RESUMO
PURPOSE: The traditional imaging findings reported in Sturge-Weber syndrome (SWS) include endpoints of cortical injury-cortical atrophy and cortical calcifications-but also what has been termed a "leptomeningeal angiomatosis," the latter recognized and reported as a leptomeningeal enhancement on magnetic resonance imaging (MRI). The objective of this study is to demonstrate through neuropathological correlation that the "leptomeningeal angiomatosis" in patients with Sturge-Weber syndrome (SWS), represents a re-opened primitive venous network in the subarachnoid space that likely acts as an alternative venous drainage pathway, seen separately to abnormal pial enhancement. MATERIALS AND METHODS: Retrospective review of MR imaging and surgical pathology of patients that underwent surgery for epilepsy at a tertiary, children's hospital. A pediatric radiologist with more than 20 years of experience reviewed the MR imaging. Surgically resected brain specimens that had been sectioned and fixed in 10% paraformaldehyde for histologic processing, following processing and paraffin embedding, were cut into 5-µm unstained slides which were subsequently stained with hematoxylin and eosin (H&E). Slides were re-examined by a board-certified pediatric neuropathologist, and histologic features specifically relating to cerebral surface and vascularity were documented for correlation with MR imaging of the resected region performed prior to resection. RESULTS: Five patients were reviewed (3 boys and 2 girls; the median age at the onset of seizures was 12 months (IQR, 7 to 45 months); the median age at surgery was 33 months (IQR, 23.5 to 56.5 months)). Surgical procedures included the following: 4, hemispherotomy (right: 2, left: 2) and 1, hemispherectomy (right). A subarachnoid space varicose network was present on both MRI and histology in 4 patients. Calcifications were seen on both MRI and histology in 3 patients. Abnormal leptomeningeal enhancement was present in 5 patients and seen separately from the subarachnoid vascular network in 4 patients. CONCLUSION: Histopathology confirmed the MRI findings of a subarachnoid space varicose network seen separately from leptomeningeal enhancement and presumed to represent an alternative venous drainage pathway to compensate for maldevelopment of cortical veins, the primary abnormality in SWS. No pial-based angioma was identified.
Assuntos
Imageamento por Ressonância Magnética , Síndrome de Sturge-Weber , Humanos , Síndrome de Sturge-Weber/diagnóstico por imagem , Síndrome de Sturge-Weber/cirurgia , Síndrome de Sturge-Weber/patologia , Masculino , Feminino , Estudos Retrospectivos , Pré-Escolar , Imageamento por Ressonância Magnética/métodos , Criança , Lactente , Pia-Máter/diagnóstico por imagem , Pia-Máter/patologia , Espaço Subaracnóideo/diagnóstico por imagem , Espaço Subaracnóideo/patologia , Espaço Subaracnóideo/cirurgia , Adolescente , Angiomatose/cirurgia , Angiomatose/diagnóstico por imagem , Angiomatose/patologia , Varizes/diagnóstico por imagem , Varizes/cirurgia , Varizes/patologiaRESUMO
Sturge-Weber syndrome (SWS), a neurocutaneous disorder, is characterized by capillary malformations (CM) in the skin, brain, and eyes. Patients may suffer from seizures, strokes, and glaucoma, and only symptomatic treatment is available. CM are comprised of enlarged vessels with endothelial cells (ECs) and disorganized mural cells. Our recent finding indicated that the R183Q mutation in ECs leads to heightened signaling through phospholipase Cß3 and protein kinase C, leading to increased angiopoietin-2 (ANGPT2). Furthermore, knockdown of ANGPT2, a crucial mediator of pro-angiogenic signaling, inflammation, and vascular remodeling, in EC-R183Q rescued the enlarged vessel phenotype in vivo. This prompted us to look closer at the microenvironment in CM-affected vascular beds. We analyzed multiple brain histological sections from patients with GNAQ-R183Q CM and found enlarged vessels devoid of mural cells along with increased macrophage-like cells co-expressing MRC1 (CD206, a mannose receptor), CD163 (a scavenger receptor and marker of the monocyte/macrophage lineage), CD68 (a pan macrophage marker), and LYVE1 (a lymphatic marker expressed by some macrophages). These macrophages were not found in non-SWS control brain sections. To investigate the mechanism of increased macrophages in the perivascular environment, we examined THP1 (monocytic/macrophage cell line) cell adhesion to EC-R183Q versus EC-WT under static and laminar flow conditions. First, we observed increased THP1 cell adhesion to EC-R183Q compared to EC-WT under static conditions. Next, using live cell imaging, we found THP1 cell adhesion to EC-R183Q was dramatically increased under laminar flow conditions and could be inhibited by anti-ICAM1. ICAM1, an endothelial cell adhesion molecule required for leukocyte adhesion, was strongly expressed in the endothelium in SWS brain histological sections, suggesting a mechanism for recruitment of macrophages. In conclusion, our findings demonstrate that macrophages are an important component of the perivascular environment in CM suggesting they may contribute to the CM formation and SWS disease progression.
