RESUMO
Due to abnormal prenatal ultrasound findings of femoral shortening and flattened facial profile, a G2P0 pregnant patient underwent an amniocentesis at 15 weeks of gestation for proband-only exome sequencing. Bioinformatic filtering for genes included on the laboratory's extended skeletal dysplasia panel identified a heterozygous, likely pathogenic, frameshift variant in DVL1 NM_001330311.2:c.1575_1582dup; (p.Pro528ArgfsTer149). Pathogenic variants in DVL1 are associated with autosomal dominant Robinow syndrome (ADRS), a genetic disorder characterized by skeletal dysplasia with genital and craniofacial abnormalities. Prenatal ultrasound in the third trimester noted shortened long bones (first percentile for gestational age), macrocephaly with frontal bossing, short and upturned nose with a wide nasal root, triangular mouth, low pedal arches concerning for rocker-bottom feet, and ambiguous genitalia. A postnatal exam by Medical Genetics confirmed the prenatal findings in addition to hypertelorism, brachydactyly with broad thumbs and halluces, clinodactyly of second fingers, rigid gums with a frontal frenulum, and a sacral dimple. This case describes a novel variant in DVL1 identified in a fetus with prenatal and postnatal phenotypic features consistent with ADRS. To our knowledge, this is the first reported case of a prenatal molecular diagnosis of the dominant form of Robinow syndrome and the third case to describe prenatal ultrasound findings associated with this diagnosis.
Assuntos
Anormalidades Craniofaciais , Proteínas Desgrenhadas , Deformidades Congênitas dos Membros , Fenótipo , Ultrassonografia Pré-Natal , Humanos , Feminino , Gravidez , Proteínas Desgrenhadas/genética , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/diagnóstico por imagem , Adulto , Mutação da Fase de Leitura , Nanismo/genética , Nanismo/diagnóstico , Nanismo/diagnóstico por imagem , Anormalidades UrogenitaisRESUMO
Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common primary brain tumor; many NF2 patients suffer from multiple meningiomas. In NF2, patients have mutations in the NF2 gene, specifically with loss of function in a tumor-suppressor protein that has a number of synonymous names, including: Merlin, Neurofibromin 2, and schwannomin. Merlin is a 70 kDa protein that has 10 different isoforms. The Hippo Tumor Suppressor pathway is regulated upstream by Merlin. This pathway is critical in regulating cell proliferation and apoptosis, characteristics that are important for tumor progression. Mutations of the NF2 gene are strongly associated with NF2 diagnosis, leading to benign proliferative conditions such as vestibular schwannomas and meningiomas. Unfortunately, even though these tumors are benign, they are associated with significant morbidity and the potential for early mortality. In this review, we aim to encompass meningiomas and vestibular schwannomas as they pertain to NF2 by assessing molecular genetics, common tumor types, and tumor pathogenesis.
Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Meníngeas/patologia , Meningioma/patologia , Neurofibromatose 2/patologia , Neuroma Acústico/patologia , Animais , Apoptose/genética , Neoplasias Encefálicas/genética , Proliferação de Células/genética , Humanos , Neoplasias Meníngeas/genética , Meningioma/genética , Mutação/genética , Neurofibromatose 2/genética , Neuroma Acústico/genéticaAssuntos
Betacoronavirus , Encéfalo/diagnóstico por imagem , Infecções por Coronavirus/complicações , Pacientes Internados/estatística & dados numéricos , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/etiologia , Pneumonia Viral/complicações , Adolescente , Adulto , COVID-19 , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Retrospectivos , SARS-CoV-2 , Adulto JovemRESUMO
BACKGROUND: Evaluate the utility of diffusion-weighted imaging (DWI) for the assessment of local recurrence of glioblastoma (GBM) on imaging performed 24 h following MRI-guided laser interstitial thermal therapy (LITT). We hypothesize that microscopic peritumoral infiltration correlates with early subtle variations on DWI images and apparent diffusion coefficient (ADC) maps. METHODS: Of 64 patients with GBM treated with LITT, 39 had MRI scans within 24 h after undergoing LITT. Patterns on DWI images and ADC maps 24 h following LITT were correlated with areas of future GBM recurrence identified through coregistration of subsequent MRI examinations. In the areas of suspected recurrence within the periphery of post-LITT lesions, signal intensity values on ADC maps were recorded and compared with the remaining peritumoral ring. RESULTS: Thirty-nine patients with GBM met the inclusion criteria. For predicting recurrent GBM, areas of decreased DWI signal and increased signal on ADC maps within the expected peritumoral ring of restricted diffusion identified 24 h following LITT showed 86.1% sensitivity, 75.2% specificity, and high correlation (r = 0.53) with future areas of GBM recurrence (P < .01). Areas of future recurrence demonstrated a 37% increase in the ADC value (P < .001), compared with findings in the surrounding treated peritumoral region. A significantly greater area under the receiver operating characteristics curve was determined for ADC values (P < .01). CONCLUSIONS: DWI obtained 24 h following LITT can help predict the location of GBM recurrence months before the development of abnormal enhancement. This may alter future treatment planning, perhaps suggesting areas that may be targeted for additional therapy.
