RESUMO
Complex heart defects (CHD) are a common malformation associated with disruption of developmental pathways. The Cullin-RING ligases (CRLs) are multi-subunit E3 ubiquitin ligases in which Cullin 3 (CUL3) serves as a scaffolding subunit. Heterozygous CUL3 variants have been associated with neurodevelopmental disorders and pseudohypoaldosteronism type IIE. We report a fetus with CHD and a de novo CUL3 variant (NM_003590.4:c.[1549_1552del];[=], p.(Ser517Profs*23)) and review CUL3 variants reported with CHD. We postulate that CUL3 variants predispose to CHD and hypothesize mechanisms of pathogenesis.
Assuntos
Proteínas Culina , Cardiopatias Congênitas , Humanos , Proteínas Culina/genética , Proteínas Culina/metabolismo , Ubiquitina-Proteína Ligases , Cardiopatias Congênitas/genéticaRESUMO
Distal arthrogryposes (DA) are a group of conditions presenting with multiple congenital contractures in the distal joints. The 10 types of DA are distinguished by different extra-articular manifestations. Heterozygous gain-of-function variants in PIEZO2 are known to cause a spectrum of DA conditions including DA type 3, DA type 5, and possibly Marden Walker syndrome, which are usually distinguished by the presence of cleft palate (DA3), ptosis and restriction in eye movements (DA5), and specific facial abnormalities and central nervous system involvement, respectively. We report on a boy with a recurrent de novo heterozygous PIEZO2 variant in exon 20 (NM_022068.3: c.2994G > A, p.(Met998Ile); NM_001378183.1: c.3069G > A, p.(Met1023Ile)), who presented at birth with DA and later developed respiratory insufficiency. His phenotype broadly fits the PIEZO2 phenotypic spectrum and potentially extends it with novel phenotypic features of pretibial linear vertical crease, immobile skin, immobile tongue, and lipid myopathy.
Assuntos
Artrogripose , Humanos , Artrogripose/diagnóstico , Artrogripose/genética , Linhagem , Fenótipo , Canais Iônicos/genéticaRESUMO
Low-grade diffusely infiltrative tumour (LGDIT), SMARCB1-mutant, is a histopathological distinct low-grade lesion encountered in older children and young adults that shows epigenetic similarity with ATRT-MYC and has the potential for malignant progression.
Assuntos
Tumor Rabdoide , Teratoma , Criança , Epigênese Genética , Humanos , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Adulto JovemRESUMO
Monoallelic pathogenic variants in BICD2 are associated with autosomal dominant Spinal Muscular Atrophy Lower Extremity Predominant 2A and 2B (SMALED2A, SMALED2B). As part of the cellular vesicular transport, complex BICD2 facilitates the flow of constitutive secretory cargoes from the trans-Golgi network, and its dysfunction results in motor neuron loss. The reported phenotypes among patients with SMALED2A and SMALED2B range from a congenital onset disorder of respiratory insufficiency, arthrogryposis, and proximal or distal limb weakness to an adult-onset disorder of limb weakness and contractures. We report an infant with congenital respiratory insufficiency requiring mechanical ventilation, congenital diaphragmatic paralysis, decreased lung volume, and single finger camptodactyly. The infant displayed appropriate antigravity limb movements but had radiological, electrophysiological, and histopathological evidence of myopathy. Exome sequencing and long-read whole-genome sequencing detected a novel de novo BICD2 variant (NM_001003800.1:c.[1543G>A];[=]). This is predicted to encode p.(Glu515Lys); p.Glu515 is located in the coiled-coil 2 mutation hotspot. We hypothesize that this novel phenotype of diaphragmatic paralysis without clear appendicular muscle weakness and contractures of large joints is a presentation of BICD2-related disease.
