a spectrum of cerebral malformations, their MR imaging features, and the clinical implications of these findings. Additionally, it outlines the growing importance of fetal MR imaging in the context of perinatal care.


Sujet(s)
Encéphale , Imagerie par résonance magnétique , Diagnostic prénatal , Humains , Grossesse , Femelle , Imagerie par résonance magnétique/méthodes , Diagnostic prénatal/méthodes , Encéphale/imagerie diagnostique , Encéphale/malformations , Encéphale/embryologie
2.
Semin Fetal Neonatal Med ; 29(1): 101525, 2024 Feb.
Article de Anglais | MEDLINE | ID: mdl-38632010

RÉSUMÉ

Advances in fetal brain neuroimaging, especially fetal neurosonography and brain magnetic resonance imaging (MRI), allow safe and accurate anatomical assessments of fetal brain structures that serve as a foundation for prenatal diagnosis and counseling regarding fetal brain anomalies. Fetal neurosonography strategically assesses fetal brain anomalies suspected by screening ultrasound. Fetal brain MRI has unique technological features that overcome the anatomical limits of smaller fetal brain size and the unpredictable variable of intrauterine motion artifact. Recent studies of fetal brain MRI provide evidence of improved diagnostic and prognostic accuracy, beginning with prenatal diagnosis. Despite technological advances over the last several decades, the combined use of different qualitative structural biomarkers has limitations in providing an accurate prognosis. Quantitative analyses of fetal brain MRIs offer measurable imaging biomarkers that will more accurately associate with clinical outcomes. First-trimester ultrasound opens new opportunities for risk assessment and fetal brain anomaly diagnosis at the earliest time in pregnancy. This review includes a case vignette to illustrate how fetal brain MRI results interpreted by the fetal neurologist can improve diagnostic perspectives. The strength and limitations of conventional ultrasound and fetal brain MRI will be compared with recent research advances in quantitative methods to better correlate fetal neuroimaging biomarkers of neuropathology to predict functional childhood deficits. Discussion of these fetal sonogram and brain MRI advances will highlight the need for further interdisciplinary collaboration using complementary skills to continue improving clinical decision-making following precision medicine principles.


Sujet(s)
Encéphale , Neuroimagerie , Diagnostic prénatal , Humains , Grossesse , Neuroimagerie/méthodes , Neuroimagerie/tendances , Femelle , Encéphale/imagerie diagnostique , Encéphale/malformations , Diagnostic prénatal/méthodes , Diagnostic prénatal/tendances , Échographie prénatale/méthodes , Imagerie par résonance magnétique/méthodes , Assistance
3.
Radiologie (Heidelb) ; 64(5): 410-419, 2024 May.
Article de Allemand | MEDLINE | ID: mdl-38639917

RÉSUMÉ

CLINICAL ISSUE: Malformations of the central nervous system belong to the most common developmental disorders in humans. The clinical presentation of brain malformations is nonspecific including developmental delay, hypotonia, and/or epilepsy. The great heterogeneity concerning etiology, mechanisms of development and morphology is challenging for diagnosis and classification of brain malformations. Thereby recognizing specific malformations is essential for optimal patient management and prognostic evaluation. The aim of this article is to give an overview of several clinically relevant brain malformations occurring from different disrupted developmental processes in brain formation. STANDARD RADIOLOGICAL METHODS: Several brain malformations are already diagnosed during routine ultrasound in pregnancy. However pre- and postnatal magnetic resonance imaging remains the gold standard in detecting the partially subtle changes and to classify the malformations. METHODICAL INNOVATIONS: Advances in pre- and postnatal neuroimaging techniques and increasing investigation of genetic mechanisms underlying brain formation and its abnormalities have led to a better understanding of embryologic development and pathogeneses of brain malformations. CONCLUSION: Besides patient's history and clinical phenotype, neuroimaging plays a key role in diagnosis. Not always a specific diagnosis can be made, but neuroimaging patterns often enable a focused genetic testing and therefore are revolutionary for etiologic and prognostic assignment. Basic knowledge of brain development facilitates understanding and classifying of structural brain abnormalities.