RESUMO
Rupture of brain abscesses with evolution into ventriculitis with meningitis may result in sudden and dramatic worsening of the clinical situation. We present a 57-year-old man with such an event and fatal outcome. Multiple imaging modalities including computed tomography and advanced magnetic resonance imaging were correlated with gross specimen and histologic images. The differential diagnosis of multiple lesions with ring enhancement and prominent perifocal edema includes mainly infectious and neoplastic processes, such as brain abscess, metastasis, and multicentric glioblastoma. Pyogenic ventriculitis is an uncommon manifestation of severe intracranial infection that might be clinically obscure. We discuss the characteristic magnetic resonance findings of brain abscess and its complications, including meningitis and ventriculitis with emphasis on the role of diffusion-weighted and fluid-attenuated inversion recovery imaging.
RESUMO
BACKGROUND: Multiple sclerosis (MS) is a common autoimmune and neurodegenerative disease of the central nervous system characterized by inflammatory demyelination, axonal degeneration, and neuronal loss. The exact pathogenesis of MS remains uncertain; however, studies have shown that the development of MS is influenced by genetic and environmental factors. Cerebral aneurysms (CAs) are life-threatening lesions of cerebral vessels characterized by a bulge in the intracranial arterial wall that spontaneously ruptures. It has been hypothesized that patients with MS are at increased risk of developing cerebral aneurysms. This hypothesis can be supported by analyzing the pathogenesis and genetics of the development of MS and CA. To our knowledge, no previous studies have shown an association between MS and CA. CASE DESCRIPTION: In this report, we performed middle cerebral artery aneurysm clipping for two patients with MS who were referred to our clinic for CA in the bifurcation of middle cerebral artery that was found incidentally on magnetic resonance imaging. We aim to identify any genetic correlation between MS and CA pathogenesis. CONCLUSION: This report suggests a possible genetic association between MS and CAs. The strongest evidence of association was found for the TNFRSF1A gene, a proinflammatory gene that is involved in mitogen-activated protein kinase (MAPK) and NF-Kappa B signaling pathways, and has been identified as a candidate gene in the development of MS. MAPKs were also found to be elevated in CAs.
Assuntos
Aneurisma Intracraniano/complicações , Artéria Cerebral Média/cirurgia , Esclerose Múltipla/complicações , Adulto , Angiografia Cerebral , Feminino , Humanos , Achados Incidentais , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/genética , Aneurisma Intracraniano/cirurgia , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Esclerose Múltipla/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genéticaRESUMO
Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCß) as a critical mediator of this pathway and demonstrate that the PKCß inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCß and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.
Assuntos
Bloqueadores dos Canais de Cálcio/efeitos adversos , Síndrome de Marfan/tratamento farmacológico , Síndrome de Marfan/patologia , Adulto , Animais , Anti-Hipertensivos/administração & dosagem , Bloqueadores dos Canais de Cálcio/metabolismo , Criança , Pré-Escolar , Modelos Animais de Doenças , Humanos , Hidralazina/administração & dosagem , Indóis/administração & dosagem , Estudos Longitudinais , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Proteína Quinase C beta/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
The RAS-MAPK pathway is critical for human growth and development. Abnormalities at different steps of this signaling cascade result in neuro-cardio-facial-cutaneous syndromes, or the RASopathies, a group of disorders with overlapping yet distinct phenotypes. RASopathy patients have variable degrees of intellectual disability, poor growth, relative macrocephaly, ectodermal abnormalities, dysmorphic features, and increased risk for certain malignancies. Congenital heart disease, particularly hypertrophic cardiomyopathy (HCM) and pulmonic stenosis, are prominent features in these disorders. Significant locus heterogeneity exists for many of the RASopathies. Traditionally, these diseases were thought to be inherited in an autosomal dominant manner. However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and neurofibromatosis 1 and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated PTPN11 mutation (c.1403 C > T; p.T468M) and a novel, potentially pathogenic missense SOS1 variant (c.1018 C > T; p.P340S) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position. We describe detailed clinical manifestations, cardiac histopathology, and the molecular genetic findings. Oligogenic models of inheritance with potential synergistic effects should be considered in the RASopathies.