Assuntos
Contratura , Insuficiência Respiratória , Paralisia Respiratória , Humanos , Lactente , Proteínas Associadas aos Microtúbulos/genética , Debilidade Muscular , Mutação , Linhagem , Fenótipo , Insuficiência Respiratória/genética , Paralisia Respiratória/genéticaRESUMO
Mosaic KRAS variants and other RASopathy genes cause oculoectodermal, encephalo-cranio-cutaneous lipomatosis, and Schimmelpenning-Feuerstein-Mims syndromes, and a spectrum of vascular malformations, overgrowth and other associated anomalies, the latter of which are only recently being characterized. We describe eight individuals in total (six unreported cases and two previously reported cases) with somatic KRAS variants and variably associated features. Given the findings of somatic overgrowth (in seven individuals) and vascular or lymphatic malformations (in eight individuals), we suggest mosaic RASopathies (mosaic KRAS variants) be considered in the differential diagnosis for individuals presenting with asymmetric overgrowth and lymphatic or vascular anomalies. We expand the association with embryonal tumors, including the third report of embryonal rhabdomyosarcoma, as well as novel findings of Wilms tumor and nephroblastomatosis in two individuals. Rare or novel findings in our series include the presence of epilepsy, polycystic kidneys, and T-cell deficiency in one individual, and multifocal lytic bone lesions in two individuals. Finally, we describe the first use of targeted therapy with a MEK inhibitor for an individual with a mosaic KRAS variant. The purposes of this report are to expand the phenotypic spectrum of mosaic KRAS-related disorders, and to propose possible mechanisms of pathogenesis, and surveillance of its associated findings.
Assuntos
Anormalidades Múltiplas/patologia , Neoplasias Renais/patologia , Mosaicismo , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Malformações Vasculares/patologia , Tumor de Wilms/patologia , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Neoplasias Renais/genética , Masculino , Fenótipo , Malformações Vasculares/genética , Tumor de Wilms/genéticaRESUMO
TRPV4 encodes a polymodal calcium-permeable plasma membrane channel. Dominant pathogenic mutations in TRPV4 lead to a wide spectrum of abnormal phenotypes. This is the first report of biallelic TRPV4 mutations and we describe two compound heterozygous siblings presenting with a complex phenotype including severe neuromuscular involvement. In light of previously well described dominant inheritance for TRPV4-related neuromuscular disease, our study suggests a role for compound heterozygosity and loss-of-function as a potential novel disease mechanism for this group of disorders. Profound intellectual disability was also noted in both affected children, suggesting that TRPV4 may be necessary for normal brain development.
Assuntos
Deficiência Intelectual/genética , Doenças Neuromusculares/genética , Doenças do Sistema Nervoso Periférico/genética , Canais de Cátion TRPV/genética , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto , Doenças Neuromusculares/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Fenótipo , IrmãosRESUMO
Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero- or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro functional assessment in HEK293 cells of the impact of the identified SCN4A mutations showed loss-of-function of the mutant Nav1.4 channels. All, apart from one, of the mutations either caused fully non-functional channels, or resulted in a reduced channel activity. Each of the affected cases carried at least one full loss-of-function mutation. In five out of six families, a second loss-of-function mutation was present on the trans allele. These functional results provide convincing evidence for the pathogenicity of the identified mutations and suggest that different degrees of loss-of-function in mutant Nav1.4 channels are associated with attenuation of the skeletal muscle action potential amplitude to a level insufficient to support normal muscle function. The results demonstrate that recessive loss-of-function SCN4A mutations should be considered in patients with a congenital myopathy.
Assuntos
Hipocinesia/diagnóstico , Hipocinesia/genética , Mutação/genética , Miopatias Congênitas Estruturais/diagnóstico , Miopatias Congênitas Estruturais/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Feminino , Células HEK293 , Humanos , Recém-Nascido , Masculino , Linhagem , Índice de Gravidade de Doença , Xenopus laevisRESUMO
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.