Sujet(s)
Encéphale , Femelle , Humains , Nouveau-né , Grossesse , Encéphale/malformations , Encéphale/imagerie diagnostique , Encéphale/anatomopathologie , Imagerie par résonance magnétique , Malformations du système nerveux/diagnostic , Malformations du système nerveux/imagerie diagnostique , Malformations du système nerveux/génétique , Malformations du système nerveux/anatomopathologie , Malformations du système nerveux/classification , Neuroimagerie/méthodes
4.
Am J Med Genet A ; 194(8): e63593, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-38549403

RÉSUMÉ

Biallelic pathogenic variants in ZNF335 are one of the genetic causes of microcephaly, reported only in the past decade. It regulates neural progenitor proliferation and neurogenesis by interacting with a H3K4 methyltransferase complex. Biallelic pathogenic ZNF335 variants predispose to neuronal cell death and aberrant differentiation, thus causing secondary microcephaly. These neurodevelopmental anomalies lead to imaging findings in the cortex, posterior fossa, and basal ganglia. We report an individual of Nepalese ancestry with a novel homozygous ZNF335 variant (c.3591 + 2dup) (p.?) (NM_022095.3) which on further RNA analysis confirmed a splice site variant in intron 23. The patient presented with primary microcephaly with atrophic cerebral hemispheres, oversimplification of gyri, basal ganglia, and corpus callosal atrophy. Literature review on the topic revealed a spectrum of brain abnormalities, which can present either with a primary or secondary microcephaly depending upon the underlying genetic variant.


Sujet(s)
Allèles , Protéines de liaison à l'ADN , Microcéphalie , Facteurs de transcription , Humains , Encéphale/imagerie diagnostique , Encéphale/anatomopathologie , Encéphale/malformations , Protéines de liaison à l'ADN/génétique , Prédisposition génétique à une maladie , Homozygote , Imagerie par résonance magnétique , Microcéphalie/génétique , Microcéphalie/anatomopathologie , Mutation/génétique , Facteurs de transcription/génétique
5.
J Hum Genet ; 69(6): 263-270, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-38459224

RÉSUMÉ

Biallelic pathogenic variants in MADD lead to a very rare neurodevelopmental disorder which is phenotypically pleiotropic grossly ranging from severe neonatal hypotonia, failure to thrive, multiple organ dysfunction, and early lethality to a similar but milder phenotype with better survival. Here, we report 5 patients from 3 unrelated Egyptian families in whom 4 patients showed the severe end of the spectrum displaying neonatal respiratory distress, hypotonia and chronic diarrhea while one patient presented with the mild form displaying moderate intellectual disability and myopathy. In addition, we observed distal arthrogryposis and nonspecific structural brain anomalies in all our patients. Interestingly, cerebellar and brainstem hypoplasia were noted in one patient. Whole exome sequencing identified three novel homozygous variants in the MADD gene: two likely pathogenic [c.4321delC p.(Gln1441ArgfsTer46) and c.2620 C > T p.(Arg874Ter)] and one variant of uncertain significance (c.4307 G > A, p.Arg1436Gln). The variants segregated with the disease in all available family members. Our findings confirm that arthrogryposis, genital, cardiac and structural brain anomalies are manifestations of MADD which expand the spectrum of MADD-related neurodevelopmental disorder. Moreover, they further highlight the convergence of MADD variants on different organ systems leading to complex phenotypes.


Sujet(s)
Troubles du développement neurologique , Pedigree , Phénotype , Femelle , Humains , Nourrisson , Nouveau-né , Mâle , Arthrogrypose/génétique , Arthrogrypose/anatomopathologie , Encéphale/anatomopathologie , Encéphale/malformations , Égypte , , Homozygote , Déficience intellectuelle/génétique , Déficience intellectuelle/anatomopathologie , Hypotonie musculaire/génétique , Hypotonie musculaire/anatomopathologie , Mutation , Troubles du développement neurologique/génétique , Troubles du développement neurologique/anatomopathologie
6.
Am J Med Genet A ; 194(8): e63611, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-38528425

RÉSUMÉ

The mediator complex subunit 13 (MED13) gene is implicated in neurodevelopmental disorders including autism spectrum disorder (ASD), intellectual disability, and speech delay with varying severity and course. Additional, extra central nervous system, features include eye or vision problems, hypotonia, congenital heart abnormalities, and dysmorphisms. We describe a 7-year- and 4-month-old girl evaluated for ASD whose brain magnetic resonance imaging was suggestive of multiple cortical tubers. The exome sequencing (ES - trio analysis) uncovered a unique, de novo, frameshift variant in the MED13 gene (c.4880del, D1627Vfs*17), with a truncating effect on the protein. This case report thus expands the phenotypic spectrum of MED13-related disorders to include brain abnormalities.