Assuntos
Capilares/anormalidades , Síndrome de Sturge-Weber , Malformações Vasculares , Humanos , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patologia , Síndrome de Sturge-Weber/terapia , Células Endoteliais/metabolismo , Capilares/patologia , Macrófagos/metabolismo , Microambiente Tumoral , Proteínas de Transporte Vesicular/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismoRESUMO
OBJECTIVES: We aimed to investigate the clinicopathologic features of and genetic changes in Sturge-Weber syndrome (SWS) in patients with refractory epilepsy. METHODS: Clinical data were retrospectively analyzed. H&E and immunohistochemistry were performed to assess pathologic changes. Targeted amplicon sequencing was applied to investigate the somatic GNAQ (c.548G>A) mutation. The potential predictors of seizure outcomes were estimated by univariate and multivariate statistical analyses. RESULTS: Forty-eight patients with SWS and refractory epilepsy were enrolled. According to the imaging data and pathologic examination, ipsilateral hippocampal sclerosis (HS), calcification of leptomeningeal arteries, and focal cortical dysplasia were found in 14 (29.2%), 31 (64.6%), and 37 (77.1%) patients, respectively. A high frequency of GNAQ alteration was detected in both cerebral cortex (57.7%) and ipsilateral hippocampus (50.0%) from patients with SWS. During follow-up, 43 of 48 patients (85.4%) had achieved seizure control (Engel class I). Statistically, HS signs on imaging were found to be independent predictors of unfavorable seizure outcomes (P = .015). CONCLUSIONS: Calcification of leptomeningeal arteries, focal cortical dysplasia, and GNAQ alteration are common features in SWS pathology. Patients with refractory epilepsy caused by SWS can achieve satisfactory seizure control after surgery, but seizure control was compromised in patients with comorbid HS.
Assuntos
Epilepsia Resistente a Medicamentos , Síndrome de Sturge-Weber , Humanos , Síndrome de Sturge-Weber/complicações , Síndrome de Sturge-Weber/patologia , Masculino , Feminino , Epilepsia Resistente a Medicamentos/patologia , Epilepsia Resistente a Medicamentos/etiologia , Criança , Adolescente , Estudos Retrospectivos , Adulto , Pré-Escolar , Adulto Jovem , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Mutação , Hipocampo/patologia , Lactente , Pessoa de Meia-IdadeRESUMO
Objective: To investigate the clinicopathological features of children with Sturge-Weber syndrome and to analyze the correlation between the distribution area of leptomeningeal angiomatosis, the degree of cerebral cortical calcification, and the degree of cerebral atrophy associated with epileptic seizures. Methods: 10 children were diagnosed with SWS with FCD IIIc by histopathology and immunohistochemistry. Spearman correlation analysis was used to calculate the association of SWS with FCD IIIc and seizures in children. Results: The leptomeningeal angiomatosis area was markedly positively correlated with the degree of brain atrophy in 10 children with SWS (r = 0.783, p = 0.007). The distribution of leptomeningeal hemangiomatosis, the degree of cortical calcification, and brain atrophy were not significantly correlated with epilepsy. Conclusion: SWS may be accompanied by FCD IIIc. The more extensive the cerebral lobes of leptomeningeal angiomatosis in SWS, the more pronounced the brain atrophy.