Assuntos
Genoma Humano , Impressão Genômica , Síndrome da Persistência do Padrão de Circulação Fetal/patologia , Alvéolos Pulmonares/anormalidades , Veias Pulmonares/patologia , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Feminino , Fatores de Transcrição Forkhead/genética , Genes Letais , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Masculino , Linhagem , Síndrome da Persistência do Padrão de Circulação Fetal/genética , Alvéolos Pulmonares/patologia , Deleção de SequênciaRESUMO
PURPOSE: To compare histologically transected fila from pediatric patients with tethered cord syndrome (TCS), with and without a low conus, with controls, focusing on collagenous and elastic tissue. METHODS: Thirty fila from patients with TCS, including 5 where minimal cautery was used prior to filum section, were compared with fila from 27 pediatric cadavers without TCS (controls). Sections of fila were stained with H&E, Masson trichrome and Verhoeff von Gieson elastic stains, and 7 with Gordon and Sweet's reticulin stain. RESULTS: Fila from controls showed loose fibrous connective tissue (FCT) with thin and evenly dispersed elastic fibers (EFs). Reticulin fibers (RFs) were seen in blood vessel walls and nerve twigs. Fat was identified microscopically in 2 fila. All fila from patients with TCS had dense FCT. The EFs were in normal numbers in 17, and focally or diffusely decreased in 13. All 25 patients where the fila were cauterized during resection had thick and coiled EFs. Coiling was not seen when minimal cautery was applied. RFs were seen in blood vessel walls and nerve twigs. Fat was identified in 19 patients. Findings were similar, whether the conus termination was normal or low. CONCLUSION: The fila of all patients with TCS, whether or not the conus was low, showed abnormal FCT. EFs were decreased in 48 % of patients; however, there were thick and coiled EFs in all patients. Coiling of EFs, initially thought to be an abnormality in patients, is considered most likely to be a result of cautery (i.e., artifactual/iatrogenic coiling).
Assuntos
Atenção , Cauda Equina/patologia , Tecido Conjuntivo/patologia , Tecido Elástico/patologia , Defeitos do Tubo Neural/patologia , Adolescente , Cauda Equina/diagnóstico por imagem , Criança , Pré-Escolar , Tecido Conjuntivo/diagnóstico por imagem , Tecido Elástico/diagnóstico por imagem , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Defeitos do Tubo Neural/diagnóstico por imagemRESUMO
BACKGROUND: The cure rate for childhood intracranial ependymoma is approximately 70% in the setting of a gross total resection followed by radiation, but management remains challenging in patients with residual disease. Therefore, robust biomarkers are needed to guide the development of new targeted therapy. The authors evaluated the expression of several biomarkers in pediatric intracranial ependymoma and observed that the expression of enhancer of zeste homolog 2 (EZH2), a polycomb complex protein involved in epigenetic regulation of gene expression, was independently associated with poor survival. METHODS: Tissue microarray immunostaining was performed on 180 ependymoma samples from 12 of 16 Canadian pediatric centers. Expression levels of EZH2, Ki-67, B lymphoma Moloney-murine leukemia virus insertion region 1 homolog, tumor protein 16 (P16), Y-box binding protein 1, phosphorylated protein kinase B (pAKT), and epidermal growth factor receptor were evaluated. Cox regression analyses were performed, and the Kaplan-Meier method was used to construct survival curves. RESULTS: EZH2 expressed in 16% of tumors was associated with inferior 5-year overall survival. Ki-67 and pAKT levels were associated with a poor outcome in patients with posterior fossa ependymoma, and the absence of P16 was associated with a poor outcome in patients with supratentorial ependymoma. Multivariate analysis revealed that younger age and EZH2 expression (95% confidence interval, 1.1-36.0) were independent markers of a poor prognosis. CONCLUSIONS: EZH2 is a novel, independent marker of a poor prognosis in patients with ependymoma, especially in those who have tumors located in the posterior fossa. EZH2, pAKT, and P16 are potential therapeutic targets, particularly for patients who have tumors in which standard gross total resection plus fractionated radiotherapy is not feasible.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Ependimoma/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Adolescente , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Proteína Potenciadora do Homólogo 2 de Zeste , Ependimoma/mortalidade , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by mutations in SMARCAL1. A frequent complication is arteriosclerosis associated with reduced elastin expression; however, the mechanism underlying the reduced elastin expression remains unknown. METHODS: Expression of transcriptional regulators of elastin (ELN) and microRNA (miRNA) regulators of ELN messenger RNA (mRNA), ELN promoter methylation, and ELN mRNA poly(A) tail length were assessed by quantitative RT-PCR, bisulfite Sanger sequencing, and the Poly(A) Tail Length Assay Kit, respectively, in unaffected developing human aortae and in an SIOD aorta. RESULTS: Comparing unaffected fetal and adult aortae, ELN precursor mRNA (pre-mRNA) levels remained nearly constant, whereas mRNA levels declined by ~10(2)-fold. This corresponded with a reduction in poly(A) tail length but not with changes in the other parameters. In contrast, compared to the unaffected fetal aortae, the SIOD aorta had 18-fold less ELN pre-mRNA and 10(4)-fold less mRNA. This corresponded with increased expression of miRNA regulators and shorter ELN mRNA poly(A) tail lengths but not with altered expression of ELN transcriptional regulators or ELN promoter methylation. CONCLUSION: Posttranscriptional mechanisms account for the reduction in ELN mRNA levels in unaffected aortae, whereas transcriptional and posttranscriptional mechanisms reduce elastin expression in SIOD aorta and predispose to arteriosclerosis.