Sujet(s)
Trouble du spectre autistique , Mutation avec décalage du cadre de lecture , Imagerie par résonance magnétique , Complexe médiateur , Complexe de la sclérose tubéreuse , Humains , Femelle , Trouble du spectre autistique/génétique , Trouble du spectre autistique/imagerie diagnostique , Trouble du spectre autistique/anatomopathologie , Trouble du spectre autistique/diagnostic , Complexe médiateur/génétique , Mutation avec décalage du cadre de lecture/génétique , Complexe de la sclérose tubéreuse/génétique , Complexe de la sclérose tubéreuse/diagnostic , Complexe de la sclérose tubéreuse/imagerie diagnostique , Complexe de la sclérose tubéreuse/anatomopathologie , Enfant , Encéphale/imagerie diagnostique , Encéphale/anatomopathologie , Encéphale/malformations , , Phénotype
7.
Pediatr Nephrol ; 39(7): 2115-2129, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38376554

RÉSUMÉ

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent 20-30% of all birth defects and are often associated with extra-renal malformations. We investigated the frequency of brain/spine malformations and neurological features in children with CAKUT. METHODS: We reviewed the clinico-radiological and genetic data of 199 out of 1,165 children with CAKUT evaluated from 2006 to 2023 (99 males, mean age at MRI 6.4 years) who underwent brain and/or spine MRI. Patients were grouped according to the type of CAKUT (CAKUT-K involving the kidney and CAKUT-H involving the inferior urinary tract). Group comparisons were performed using χ2 and Fisher exact tests. RESULTS: Brain/spine malformations were observed in 101/199 subjects (50.7%), 8.6% (101/1165) of our CAKUT population, including midbrain-hindbrain anomalies (40/158, 25.3%), commissural malformations (36/158, 22.7%), malformation of cortical development (23/158, 14.5%), Chiari I anomaly (12/199, 6%), cranio-cervical junction malformations (12/199, 6%), vertebral defects (46/94, 48.9%), caudal regression syndrome (29/94, 30.8%), and other spinal dysraphisms (13/94, 13.8%). Brain/spine malformations were more frequent in the CAKUT-K group (62.4%, p < 0.001). Sixty-two subjects (62/199, 31.2%) had developmental delay/intellectual disability. Neurological examination was abnormal in 40/199 (20.1%). Seizures and/or electroencephalographic anomalies were reported in 28/199 (14%) and behavior problems in 19/199 subjects (9%). Developmental delay/intellectual disability was more frequent in kidney dysplasia (65.2%) and agenesis (40.7%) (p = 0.001). CONCLUSIONS: We report a relative high frequency of brain/spine malformations and neurodevelopmental disorders in children with CAKUT who underwent MRI examinations in a tertiary referral center, widening the spectrum of anomalies associated with this condition.


Sujet(s)
Encéphale , Imagerie par résonance magnétique , Troubles du développement neurologique , Rachis , Malformations urogénitales , Humains , Mâle , Femelle , Enfant , Enfant d'âge préscolaire , Troubles du développement neurologique/épidémiologie , Troubles du développement neurologique/étiologie , Troubles du développement neurologique/diagnostic , Rachis/malformations , Rachis/imagerie diagnostique , Malformations urogénitales/épidémiologie , Malformations urogénitales/complications , Malformations urogénitales/diagnostic , Encéphale/imagerie diagnostique , Encéphale/malformations , Encéphale/anatomopathologie , Études rétrospectives , Nourrisson , Adolescent , Reflux vésico-urétéral
8.
Prenat Diagn ; 44(3): 357-359, 2024 Mar.
Article de Anglais | MEDLINE | ID: mdl-38366977