Assuntos
Angiomatose , Epilepsia , Displasia Cortical Focal , Síndrome de Sturge-Weber , Criança , Humanos , Síndrome de Sturge-Weber/complicações , Síndrome de Sturge-Weber/diagnóstico , Síndrome de Sturge-Weber/patologia , Convulsões/etiologia , Angiomatose/complicações , Angiomatose/diagnóstico , Atrofia/complicaçõesRESUMO
Sturge-Weber syndrome (SWS) is a rare, noninherited neurovascular disorder characterized by abnormal vasculature in the brain, skin, and eye. Patients with SWS characteristically have facial capillary malformation, also known as port-wine birthmark, a leptomeningeal vascular malformation seen on contrast-enhanced magnetic resonance imaging images, abnormal blood vessels in the eye, and glaucoma. Patients with SWS have impaired perfusion to the brain and are at high risk of venous stroke and stroke-like episodes, seizures, and both motor and cognitive difficulties. While the activating R183Q GNAQ somatic mutation is the most common somatic mutation underlying SWS, recent research also implicates that GNA11 and GNB2 somatic mutations are related to SWS. Recent retrospective studies suggest the use of low-dose aspirin and vitamin D in treatment for SWS and prospective drug trials have supported the usefulness of cannabidiol and Sirolimus. Presymptomatic treatment with low-dose aspirin and antiepileptic drugs shows promising results in delaying seizure onset in some patients. This review focuses on the latest progress in the field of research for Sturge-Weber syndrome and highlights directions for future research.
Assuntos
Acidente Vascular Cerebral , Síndrome de Sturge-Weber , Humanos , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patologia , Síndrome de Sturge-Weber/terapia , Convulsões , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Acidente Vascular Cerebral/patologia , AspirinaRESUMO
BACKGROUND AND PURPOSE: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by clinical manifestations involving the brain, eye and skin. SWS is commonly caused by somatic mutations in G protein subunit Alpha Q (GNAQ). Five cases of subunit Alpha 11 (GNA11) mutations have been reported. We studied phenotypic features of GNA11-SWS and compared them with those of classic SWS. METHODS: Within two European multidisciplinary centers we looked for patients with clinical characteristics of SWS and a GNA11 mutation. Clinical and radiological data were collected retrospectively and prospectively. RESULTS: We identified three patients with SWS associated with a somatic GNA11 mutation. All had disseminated capillary malformation (CM) and hyper- or hypotrophy of an extremity. At birth, the CMs of the face, trunk and limbs were pink and patchy, and slowly darkened with age, evolving to a purple color. Two of the patients had glaucoma. All had neurological symptoms and moderate brain atrophy with a lower degree of severity than that classically associated with SWS. Susceptibility-weighted imaging (SWI) and contrast-enhanced fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging demonstrated the best sensitivity to reveal the pial angiomas. CONCLUSIONS: We have differentiated two distinct clinical/radiological phenotypes of SWS; GNAQ- and GNA11-SWS. The classic GNAQ-SWS is characterized by a homogeneous dark-red CM, commonly associated with underlying soft tissue hypertrophy. The CM in GNA11-SWS is more reticulate and darkens with time, and the neurological picture is milder. SWI and post-contrast FLAIR sequences appear to be necessary to demonstrate leptomeningeal angiomatosis. Anti-epileptic medication or future targeted therapies may be useful, as in classic SWS.
Assuntos
Subunidades alfa de Proteínas de Ligação ao GTP , Síndrome de Sturge-Weber , Anticonvulsivantes , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Humanos , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Síndrome de Sturge-Weber/complicações , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patologiaRESUMO
Sturge-Weber syndrome (SWS) is a sporadic, congenital, neuro-cutaneous disorder characterized by a mosaic, capillary malformation. SWS and non-syndromic capillary malformations are both caused by a somatic activating mutation in GNAQ encoding the G protein subunit alpha-q protein. The missense mutation R183Q is the sole GNAQ mutation identified thus far in 90% of SWS-associated or isolated capillary malformations. In this study, we sequenced skin biopsies of capillary malformations from 9 patients. We identified the R183Q mutation in nearly all samples, but one sample exhibited a Q209R mutation. This new mutation occurs at the same residue as the constitutively-activating Q209L mutation, commonly seen in tumors. However, Q209R is a rare variant in this gene. To compare the effect of the Q209R mutation on downstream signaling, we performed reporter assays with a GNAQ-responsive reporter co-transfected with either GNAQ WT, R183Q, Q209L, Q209R, or C9X (representing a null allele). Q209L showed the highest reporter activation, with R183Q and Q209R showing significantly lower activation. To determine whether these mutations had similar or different downstream consequences we performed RNA-seq analysis in microvascular endothelial cells (HMEC-1) electroporated with the same GNAQ variants. The R183 and Q209 missense variants caused extensive dysregulation of a broad range of transcripts compared to the WT or null allele, confirming that these are all activating mutations. However, the missense variants exhibited very few differentially expressed genes (DEGs) when compared to each other. These data suggest that these activating GNAQ mutations differ in magnitude of activation but have similar downstream effects.