Assuntos
Aorta/metabolismo , Arteriosclerose/genética , Elastina/genética , Síndromes de Imunodeficiência/genética , Síndrome Nefrótica/genética , Osteocondrodisplasias/genética , Embolia Pulmonar/genética , Precursores de RNA/genética , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , Transcrição Gênica , Adolescente , Adulto , Aorta/embriologia , Aorta/patologia , Arteriosclerose/embriologia , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Metilação de DNA , Regulação para Baixo , Elastina/metabolismo , Feminino , Idade Gestacional , Humanos , Síndromes de Imunodeficiência/embriologia , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Síndrome Nefrótica/embriologia , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Osteocondrodisplasias/embriologia , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patologia , Doenças da Imunodeficiência Primária , Regiões Promotoras Genéticas , Embolia Pulmonar/embriologia , Embolia Pulmonar/metabolismo , Embolia Pulmonar/patologia , Precursores de RNA/metabolismo , RNA Mensageiro/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
PURPOSE: Gross total resection (GTR) of intracranial ependymoma is an accepted goal. More controversial is radiotherapy deferral. This study reports on children treated with gross total resection who did not receive upfront adjuvant radiotherapy. METHODS: We conducted a retrospective review of children with intracranial ependymoma in 12 Canadian centers. Patients who had GTR of their tumor and no upfront radiotherapy were identified. Immunostaining was performed for Ki-67, epidermal growth factor receptor (EGFR), and EZH2 on archived tissue. The Kaplan-Meier survival analysis was performed and compared with those who had GTR followed by radiation. RESULTS: Twenty-six children were identified treated with GTR alone at diagnosis; 12 posterior fossa ependymoma (PFE) WHO grade II, and 14 supratentorial ependymoma (STE). Progression-free survival (PFS) in ependymoma treated with GTR alone at diagnosis was inferior in those with high Ki-67 or positive EZH2 immunostaining. Survival was inferior for patients less than 2 years old at diagnosis (p = 0.002). Survival was comparable to PFE WHO grade II and STE who had GTR followed by radiation (p = 0.62). Five-year PFS and overall survival (OS) of those treated with GTR alone were 60 and 70% respectively for PFE and 45 and 70% respectively for STE (p = 0.2; 0.55). CONCLUSIONS: This study suggests that there is a subset of children with certain biologic features who, in the setting of a prospective clinical trial, might be candidates for observation following GTR. Good risk factors for this approach include age of 2 years or older, low Ki-67, and negative EZH2. If relapse occurs, it may be confined to the primary site, allowing for possible salvage with GTR followed by XRT.
Assuntos
Neoplasias Encefálicas/cirurgia , Ependimoma/cirurgia , Neurocirurgia/métodos , Adolescente , Neoplasias Encefálicas/mortalidade , Canadá , Criança , Pré-Escolar , Planejamento em Saúde Comunitária , Proteína Potenciadora do Homólogo 2 de Zeste , Ependimoma/mortalidade , Receptores ErbB/metabolismo , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Masculino , Complexo Repressor Polycomb 2/metabolismo , Radioterapia Adjuvante , Estudos RetrospectivosRESUMO
CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development.