RÉSUMÉ

A 36 years old woman in her first pregnancy was referred at 24w3d for a dedicated neurosonographic examination due to a suspected short corpus callosum (CC). The examination depicted a dysgenetic CC with asymmetric thickness at the level of the body in coronal views, very thin in the midline and thicker in both sides, suggesting bilateral formation of Probst bundles. The BPD, HC, and transverse cerebellar diameters were in the normal low range without associated growth restriction. Associated anomalies were not detected in the brain or other organs. Following genetic consultation and a normal CMA, trio exome sequencing was performed and a de novo missense pathogenic mutation c.2353 C > T in the DHX30 gene was detected. This variant has been previously reported in children and adults, mostly with a severe phenotype including neurodevelopmental disorder with variable motor and language impairment, but also mild phenotypes have been reported. MRI describes delayed myelination, ventriculomegaly, and cortical and cerebellar atrophy as imaging features in affected patients. This is the first prenatal report of a DHX30-associated neurodevelopmental disorder in which the fetus presents with isolated callosal dysgenesis, stressing the importance of exome sequencing in fetuses with this condition, as far as it is phenotypic presentation of numerous syndromes with different outcomes.


Sujet(s)
Corps calleux , Hydrocéphalie , Adulte , Femelle , Humains , Grossesse , Agénésie du corps calleux/imagerie diagnostique , Agénésie du corps calleux/génétique , Encéphale/malformations , Corps calleux/imagerie diagnostique , Foetus , Hydrocéphalie/anatomopathologie , Imagerie par résonance magnétique/méthodes , RNA helicases
9.
Cereb Cortex ; 34(2)2024 01 31.
Article de Anglais | MEDLINE | ID: mdl-38365268

RÉSUMÉ

Cleft lip/palate is a common orofacial malformation that often leads to speech/language difficulties as well as developmental delays in affected children, despite surgical repair. Our understanding of brain development in these children is limited. This study aimed to analyze prenatal brain development in fetuses with cleft lip/palate and controls. We examined in utero MRIs of 30 controls and 42 cleft lip/palate fetal cases and measured regional brain volumes. Cleft lip/palate was categorized into groups A (cleft lip or alveolus) and B (any combination of clefts involving the primary and secondary palates). Using a repeated-measures regression model with relative brain hemisphere volumes (%), and after adjusting for multiple comparisons, we did not identify significant differences in regional brain growth between group A and controls. Group B clefts had significantly slower weekly cerebellar growth compared with controls. We also observed divergent brain growth in transient brain structures (cortical plate, subplate, ganglionic eminence) within group B clefts, depending on severity (unilateral or bilateral) and defect location (hemisphere ipsilateral or contralateral to the defect). Further research is needed to explore the association between regional fetal brain growth and cleft lip/palate severity, with the potential to inform early neurodevelopmental biomarkers and personalized diagnostics.


Sujet(s)
Bec-de-lièvre , Fente palatine , Femelle , Enfant , Grossesse , Humains , Bec-de-lièvre/imagerie diagnostique , Bec-de-lièvre/chirurgie , Fente palatine/imagerie diagnostique , Fente palatine/chirurgie , Encéphale/imagerie diagnostique , Encéphale/malformations , Foetus
10.
Gene ; 907: 148280, 2024 May 20.
Article de Anglais | MEDLINE | ID: mdl-38360123

RÉSUMÉ

Orofacial clefts (OFCs) represent the most prevalent congenital craniofacial anomalies, significantly impacting patients' appearance, oral function, and psychological well-being. Among these, non-syndromic OFCs (NSOFCs) are the most predominant type, with the etiology attributed to a combination of genetic and environmental factors. Rare variants of key genes involved in craniofacial development-related signaling pathway are crucial in the occurrence of NSOFCs, and our recent studies have identified PTCH1, a receptor-coding gene in the Hedgehog signaling pathway, as a causative gene for NSOFCs. However, the role of PTCH2, the paralog of PTCH1, in pathogenesis of NSOFCs remains unclear. Here, we perform whole-exome sequencing to explore the genetic basis of 144 sporadic NSOFC patients. We identify five heterozygous variants of PTCH2 in four patients: p.L104P, p.A131G, p.R557H, p.I927S, and p.V978D, with the latter two co-occurring in a single patient. These variants, all proven to be rare through multiple genomic databases, with p.I927S and p.V978D being novel variants and previously unreported. Sequence alignment suggests that these affected amino acids are evolutionarily conserved across vertebrates. Utilizing predictive structural modeling tools such as AlphaFold and SWISS-MODEL, we propose that these variants may disrupt the protein's structure and function. In summary, our findings suggest that PTCH2 may be a novel candidate gene predicted to be associated with NSOFCs, thereby broadening the spectrum of causative genes implicated in the craniofacial anomalies.