Assuntos
Síndrome de Sturge-Weber , Capilares/anormalidades , Células Endoteliais/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Humanos , Mutação/genética , Subunidades Proteicas/metabolismo , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/metabolismo , Síndrome de Sturge-Weber/patologia , Malformações VascularesRESUMO
OBJECTIVE: Capillary malformation (CM) occurs sporadically and is associated with Sturge-Weber syndrome. The somatic mosaic mutation in GNAQ (c.548G>A, p.R183Q) is enriched in endothelial cells (ECs) in skin CM and Sturge-Weber syndrome brain CM. Our goal was to investigate how the mutant Gαq (G-protein αq subunit) alters EC signaling and disrupts capillary morphogenesis. Approach and Results: We used lentiviral constructs to express p.R183Q or wild-type GNAQ in normal human endothelial colony forming cells (EC-R183Q and EC-WT, respectively). EC-R183Q constitutively activated PLC (phospholipase C) ß3, a downstream effector of Gαq. Activated PLCß3 was also detected in human CM tissue sections. Bulk RNA sequencing analyses of mutant versus wild-type EC indicated constitutive activation of PKC (protein kinase C), NF-κB (nuclear factor kappa B) and calcineurin signaling in EC-R183Q. Increased expression of downstream targets in these pathways, ANGPT2 (angiopoietin-2) and DSCR (Down syndrome critical region protein) 1.4 were confirmed by quantitative PCR and immunostaining of human CM tissue sections. The Gαq inhibitor YM-254890 as well as siRNA targeted to PLCß3 reduced mRNA expression levels of these targets in EC-R183Q while the pan-PKC inhibitor AEB071 reduced ANGPT2 but not DSCR1.4. EC-R183Q formed enlarged blood vessels in mice, reminiscent of those found in human CM. shRNA knockdown of ANGPT2 in EC-R183Q normalized the enlarged vessels to sizes comparable those formed by EC-WT. CONCLUSIONS: Gαq-R183Q, when expressed in ECs, establishes constitutively active PLCß3 signaling that leads to increased ANGPT2 and a proangiogenic, proinflammatory phenotype. EC-R183Q are sufficient to form enlarged CM-like vessels in mice, and suppression of ANGPT2 prevents the enlargement. Our study provides the first evidence that endothelial Gαq-R183Q is causative for CM and identifies ANGPT2 as a contributor to CM vascular phenotype.
Assuntos
Angiopoietina-2/metabolismo , Capilares/metabolismo , Células Progenitoras Endoteliais/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Neovascularização Patológica , Síndrome de Sturge-Weber/metabolismo , Adolescente , Adulto , Idoso , Angiopoietina-2/genética , Animais , Capilares/anormalidades , Células Cultivadas , Criança , Pré-Escolar , Células Progenitoras Endoteliais/patologia , Células Progenitoras Endoteliais/transplante , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos Nus , Mutação , Fenótipo , Fosfolipase C beta/genética , Fosfolipase C beta/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patologia , Regulação para CimaRESUMO
AIMS: To determine the correspondence between GNAQ R183Q (c.548Gï¼A) mutation in abnormal scleral tissue of patients with Sturge-Weber syndrome (SWS) secondary glaucoma and explore the role of GNAQ R183Q in glaucoma pathogenesis. METHODS: Episcleral tissues were obtained from 8 patients: SWS secondary glaucoma (n=5) and primary congenital glaucoma (PCG, n=3). Scleral tissues were obtained from 7 patients: SWS secondary glaucoma (n=2), PCG (n=1) and juvenile open-angle glaucoma (n=4). GNAQ R183Q mutation was detected in scleral tissue by droplet digital PCR. Tissue sections from SWS were examined by immunohistochemistry to determine the expression of p-ERK. RESULTS: The GNAQ R183Q mutation was present in 100% of the SWS abnormal sclera. Five cases were SWS patient-derived episcleral tissue, and the mutant allelic frequencies range from 6.9% to 12.5%. The other two were deep scleral tissues and the mutant frequencies were 1.5% and 5.3%. No mutations in GNAQ R183 codon were found in the sclera of PCG and juvenile open-angle glaucoma. Increased expression of p-ERK and p-JNK was detected in the endothelial cells of SWS abnormal scleral blood vessels. CONCLUSIONS: GNAQ R183Q occurred in all abnormal scleral tissue of SWS secondary glaucoma. Increased expression of p-ERK and p-JNK in endothelial cells of blood vessels was detected in the abnormal scleral tissue. This study suggests GNAQ R183Q may regulate episcleral vessels of patients with SWS through abnormal activation of ERK and JNK, providing new genetic evidence of pathogenesis of glaucoma in SWS, and the dysplasia of scleral tissue in anterior segment may be used as an early diagnostic method or treatment targets to prevent the development and progression of glaucoma in patients with SWS.