Assuntos
3-Hidroxiesteroide Desidrogenases/genética , Anormalidades Múltiplas/genética , Alelos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Temperatura , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Éxons , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Homologia de Sequência de Aminoácidos , Adulto JovemRESUMO
OBJECTIVE: The major form of magnetic resonance imaging-defined white matter injury (WMI) comprises diffuse lesions where the burden of small necrotic foci (microscopic necrosis) is poorly defined. We hypothesized that myelination failure associated with diffuse WMI involves an aberrant injury response linked to arrested preoligodendrocyte (preOL) maturation in reactive astrocyte-rich lesions. METHODS: A retrospective autopsy series (1983-2000) was selected for cases with diffuse WMI and analyzed relative to prospectively collected contemporary cases (2003-2010). Controls were age- and region-matched to address regional variation in preOL maturation. Successive oligodendrocyte stages were analyzed with lineage-specific markers. Microscopic necrosis was quantified with microglial markers. Axon injury markers defined the burden of axonopathy. Extracellular matrix remodeling was defined by detection of hyaluronic acid (HA), an inhibitor of preOL maturation, and the HA receptor, CD44. RESULTS: In the contemporary case series, diffuse WMI was accompanied by a significant reduction in the burden of microscopic necrosis and axonopathy. Diffuse astrogliosis extended into the lesion surround with elevated HA and astrocyte-expressed CD44. The total population of OL lineage stages was significantly increased in lesions. This increase coincided with significant expansion of the preOL pool. INTERPRETATION: Although these data confirm that microscopic necrosis occurs in contemporary cases, the markedly decreased burden supports that it does not contribute substantially to myelination failure. The primary mechanism of myelination failure involves a disrupted cellular response whereby preOLs fail to differentiate in diffuse astrogliotic lesions. PreOL maturation arrest converts chronic WMI to a more immature state related to the burden of astrogliosis.
Assuntos
Proliferação de Células , Doenças do Prematuro/patologia , Bainha de Mielina/patologia , Oligodendroglia/patologia , Células-Tronco/patologia , Astrócitos/patologia , Diferenciação Celular/fisiologia , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Leucoencefalopatias/patologia , Masculino , Necrose , Fibras Nervosas Mielinizadas/patologia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
We describe respiratory chain complex IV deficiency (cytochrome c oxidase deficiency) in a female infant with a neonatal rapidly progressive fatal course characterized by microcephaly, encephalopathy, persistent lactic acidosis, and hypertrophic cardiomyopathy. Postmortem cardiac muscle study showed marked complex IV deficiency. In contrast, complex IV activity was only slightly decreased in the skeletal muscle. Subsequent molecular investigations showed compound heterozygosity for two known pathogenic mutations in the COX15 gene. We compare the findings in our patient to those of the three previously reported cases.
Assuntos
Encefalopatias Metabólicas Congênitas/genética , Deficiência de Citocromo-c Oxidase/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Encéfalo/patologia , Encefalopatias Metabólicas Congênitas/diagnóstico , Deficiência de Citocromo-c Oxidase/diagnóstico , Deficiência de Citocromo-c Oxidase/patologia , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Cardiopatias/diagnóstico , Cardiopatias/genética , Cardiopatias/patologia , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Mutação/genética , Miocárdio/patologiaRESUMO
INTRODUCTION: Spontaneous regression of pilocytic astrocytoma after incomplete resection is well recognized, especially for cerebellar and optic pathway tumors, and tumors associated with Neurofibromatosis type-1 (NF1). The purpose of this report is to document spontaneous regression of pilocytic astrocytomas of the septum pellucidum and to discuss the possible role of cannabis in promoting regression. CASE REPORT: We report two children with septum pellucidum/forniceal pilocytic astrocytoma (PA) tumors in the absence of NF-1, who underwent craniotomy and subtotal excision, leaving behind a small residual in each case. During Magnetic Resonance Imaging (MRI) surveillance in the first three years, one case was dormant and the other showed slight increase in size, followed by clear regression of both residual tumors over the following 3-year period. Neither patient received any conventional adjuvant treatment. The tumors regressed over the same period of time that cannabis was consumed via inhalation, raising the possibility that the cannabis played a role in the tumor regression. CONCLUSION: We advise caution against instituting adjuvant therapy or further aggressive surgery for small residual PAs, especially in eloquent locations, even if there appears to be slight progression, since regression may occur later. Further research may be appropriate to elucidate the increasingly recognized effect of cannabis/cannabinoids on gliomas.
Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Fórnice/patologia , Fumar Maconha , Regressão Neoplásica Espontânea/patologia , Septo Pelúcido/patologia , Adolescente , Astrocitoma/cirurgia , Neoplasias Encefálicas/cirurgia , Criança , Feminino , Fórnice/cirurgia , Humanos , Inalação , Imageamento por Ressonância Magnética , Neoplasia Residual/patologia , Septo Pelúcido/cirurgiaRESUMO
INTRODUCTION: Choroid plexus hyperplasia (CPH) is a rare cause of cerebrospinal fluid (CSF) overproduction and shunt-resistant hydrocephalus in infants. If treated with a ventriculoperitoneal (VP) shunt, these patients secondarily develop CSF accumulation along the shunt tract and within the peritoneum. The surgical management of this condition is not as clearly defined as in the case of a choroid plexus papilloma or carcinoma. CASE REPORT: An 8-day-old male patient presented with bulging fontanelle, head circumference = 42 cm (>98th percentile), and cranial ultrasound demonstrating communicating hydrocephalus with enlarged choroid plexuses. A VP shunt was inserted, and secondarily progressive hydrocephalus, shunt tract fluid accumulation, and ascites developed. The infant underwent staged bilateral plexectomy and is tolerating CSF diversion. The pathology confirmed CPH. DISCUSSION: Of the cases reported in the literature, treatments have included CSF shunting, endoscopic coagulation, and craniotomy with plexectomy. CSF shunting was required in the majority but not all. Only those having undergone bilateral choroid plexectomy have been rendered shunt free.
Assuntos
Plexo Corióideo/cirurgia , Hidrocefalia/cirurgia , Hiperplasia/cirurgia , Plexo Corióideo/patologia , Humanos , Hidrocefalia/patologia , Hiperplasia/diagnóstico , Hiperplasia/patologia , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Resultado do Tratamento , Derivação VentriculoperitonealRESUMO
INTRODUCTION: Surgical resection is generally recommended for cervicomedullary tumors, but morbidity of resection may be significant. This study sought to identify MRI characteristics that might predict morbidity and extent of resection. MATERIALS AND METHODS: A retrospective review was performed of MRI findings, histopathology, extent, and morbidity of resection in cervicomedullary gliomas undergoing resection during 1985-2008. RESULTS: Of 78 brainstem tumors, nine cervicomedullary tumors undergoing resection were identified: two pilocytic astrocytomas, two gangliogliomas, and five grade II astrocytomas. Mean age was 6.3 years (range 1.7-11.2 years). Initial treatment was surgery in seven: biopsy (1), <25% resection (4), and 25-50% resections (2). Bulbar worsening occurred in five of six patients with interposed areas of non-enhancement versus one of three patients without interposed non-enhancing tissue (P = 0.014). Additionally, bulbar worsening occurred in five of five patients with a poorly defined tumor/brainstem interface and abnormal low T1 signal extending beyond obvious tumor into the brainstem versus one of four with a well-defined tumor margin (P = 0.008). Following chemo- or radiotherapy, the definition of the brainstem/tumor interface improved. In four patients undergoing surgery after chemo/radiotherapy, more extensive resections were achieved without neurologic worsening: >80% in three and 30% in one. CONCLUSION: A less aggressive initial surgical approach, supplemented by postoperative chemotherapy, designed to preserve brainstem function, is proposed for patients with interposed non-enhancing tissue continuous with normal cervical cord or medulla and/or a poorly defined ventral tumor/brainstem interface with abnormal low T1 signal extending beyond obvious tumor into the brainstem.
Assuntos
Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/cirurgia , Glioma/patologia , Glioma/cirurgia , Neoplasias do Tronco Encefálico/terapia , Vértebras Cervicais , Quimioterapia Adjuvante , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Glioma/terapia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Bulbo/patologia , Bulbo/cirurgia , Neurônios/patologia , Radioterapia Adjuvante , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1. Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874Gâ¯>â¯A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.