Sujet(s)
Bec-de-lièvre , Fente palatine , Récepteur Patched-2 , Animaux , Humains , Encéphale/malformations , Bec-de-lièvre/génétique , Fente palatine/génétique , Protéines Hedgehog/génétique , Récepteur Patched-2/génétique , Transduction du signal
12.
Mol Biol Rep ; 51(1): 188, 2024 Jan 25.
Article de Anglais | MEDLINE | ID: mdl-38270710

RÉSUMÉ

BACKGROUND: Fetal ventriculomegaly (VM), a common brain structure malformation detected during prenatal ultrasound diagnosis, is associated with an increased risk of neurodevelopmental disorders (NDDs) after birth. KDM4B encodes a lysine-specific demethylase that interacts with histone H3K23me3. Variations in KDM4B are reportedly associated with human NDDs; however, only 11 such patients have been reported. Herein, we report a fetus with VM and agenesis of the corpus callosum (ACC), which suggests that KDM4B plays an important role in fetal brain development. METHODS: Fetal skin tissue and parental peripheral venous blood samples were collected. Whole-exome and Sanger sequencing were performed to analyze fetal germline variants. Human 293T cells transfected with wild-type or mutant KDM4B were used for western blotting (WB) to analyze protein expression levels. RESULTS: An insertion variant of KDM4B, NM_015015.3: c.2889_2890insGAGAGCATCACGGTGAGCTGTGGGGTGGGGCAGGGGGCGGGGGGAGGCTGGGAGCACAGTGACAACCTGTACCCC, was identified in the fetal tissue; however, the parents carried the wild-type gene. The WB results indicated significantly reduced expression of the mutant protein, likely owing to decreased stability. CONCLUSIONS: The structural abnormalities in the brain of the studied fetus may be attributed to an insertion variant of KDM4B. This study highlights the importance of screening for KDM4B variants and considering potential copy number variations when observing VM or ACC in prenatal ultrasound imaging.


Sujet(s)
Encéphale , Variations de nombre de copies de segment d'ADN , Histone , Femelle , Humains , Grossesse , Technique de Western , Encéphale/malformations , Encéphale/imagerie diagnostique , Foetus/imagerie diagnostique , Jumonji Domain-Containing Histone Demethylases/génétique
13.
Neurogenetics ; 25(2): 93-102, 2024 Apr.
Article de Anglais | MEDLINE | ID: mdl-38296890

RÉSUMÉ

Congenital muscular dystrophies (CMDs) are a group of rare muscle disorders characterized by early onset hypotonia and motor developmental delay associated with brain malformations with or without eye anomalies in the most severe cases. In this study, we aimed to uncover the genetic basis of severe CMD in Egypt and to determine the efficacy of whole exome sequencing (WES)-based genetic diagnosis in this population. We recruited twelve individuals from eleven families with a clinical diagnosis of CMD with brain malformations that fell into two groups: seven patients with suspected dystroglycanopathy and five patients with suspected merosin-deficient CMD. WES was analyzed by variant filtering using multiple approaches including splicing and copy number variant (CNV) analysis. We identified likely pathogenic variants in FKRP in two cases and variants in POMT1, POMK, and B3GALNT2 in three individuals. All individuals with merosin-deficient CMD had truncating variants in LAMA2. Further analysis in one of the two unsolved cases showed a homozygous protein-truncating variant in Feline Leukemia Virus subgroup C Receptor 1 (FLVCR1). FLVCR1 loss of function has never been previously reported. Yet, loss of function of its paralog, FLVCR2, causes lethal hydranencephaly-hydrocephaly syndrome (Fowler Syndrome) which should be considered in the differential diagnosis for dystroglycanopathy. Overall, we reached a diagnostic rate of 86% (6/7) for dystroglycanopathies and 100% (5/5) for merosinopathy. In conclusion, our results provide further evidence that WES is an important diagnostic method in CMD in developing countries to improve the diagnostic rate, management plan, and genetic counseling for these disorders.


Sujet(s)
Encéphale , , Dystrophies musculaires , N-acetylglucosaminyltransferase , Humains , Mâle , Égypte , Femelle , Dystrophies musculaires/génétique , Dystrophies musculaires/diagnostic , Enfant d'âge préscolaire , Encéphale/malformations , Encéphale/anatomopathologie , Enfant , Nourrisson , Laminine/génétique , Récepteurs viraux/génétique , Mannosyltransferases/génétique , Pedigree , Pentosyltransferases/génétique , Variations de nombre de copies de segment d'ADN , Mutation , Adolescent , Malformations du système nerveux/génétique
14.
Nicotine Tob Res ; 26(3): 385-391, 2024 Feb 22.
Article de Anglais | MEDLINE | ID: mdl-37578845

RÉSUMÉ

INTRODUCTION: Tobacco product flavors can increase product appeal, adolescent initiation and experimentation, and difficulty quitting. Flavored tobacco products are not restricted in Vietnam or the Philippines despite the high smoking prevalence among those 15 years of age and older (24% and 23%, respectively). There are no published reports to our knowledge on the levels of flavor chemicals in the cigarettes sold in these two countries. METHODS: Cigarettes were purchased in Vietnam (32 brand variants) and the Philippines (19 brand variants) during 2020. Chemical analyses gave the mg/filter, mg/rod, and mg/stick (= mg/(filter + rod)) values for 180 individual flavor chemicals. Values were calculated for menthol, clove-related compounds, and "other flavor chemicals" (OFCs). RESULTS: Five flavor groupings were found among the brand variants purchased in Vietnam: menthol + OFCs (n = 15), OFCs only (n = 8), nonflavored (n = 7), menthol + OFCs with a clove flavorant (n = 1) and menthol only (n = 1). Three flavor groupings were found among the brand variants purchased in the Philippines: menthol + OFCs (n = 10), nonflavored (n = 5), and menthol only (n = 4). CONCLUSIONS: A range of flavored cigarette products are being offered by tobacco companies in Vietnam and the Philippines, presumably to maximize cigarette sales. Regulation of flavor chemicals should be considered in these two countries. IMPLICATIONS: Article 9 of the WHO Framework Convention on Tobacco Control (FCTC), ratified by both Vietnam and the Philippines, states that "there is no justification for permitting the use of ingredients, such as flavoring agents, which help make tobacco products attractive." Flavors increase product appeal, adolescent initiation and experimentation, and difficulty quitting. These analyses found that cigarettes purchased in Vietnam and the Philippines contained menthol and other flavor chemicals. Tobacco companies are offering multiple flavor chemical profiles and nominally nonflavored versions in these countries; regulation of flavor chemicals should be considered in these two countries.


Sujet(s)
Encéphale/malformations , Bec-de-lièvre , Fente palatine , Dispositifs électroniques d'administration de nicotine , Produits du tabac , Adolescent , Humains , Menthol/analyse , Philippines , Vietnam/épidémiologie , Aromatisants/analyse
15.
Nephron ; 148(4): 264-272, 2024.
Article de Anglais | MEDLINE | ID: mdl-36617405

RÉSUMÉ

The clinical features of cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis (COACH) characterize the rare autosomal recessive multisystem disorder called COACH syndrome. COACH syndrome belongs to the spectrum of Joubert syndrome and related disorders (JSRDs) and liver involvement distinguishes COACH syndrome from the rest of the JSRD spectrum. Developmental delay and oculomotor apraxia occur early but with time, these can improve and may not be readily apparent or no longer need active medical management. Congenital hepatic fibrosis and renal disease, on the other hand, may develop late, and the temporal incongruity in organ system involvement may delay the recognition of COACH syndrome. We present a case of a young adult presenting late to a Renal Genetics Clinic for evaluation of renal cystic disease with congenital hepatic fibrosis, clinically suspected to have autosomal recessive polycystic kidney disease. Following genetic testing, a reevaluation of his medical records from infancy, together with reverse phenotyping and genetic phasing, led to a diagnosis of COACH syndrome.


Sujet(s)
Malformations multiples , Encéphale/malformations , Vermis cérébelleux , Cervelet/malformations , Cholestase , Colobome , Maladies génétiques congénitales , Déficience intellectuelle , Maladies du foie , Malformations du système nerveux , Polykystose rénale autosomique récessive , Jeune adulte , Humains , Colobome/diagnostic , Colobome/génétique , Polykystose rénale autosomique récessive/diagnostic , Polykystose rénale autosomique récessive/génétique , Retard de diagnostic , Génotype , Cirrhose du foie/génétique , Ataxie/diagnostic , Ataxie/génétique , Déficience intellectuelle/génétique , Incapacités de développement
16.
J Genet Genomics ; 51(2): 222-229, 2024 Feb.
Article de Anglais | MEDLINE | ID: mdl-37003352

RÉSUMÉ

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb-/- embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.


Sujet(s)
Encéphale , Bec-de-lièvre , Fente palatine , Animaux , Humains , Souris , Encéphale/malformations , Bec-de-lièvre/génétique , Fente palatine/génétique , Filamines/génétique , Mammifères , Mutation
17.
Pediatr Transplant ; 28(1): e14640, 2024 Feb.
Article de Anglais | MEDLINE | ID: mdl-37965976

RÉSUMÉ

BACKGROUND: COACH syndrome is a rare autosomal recessive genetic disease characterized by liver fibrosis, which leads to severe complications related to portal hypertension. However, only a few patients with COACH syndrome undergoing liver transplantation (LT) have been reported. MATERIALS AND METHODS: We herein report the outcomes of four children who underwent LT for COACH syndrome at our institute and review three previously reported cases to elucidate the role of LT in COACH syndrome. RESULTS: All four patients in our institute were female, and three received living donors LT. All patients were diagnosed with COACH syndrome by genetic testing. LT was performed in these patients at 3, 7, 9, and 14 years old. The indication for LT was varices related to portal hypertension in all patients. One showed an intrapulmonary shunt. Blood tests revealed renal impairment due to nephronophthisis in three patients, and one developed renal insufficiency after LT. The liver function was maintained in all patients. A literature review revealed detailed information for three more patients. The indication for LT in these three cases was portal hypertension, such as bleeding from esophageal varices. One patient had chronic renal failure on hemodialysis at LT and underwent combined liver and kidney transplantation. Of these three previous patients, one died from hepatic failure due to de novo HCV infection 3 years after LT. CONCLUSIONS: LT should be considered an effective treatment for COACH syndrome in patients with severe portal hypertension. However, a detailed follow-up of the renal function is necessary.


Sujet(s)
Malformations multiples , Ataxie , Encéphale , Cholestase , Colobome , Malformations oculaires , Maladies génétiques congénitales , Hypertension portale , Maladies kystiques rénales , Maladies du foie , Transplantation hépatique , Insuffisance rénale , Enfant , Femelle , Humains , Encéphale/malformations , Cervelet/malformations , Hypertension portale/complications , Hypertension portale/chirurgie , Maladies kystiques rénales/complications , Cirrhose du foie/complications , Cirrhose du foie/chirurgie , Transplantation hépatique/effets indésirables , Insuffisance rénale/complications , Insuffisance rénale/chirurgie , Rétine
18.
Semin Pediatr Neurol ; 47: 101075, 2023 10.
Article de Anglais | MEDLINE | ID: mdl-37919030

RÉSUMÉ

BRAIN INJURY DURING TRANSITION IN THE NEWBORN WITH CONGENITAL HEART DISEASE: HAZARDS OF THE PREOPERATIVE PERIOD: Jennifer M. Lynch, J. William Gaynor, Daniel J. Licht Seminars in Pediatric Neurology Volume 28, December 2018, Pages 60-65 Infants born with critical congenital heart disease are at risk for neurodevelopmental morbidities later in life. In-utero differences in fetal circulation lead to vulnerabilities which lead to an increased incidence of stroke, white matter injury, and brain immaturity. Recent work has shown these infants may be most vulnerable to brain injury during the early neonatal period when they are awaiting their cardiac surgeries. Novel imaging and monitoring modalities are being employed to investigate this crucial time period and elucidate the precise timing and cause of brain injury in this population.