Assuntos
Glaucoma de Ângulo Aberto , Glaucoma , Síndrome de Sturge-Weber , Células Endoteliais , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Glaucoma/patologia , Glaucoma de Ângulo Aberto/diagnóstico , Glaucoma de Ângulo Aberto/genética , Glaucoma de Ângulo Aberto/metabolismo , Humanos , Mutação , Esclera/patologia , Síndrome de Sturge-Weber/diagnóstico , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patologiaRESUMO
BACKGROUND: Individuals with Sturge-Weber syndrome (SWS) often expereince intractable epilepsy and cognitive decline. We hypothesized that the extent of the leptomeningeal capillary malformation (LCM) may correlate with the severity of neurological impairment due to SWS. We tested the hypothesis in a cross-sectional study of seizure severity and electroencephalographic (EEG) findings and a retrospective cohort study for surgical indications related to the extent of the LCM. METHODS: We enrolled 112 patients and classified them according to LCM distribution: (1) bilateral, (2) hemispheric, (3) multilobar, and (4) single lobe. Age at seizure onset, seizure semiology and frequency, and EEG findings were compared. Surgical indications were evaluated for each group by Fisher exact test, and predictors for surgery were evaluated by univariate and multivariate analyses. Therapeutic efficacy was evaluated by the SWS-Neurological Score (SWS-NS). RESULTS: The bilateral and hemispheric groups had early seizure onset (4.0 months old and 3.0 months old), frequent seizures (88.9% and 80.6% had more than one per month), focal-to-bilateral tonic-clonic seizures (88.9% and 74.2%), and status epilepticus (100% and 87.1%). The groups' EEG findings did not differ substantially. Surgical indications were present in 77.8% of the bilateral, 88.1% of the hemispheric, and 46.8% of the multilobar groups. Seizure more than once per month was a predictor of surgical treatment. Seizure subscore improved postoperatively in the hemispheric and multilobar groups. Even after surgical treatment, the bilateral and hemispheric groups exhibited higher SWS-NSs than members of the other groups. CONCLUSION: Our study demonstrated a strong association between extensive LCM and epilepsy severity. Surgical intervention improved seizure outcome in patients with SWS with large LCMs.
Assuntos
Capilares/anormalidades , Epilepsia/etiologia , Epilepsia/fisiopatologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Meninges/patologia , Síndrome de Sturge-Weber/patologia , Malformações Vasculares/patologia , Capilares/patologia , Capilares/cirurgia , Pré-Escolar , Estudos Transversais , Eletroencefalografia , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Hemangioma Cavernoso do Sistema Nervoso Central/cirurgia , Humanos , Lactente , Masculino , Meninges/irrigação sanguínea , Meninges/cirurgia , Gravidade do Paciente , Estudos Retrospectivos , Síndrome de Sturge-Weber/complicações , Síndrome de Sturge-Weber/cirurgia , Resultado do Tratamento , Malformações Vasculares/complicações , Malformações Vasculares/cirurgiaRESUMO
Sturge-Weber syndrome (SWS) is a rare neurocutaneous disorder. Almost all cases of SWS are diagnosed in children, but some are diagnosed in adults. We describe a case of isolated leptomeningeal angiomatosis without intracranial calcification. A 33-year-old woman was admitted because of sudden-onset right homonymous hemianopia with headache and nausea. These symptoms disappeared by the next morning. She had no history of seizure or mental retardation. No facial angioma was found on physical examination. Brain CT showed no intracranial calcification or atrophic cortex. The blood and cerebrospinal fluid analyses yielded normal results. The findings in the electroencephalogram were unremarkable. MRI with susceptibility weighting (SWI) revealed dilated transmedullary veins in the left occipital lobe. Contrast-enhanced T1-weighted imaging (CE-T1WI) illustrated abnormal leptomeningeal enhancement in the left occipitoparietal cortex and enhancement and enlargement of the choroid plexus in the left lateral ventricle. Post-gadolinium contrast-enhanced f FLAIR imaging demonstrated more extensive enhancement of the leptomeningeal lesions than did CE-T1WI. The symptoms and the findings on these images were suggestive of a diagnosis of SWS type III. Clinicians should keep in mind that some cases of SWS manifest with only minor symptoms, such as migraine. If SWS is suspected, SWI and contrast-enhanced MRI should be performed.
Assuntos
Hemianopsia/etiologia , Síndrome de Sturge-Weber/complicações , Síndrome de Sturge-Weber/diagnóstico , Adulto , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Calcinose , Feminino , Humanos , Imageamento por Ressonância Magnética , Síndrome de Sturge-Weber/patologia , Tomografia Computadorizada por Raios XRESUMO
Mutations occurring during embryonic development affect only a subset of cells resulting in two or more distinct cell populations that are present at different levels, also known as postzygotic mosaicism (PZM). Although PZM is a common biological phenomenon, it is often overlooked as a source of disease due to the challenges associated with its detection and characterization, especially for very low-frequency variants. Moreover, PZM can cause a different phenotype compared to constitutional mutations. Especially, lethal mutations in receptor tyrosine kinase (RTK) pathway genes, which exist only in a mosaic state, can have completely new clinical manifestations and can look very different from the associated monogenic disorder. However, some key questions are still not addressed, such as the level of mosaicism resulting in a pathogenic phenotype and how the clinical outcome changes with the development and age. Addressing these questions is not trivial as we require methods with the sensitivity to capture some of these variants hidden away in very few cells. Recent ultra-accurate deep-sequencing approaches can now identify these low-level mosaics and will be central to understand systemic and local effects of mosaicism in the RTK pathway. The main focus of this review is to highlight the importance of low-level mosaics and the need to include their detection in studies of genomic variation associated with disease.
Assuntos
Displasia Fibrosa Poliostótica/genética , Mutação em Linhagem Germinativa , Mosaicismo , Síndrome de Proteu/genética , Receptores Proteína Tirosina Quinases/genética , Síndrome de Sturge-Weber/genética , Criança , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Embrião de Mamíferos , Displasia Fibrosa Poliostótica/enzimologia , Displasia Fibrosa Poliostótica/patologia , Expressão Gênica , Genes Letais , Humanos , Lactente , Recém-Nascido , Fenótipo , Síndrome de Proteu/enzimologia , Síndrome de Proteu/patologia , Receptores Proteína Tirosina Quinases/deficiência , Transdução de Sinais , Síndrome de Sturge-Weber/enzimologia , Síndrome de Sturge-Weber/patologiaAssuntos
Subunidades alfa de Proteínas de Ligação ao GTP/genética , Síndrome de Sturge-Weber/genética , Adolescente , Encéfalo/patologia , Pré-Escolar , Análise Mutacional de DNA , Feminino , Mutação com Ganho de Função , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Pele/patologia , Síndrome de Sturge-Weber/sangue , Síndrome de Sturge-Weber/patologia , Sequenciamento do Exoma , Adulto JovemRESUMO
BACKGROUND: Sturge-Weber syndrome (SWS) is primarily diagnosed in pediatric population, but clinical presentation in late adulthood is rarely reported. Evolution of radiological findings in the adulthood variant of SWS with isolated leptomeningeal angiomatosis has never been reported to our knowledge. CASE PRESENTATION: We report here a case of an isolated temporo-parieto-occipital leptomeningeal angiomatosis on the right cerebral hemisphere in a sixty-two-year-old male who presented with generalized seizure, GCS score 14/15 (E4 V4 M6) with equal and reacting pupils, psychomotor slowing, left hemineglect and grade 4 power in the left upper and lower limbs. Over a period of 48 h his neurological status deteriorated, but recovered spontaneously over a week on titration with anticonvulsants. He had a prior history of treatment for focal leptomeningitis, three years ago. Cerebrospinal fluid (CSF) analysis showed glucose of 75 mg/dL, proteins of 65 mg/dL and culture grew no organisms. On follow-up, he had intermittent episodes of focal seizure for two years. Initial, computed tomography of brain showed hyperdense lesion in the parieto-occipital convexity subarachnoid space on the right cerebral hemisphere mimicking subarachnoid hemorrhage and computed tomography angiography showed no significant abnormality. Magnetic resonance imaging (MRI) of brain showed intense pial enhancement in the right temporo-parieto-occipital region with a subtle T2W hyperintense signal in the underlying subcortical white matter without edema or infarct or mass effect. Digital subtraction cerebral angiography (DSA) showed hypertrophy of the cerebral arteries, arteriolo-capillary bed and venules in the right temporo-parieto-occipital territory associated with early arterio-capillary and venous opacification. Serial MRI done after six months, one and two years showed increase in the T2W hyperintense signal in the subcortical white matter and cortical atrophy with no changes in the pial enhancement. MR perfusion imaging showed reduced cerebral blood flow (CBF) and cerebral blood volume (CBV) in the right parieto-temporo-occipital cortical and subcortical regions and increased perfusion in the leptomeninges with reduction of the NAA / Cr ratios in spectroscopy. CONCLUSION: Conglomeration of various radiological findings in MRI, Perfusion, MRS and DSA with the clinical presentation can aid in establishing the diagnosis of this rare presentation of SWS-type 3 variant in late adulthood.
Assuntos
Angiografia Digital/métodos , Encefalopatias/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Síndrome de Sturge-Weber/diagnóstico por imagem , Angiomatose/diagnóstico por imagem , Angiomatose/patologia , Encefalopatias/patologia , Humanos , Masculino , Meninges/diagnóstico por imagem , Meninges/patologia , Pessoa de Meia-Idade , Síndrome de Sturge-Weber/patologiaRESUMO
Overgrowth syndromes represent a diverse group of disorders with overlapping features. Interdisciplinary management by a team of experts in vascular anomalies is crucial for establishing the correct diagnosis and optimizing outcomes for these patients. Unique management considerations include increased risk for thrombosis and in some cases, cancer. In recent years, research has demonstrated that these disorders are primarily caused by somatic mutations in growth pathways, particularly the PI3K-mTOR pathway. This improved understanding had led to promising new therapies for this group of patients.
Assuntos
Síndrome do Hamartoma Múltiplo , Síndrome de Klippel-Trenaunay-Weber , Lipoma , Anormalidades Musculoesqueléticas , Nevo , Síndrome de Proteu , Síndrome de Sturge-Weber , Malformações Vasculares , Criança , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , Síndrome do Hamartoma Múltiplo/terapia , Humanos , Síndrome de Klippel-Trenaunay-Weber/genética , Síndrome de Klippel-Trenaunay-Weber/patologia , Síndrome de Klippel-Trenaunay-Weber/terapia , Lipoma/genética , Lipoma/patologia , Lipoma/terapia , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/patologia , Anormalidades Musculoesqueléticas/terapia , Nevo/genética , Nevo/patologia , Nevo/terapia , Síndrome de Proteu/genética , Síndrome de Proteu/patologia , Síndrome de Proteu/terapia , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patologia , Síndrome de Sturge-Weber/terapia , Malformações Vasculares/genética , Malformações Vasculares/patologia , Malformações Vasculares/terapiaAssuntos
Doença de Alzheimer/diagnóstico , Síndrome de Sturge-Weber/diagnóstico , Idoso , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Exame Neurológico , Síndrome de Sturge-Weber/patologia , Síndrome de Sturge-Weber/fisiopatologiaRESUMO
The authors report a case of a diffuse choroidal hemangioma in the left eye of a 17-year-old girl. No evidence of leptomeningeal angiomatosis was found on magnetic resonance imaging and neither the medical history nor the clinical examination revealed a port wine birthmark on the left side of the face. Fine telangiectatic vessels were found on the bulbar conjunctiva of the ipsilateral eye. Because of the shared destination of the vessel-trigeminal-ectoderm complex that migrates toward the optic placode, forming choriocapillaris, upper facial skin (upper eyelid), and conjunctival vessels, an embryological basis can be offered for ophthalmic angiomatosis of Sturge-Weber syndrome. The authors propose that vascular angiomatosis of upper eyelid skin and conjunctiva are phenotypically equivalent and may be present or absent, independent of each other. Their proposed expansion of Sturge-Weber syndrome diagnostic criteria needs to be validated by a comprehensive review of ophthalmic features of Sturge-Weber syndrome. [J Pediatr Ophthalmol Strabismus. 2020;57:e43-e47.].
