RESUMO
Cutis marmorata telangiectatica congenita (CMTC) is characterized by coarse-meshed capillary malformations arranged in asymmetrically distributed patches. The disorder may be associated with hyper- or hypoplastic limbs, syndactyly, cleft palate, and glaucoma. Because the disease usually occurs sporadically, the concept of a lethal mutation surviving by mosaicism was proposed about 30 years ago. Here we describe three children with CMTC due to a postzygotic GNA11 mutation c547C > T (p.Arg183Cys), documented in saliva (patient 1) or lesional cutaneous tissue (patients 2 and 3). All three individuals had widespread and asymmetric CMTC which was present from birth and became fainter during the first years of life. Variably associated anomalies included glaucoma, choroidal capillary malformation, and body asymmetry. In previous case reports, postzygotic GNA11 mutations were documented in two cases of phacomatosis cesiomarmorata, being characterized by CMTC coexisting with segmental dermal melanocytosis. Moreover, postzygotic GNA11 mutations were noted in two CMTC patients described under the incorrect diagnosis of "nevus vascularis mixtus". Hence, the present cases convincingly support the concept that CMTC can be caused by mosaic GNA11 mutations and thus belongs to the GNA11-Related Capillary Nevus (GNARCAN) spectrum. In two other bona fide cases of CMTC, however, we were unable to find a mutation in GNA11, which may be explained either by our inability to detect a very low percentage of mutant cells or by genetic heterogeneity of the phenotype.
Assuntos
Glaucoma , Nevo , Dermatopatias Vasculares , Telangiectasia , Capilares/anormalidades , Subunidades alfa de Proteínas de Ligação ao GTP , Humanos , Livedo Reticular , Mutação , Nevo/complicações , Dermatopatias Vasculares/complicações , Dermatopatias Vasculares/diagnóstico , Dermatopatias Vasculares/genética , Telangiectasia/congênito , Telangiectasia/genética , Malformações VascularesAssuntos
Dermatopatias Vasculares , Doenças Vasculares , Malformações Vasculares , Testes Genéticos , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Dermatopatias Vasculares/diagnóstico , Dermatopatias Vasculares/genética , Malformações Vasculares/diagnóstico , Malformações Vasculares/genéticaRESUMO
Cell division cycle 42 (CDC42) is a small Rho GTPase, which serves as a fundamental intracellular signal node regulating actin cytoskeletal dynamics and several other integral cellular processes. CDC42-associated disorders encompass a broad clinical spectrum including Takenouchi-Kosaki syndrome, autoinflammatory syndromes and neurodevelopmental phenotypes mimicking RASopathies. Dysregulation of CDC42 signaling by genetic defects in either DOCK6 or ARHGAP31 is also considered to play a role in the pathogenesis of Adams-Oliver syndrome (AOS). Here, we report a mother and her child carrying the previously reported pathogenic CDC42 variant c.511G>A (p.Glu171Lys). Both affected individuals presented with short stature, distinctive craniofacial features, pectus deformity as well as heart and eye anomalies, similar to the recently described Noonan syndrome-like phenotype associated with this variant. Remarkably, one of the patients additionally exhibited aplasia cutis congenita of the scalp. Multi-gene panel sequencing of the known AOS-causative genes and whole exome sequencing revealed no second pathogenic variant in any disease-associated gene explaining the aplasia cutis phenotype in our patient. This observation further expands the phenotypic spectrum of CDC42-associated disorders and underscores the role of CDC42 dysregulation in the pathogenesis of aplasia cutis congenita.
Assuntos
Anormalidades Múltiplas/genética , Displasia Ectodérmica/genética , Mutação de Sentido Incorreto , Mutação Puntual , Dermatopatias Vasculares/genética , Telangiectasia/congênito , Proteína cdc42 de Ligação ao GTP/deficiência , Adulto , Substituição de Aminoácidos , Anormalidades Craniofaciais/genética , Nanismo/genética , Anormalidades do Olho/genética , Feminino , Estudos de Associação Genética , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Livedo Reticular , Linhagem , Fenótipo , Couro Cabeludo/patologia , Telangiectasia/genética , Proteína cdc42 de Ligação ao GTP/genéticaRESUMO
Familial cerebral cavernous malformations due to the common Hispanic mutation (FCCM1-CHM) is an endemic condition among the Hispanic population of the Southwestern United States associated with significant morbidity and mortality. Cutaneous vascular malformations (CVMs) can be found in individuals with FCCM1-CHM, but their morphology, prevalence, and association with cerebral cavernous malformations (CCMs) has not been well characterized. A cross-sectional study of 140 individuals with confirmed FCCM1-CHM was performed with statistical analyses of CVM, CCM, and patient characteristics. We then compared these findings to other cohorts with Familial cerebral cavernous malformations (FCCM) due to other mutations. We observed a higher overall prevalence and a different predominant morphological subtype of CVM compared to previous FCCM cohorts. While the number of CVMs was not a reliable indicator of the number of CCMs present, each person with one or more CVMs had evidence of central nervous system (CNS) disease. Awareness of the morphology of these cutaneous lesions can aid in the diagnosis of individuals with FCCM-CHM in Hispanic patients or those with family history of CCM.
Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteína KRIT1/genética , Dermatopatias Vasculares/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Hispânico ou Latino/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Dermatopatias Vasculares/tratamento farmacológico , Dermatopatias Vasculares/patologia , Adulto JovemAssuntos
Doenças Pulmonares Intersticiais/diagnóstico , Proteínas de Membrana/genética , Dermatopatias Vasculares/diagnóstico , Doenças Vasculares/diagnóstico , