RESUMO
Background: Arthrochalasia type Ehlers-Danlos Syndrome (EDS) is a connective tissue disease characterized by severe generalized joint hypermobility, congenital bilateral hip dislocations, and recurrent joint subluxations and dislocations. Only one study has reported bone fragility resulting in fractures. The genetic abnormality underlying this disorder is a variant in the COL1A1 gene causing entire or partial loss of exon 6, resulting in defective type 1 collagen synthesis. Case Report: We report a female infant born at 35 weeks of gestation presenting with pathologic skull fracture following vaginal delivery. Genetic testing revealed a pathogenic variant in the COL1A1 gene (c.472-1G > C), consistent with arthrochalasia type EDS, reported previously. Conclusion: This report adds pathologic fractures to the phenotypic breadth of this type of EDS and reinforces the importance of including the condition on the differential diagnosis when early onset non-accidental injury or trauma is being considered.
Assuntos
Síndrome de Ehlers-Danlos , Fraturas Espontâneas , Fraturas Cranianas , Colágeno Tipo I/genética , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Éxons , Feminino , Humanos , Lactente , Recém-NascidoRESUMO
We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , Cromatina/genética , Epigenômica/métodos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Metilação de DNA , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Humanos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Tumor Rabdoide/tratamento farmacológico , Teratoma/tratamento farmacológicoRESUMO
BACKGROUND: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Genômica , Receptores Notch/biossíntese , Tumor Rabdoide/genética , Teratoma/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Lactente , Masculino , Prognóstico , Receptores Notch/genética , Tumor Rabdoide/patologia , Fatores de Risco , Transdução de Sinais/genética , Teratoma/patologiaRESUMO
Costello syndrome is characterized by constitutional mutations in the proto-oncogene HRAS, causing dysmorphic features, multiple cardiac problems, intellectual disability, and an increased risk of neoplasia. We report a male infant with dysmorphic features, born prematurely at 32 weeks, who, during his 3-month life span, had an unusually severe and ultimately fatal manifestation of hypertrophic cardiomyopathy and hyperinsulinemic hypoglycemia. Molecular studies in this patient demonstrated the uncommon Q22K mutation in the HRAS gene, diagnostic of Costello syndrome. The major autopsy findings revealed hypertrophic cardiomyopathy, congenital myopathy, and a 1.4-cm pancreatic nodule that was positive for insulin expression and morphologically identical to a focal lesion of congenital hyperinsulinism. Sequencing of KCNJ11 and ABCC8, the 2 most commonly mutated genes in focal lesion of congenital hyperinsulinism, revealed no mutations. While hyperinsulinism is a recognized feature of RASopathies, a focal proliferation of endocrine cells similar to a focal lesion of hyperinsulinism is a novel pathologic finding in Costello syndrome.
Assuntos
Cardiomiopatia Hipertrófica/congênito , Hiperinsulinismo Congênito/etiologia , Síndrome de Costello/complicações , Cardiomiopatia Hipertrófica/patologia , Hiperinsulinismo Congênito/patologia , Síndrome de Costello/genética , Síndrome de Costello/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Pâncreas/patologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
BACKGROUND: Herpes simplex virus encephalitis can manifest as a range of clinical presentations including classic adult, neonatal, and biphasic chronic-granulomatous herpes encephalitis. METHOD: We report an infant with granulomatous herpes simplex virus type 2 encephalitis with a subacute course and multicystic encephalopathy. CASE: A 2-month-old girl presented with lethargy and hypothermia. Computed tomography scan of the head showed multicystic encephalopathy and calcifications. Cerebrospinal fluid analysis by polymerase chain reaction testing for herpes simplex virus 1 and 2, enterovirus, and cytomegalovirus was negative. Normal cerebrospinal fluid interferon-α levels argued against Aicardi-Goutières syndrome. The patient died 2 weeks after presentation. At autopsy, multicystic encephalopathy was confirmed with bilateral gliosis, granulomatous inflammation with multinucleated giant cells, and calcifications. Bilateral healing necrotizing retinitis suggested a viral etiology, but retina and brain were free of viral inclusions and immunohistochemically negative for herpes simplex virus-2 and cytomegalovirus. However, polymerase chain reaction analysis showed herpes simplex virus-2 DNA in four cerebral paraffin blocks. Subsequent repeat testing of the initial cerebrospinal fluid sample using a different polymerase chain reaction assay was weakly positive for herpes simplex virus-2 DNA. CONCLUSION: Granulomatous herpes simplex virus encephalitis in infants can present with subacute course and result in multicystic encephalopathy with mineralization and minimal cerebrospinal fluid herpes simplex virus DNA load. Infectious etiologies should be carefully investigated in the differential diagnosis of multicystic encephalopathy with mineralization, in particular if multinucleated giant cells are present.
Assuntos
Encefalopatias/diagnóstico , Encefalite por Herpes Simples/diagnóstico , Herpesvirus Humano 2 , Encefalopatias/diagnóstico por imagem , Encefalopatias/fisiopatologia , DNA Viral/líquido cefalorraquidiano , Diagnóstico Diferencial , Encefalite por Herpes Simples/diagnóstico por imagem , Encefalite por Herpes Simples/fisiopatologia , Evolução Fatal , Feminino , Humanos , Lactente , Tomografia Computadorizada por Raios XRESUMO
The authors describe the case of a late preterm infant girl who presented prenatally with a low lumbar neural tube defect and features of Chiari malformation type II (CM-II). At birth, she exhibited stridor and underwent surgical repair of a lumbosacral myelomeningocele on Day 2 of life. The prognosis was deemed to be poor, and hence a "Chiari decompression" procedure was not undertaken. The patient was subsequently extubated and died on Day 10. Postmortem findings included a rarely described but characteristic granulomatous meningitic reaction to vernix caseosa, which presumably entered the subarachnoid space and spinal cord syrinx antenatally via the open neural tube defect. The significance of congenital stridor in the context of CM-II and in particular the role of vernix caseosa granulomatous meningitis are examined. The antenatal repair of myelomeningoceles, as championed by some, may prevent this ominous meningitic complication.
Assuntos
Malformação de Arnold-Chiari/complicações , Encefalocele/diagnóstico , Recém-Nascido Prematuro , Meningite/complicações , Meningite/etiologia , Microcefalia/complicações , Sons Respiratórios/etiologia , Siringomielia/diagnóstico , Verniz Caseoso , Obstrução das Vias Respiratórias/etiologia , Malformação de Arnold-Chiari/diagnóstico por imagem , Malformação de Arnold-Chiari/cirurgia , Autopsia , Encefalocele/complicações , Evolução Fatal , Feminino , Granuloma , Humanos , Hidrocefalia/diagnóstico , Recém-Nascido , Imageamento por Ressonância Magnética , Meningite/patologia , Meningomielocele/complicações , Meningomielocele/cirurgia , Microcefalia/diagnóstico por imagem , Cuidados Paliativos , Prognóstico , Siringomielia/complicações , Ultrassonografia Pré-NatalRESUMO
We present a case of a 23-year-old man with a tumor containing glial and rhabdoid elements where the former had features of a pleomorphic xanthoastrocytoma (PXA) and the latter had the immunophenotype and genetic profile of an atypical rhabdoid/teratoid tumor. The patient presented with a short history of raised intracranial pressure with rapid deterioration in sensorium. He had a poor outcome despite surgery and radiotherapy. We report this case because of its unusual presentation in adulthood and its occurrence in association with a PXA. We speculate that the PXA was a quiescent tumor and that the secondary genetic alterations, including inactivation of the INI1 gene led to clinical progression.
Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Neoplasias Primárias Múltiplas/patologia , Tumor Rabdoide/patologia , Teratoma/patologia , Adulto , Astrocitoma/genética , Astrocitoma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proteínas Cromossômicas não Histona/genética , Cromossomos Humanos Par 22/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Evolução Fatal , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/metabolismo , Mutação Puntual , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Proteína SMARCB1 , Teratoma/genética , Teratoma/metabolismo , Fatores de Transcrição/genéticaRESUMO
PURPOSE: High-grade gliomas (HGGs; WHO grades 3-4) are highly diverse, with survival times ranging from months to years. WHO 2000 grading criteria for high-grade oligodendroglial neoplasms [anaplastic oligoastrocytoma (AOA) and anaplastic oligodendroglioma (AO)] remain subjective, and the existence of grade 4 variants is controversial. PATIENTS AND METHODS: Overall survival (OS) of 1,093 adult patients with a cerebral HGG newly diagnosed between 1990 and 2005 was analyzed by univariate and multivariate models for significance of the following factors: patient age, surgery type, year of diagnosis, endothelial proliferation, necrosis, oligodendroglial histology, treatment center, and chromosome 1p, 19q, 7p (EGFR), and 10q (PTEN) abnormalities by fluorescence in situ hybridization (FISH). RESULTS: Necrosis was a statistically significant predictor of poor OS on univariate and multivariate analyses in AOA but not in AO. Median OS for patients with necrotic AOA (22.8 months) was significantly worse than for patients with non-necrotic AOA (86.9 months; P < .0001) but was better than conventional glioblastomas (9.8 months; P < .0001). In addition to patient age, the following were significant independent prognostic factors (P .001): grade and surgery type for the entire HGG cohort; modified grade for AOA (3 v 4); and modified grade, 1p/19q codeletion status, and oligodendroglial histology for the 586 HGGs analyzed by FISH. CONCLUSION: Stratification of AOA, but not of pure AO, into grades 3 and 4 on the basis of necrosis is prognostically justified and is more powerful than the current approach. Both routine histology and genetic testing provide independent, prognostically useful information.