Assuntos
Neoplasias da Coroide/diagnóstico , Doenças Palpebrais/diagnóstico , Hemangioma/diagnóstico , Síndrome de Sturge-Weber/diagnóstico , Adolescente , Neoplasias da Coroide/patologia , Diagnóstico Diferencial , Diagnóstico por Imagem , Doenças Palpebrais/patologia , Feminino , Hemangioma/patologia , Humanos , Síndrome de Sturge-Weber/patologiaRESUMO
Purpose: To evaluate episcleral vasculature in corneal limbus with optical coherence tomography angiography (OCTA) in normal controls, port-wine stain (PWS) patients, and Sturge-Weber syndrome (SWS) patients. Methods: Unilateral eyes from 18 normal controls (25.41 ± 4.00 years), 16 PWS patients (21.35 ± 11.05 years), and 8 SWS patients with ipsilateral late-onset glaucoma (22.13 ± 7.82 years). Each subject underwent slit-lamp examination, applanation tonometry, and OCTA. All OCTA scans were performed using an OCTA system operating at a wavelength of 1050-nm in four quadrants (superior, inferior, nasal, and temporal). The scans were delineated into conjunctival and episcleral layers using IMAGEnet6 for analysis. Results: Slit-lamp and OCTA images demonstrated dense dilated episcleral vessels in PWS and SWS patients, particularly in the SWS group. The mean limbal involvements of episcleral vascular anomalies under slit lamp were respectively 0.00 ± 0.00, 5.44 ± 2.92, and 8.88 ± 2.70 clock hours in the control, PWS, and SWS groups (F = 58.46, P < 0.01). Quantitative analysis of OCTA scans showed that the episcleral vessel density in controls, PWS, and SWS groups were 25.03% ± 1.47%, 28.28% ± 1.96%, and 33.59% ± 3.00%, respectively (F = 18.17, P < 0.01). We also observed higher episcleral vessel diameter index in the SWS and PWS groups in comparison with the controls, particularly in the SWS group (P < 0.01). The vessel measurements, including density and diameter, were significantly correlated with the increased IOP and cup-to-disc (C/D) in SWS patients (P < 0.01). Conclusions: To our knowledge, this is the first demonstration of OCTA in PWS and SWS patients and represents direct pathoanatomic evidence for episcleral alterations in SWS patients. The episcleral vessel measurements correlated with the increased IOP and C/D in SWS patients, indicating the episcleral vascular hypertrophy may be a risk factor for glaucoma in adult SWS patients.
Assuntos
Angiografia/métodos , Glaucoma/etiologia , Mancha Vinho do Porto/diagnóstico por imagem , Síndrome de Sturge-Weber/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Adolescente , Adulto , Fatores Etários , Estudos de Casos e Controles , Criança , Feminino , Glaucoma/diagnóstico , Glaucoma/diagnóstico por imagem , Glaucoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Projetos Piloto , Mancha Vinho do Porto/complicações , Mancha Vinho do Porto/patologia , Prognóstico , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Microscopia com Lâmpada de Fenda/métodos , Síndrome de Sturge-Weber/complicações , Síndrome de Sturge-Weber/patologia , Tonometria Ocular/métodosRESUMO
Overgrowth syndromes are a large group of rare disorders characterized by generalized or segmental excessive growth. Segmental overgrowth syndromes are mainly due to genetic anomalies appearing during the embryogenesis and leading to mosaicism. The numbers of patients with segmental overgrowth with an identified molecular defect has dramatically increased following the recent advances in molecular genetic using next-generation sequencing approaches. This review discusses various syndromes and pathways involved in segmental overgrowth syndromes and presents actual and future therapeutic strategies.
TITLE: Les syndromes de surcroissance segmentaire et les stratégies thérapeutiques. ABSTRACT: Les syndromes de surcroissance sont un groupe de pathologies caractérisées par une croissance excessive généralisée ou segmentaire. Les syndromes de surcroissance segmentaires sont principalement dus à des anomalies génétiques apparaissant durant l'embryogenèse et aboutissant à un mosaïcisme. Le nombre de patients atteints d'un syndrome de surcroissance avec une mutation identifiée a fortement augmenté grâce à des avancées récentes en génétique moléculaire, en utilisant le séquençage de nouvelle génération (NGS). Cette revue détaille les différents syndromes de surcroissance segmentaire ainsi que les voies moléculaires impliquées et les options thérapeutiques envisageables.