Sujet(s)
Lésions encéphaliques , Cardiopathies congénitales , Accident vasculaire cérébral , Nouveau-né , Enfant , Humains , Période préopératoire , Cardiopathies congénitales/chirurgie , Cardiopathies congénitales/complications , Lésions encéphaliques/étiologie , Encéphale/malformations , Accident vasculaire cérébral/complications
19.
Am J Med Genet A ; 191(10): 2656-2663, 2023 10.
Article de Anglais | MEDLINE | ID: mdl-37466007

RÉSUMÉ

Biallelic pathogenic variants in LAMB1 have been associated with autosomal recessive lissencephaly 5 (OMIM 615191), which is characterized by brain malformations (cobblestone lissencephaly, hydrocephalus), developmental delay, and epilepsy. Pathogenic variants in LAMB1 are rare, with only 11 pathogenic variants and 11 patients reported to date. Here, we report on a 6-year-old patient from a consanguineous family with profound developmental delay, microcephaly, and a history of a perinatal cerebrovascular event. Brain magnetic resonance imaging (MRI) showed cerebellar cystic defects, signal intensity abnormalities, and a hypoplastic corpus callosum. Trio-exome analysis revealed a homozygous in-frame deletion of Exons 23 and 24 of LAMB1 affecting 104 amino acids including the epidermal growth factor (EGF)-like units 11 and 12 in Domain III. To our knowledge, this is the first reported in-frame deletion in LAMB1. Our findings broaden the clinical and molecular spectrum of LAMB1-associated syndromes.


Sujet(s)
Microcéphalie , Malformations du système nerveux , Grossesse , Femelle , Humains , Enfant , Malformations du système nerveux/génétique , Encéphale/malformations , Microcéphalie/génétique , Délétion de séquence/génétique , Homozygote , Laminine
20.
PLoS One ; 18(7): e0289227, 2023.
Article de Anglais | MEDLINE | ID: mdl-37506075

RÉSUMÉ

BACKGROUND: Infants with congenital Zika syndrome (CZS) are known to exhibit characteristic brain abnormalities. However, the brain anatomy of Zika virus (ZIKV)-exposed infants, born to ZIKV-positive pregnant mothers, who have normal-appearing head characteristics at birth, has not been evaluated in detail. The aim of this prospective study is, therefore, to compare the cortical and subcortical brain structural volume measures of ZIKV-exposed normocephalic infants to age-matched healthy controls. METHODS AND FINDINGS: We acquired T2-MRI of the whole brain of 18 ZIKV-exposed infants and 8 normal controls on a 3T MRI scanner. The MR images were auto-segmented into eight tissue types and anatomical regions including the white matter, cortical grey matter, deep nuclear grey matter, corticospinal fluid, amygdala, hippocampus, cerebellum, and brainstem. We determined the volumes of these regions and calculated the total intracranial volume (TICV) and head circumference (HC). We compared these measurements between the two groups, controlling for infant age at scan, by first comparing results for all subjects in each group and secondly performing a subgroup analysis for subjects below 8 weeks of postnatal age at scan. ZIKV-exposed infants demonstrated a significant decrease in amygdala volume compared to the control group in both the group and subgroup comparisons (p<0.05, corrected for multiple comparisons using FDR). No significant volume differences were observed in TICV, HC, or any specific brain tissue structures or regions. Study limitations include small sample size, which was due to abrupt cessation of extramural funding as the ZIKV epidemic waned. CONCLUSION: ZIKV-exposed infants exhibited smaller volumes in the amygdala, a brain region primarily involved in emotional and behavioral processing. This brain MRI finding may lead to poorer behavioral outcomes and warrants long-term monitoring of pediatric cases of infants with gestational exposure to Zika virus as well as other neurotropic viruses.


Sujet(s)
Craniosynostoses , Microcéphalie , Complications infectieuses de la grossesse , Infection par le virus Zika , Virus Zika , Nouveau-né , Grossesse , Femelle , Humains , Nourrisson , Enfant , Infection par le virus Zika/épidémiologie , Études prospectives , Complications infectieuses de la grossesse/épidémiologie , Imagerie par résonance magnétique , Encéphale/malformations , Microcéphalie/épidémiologie
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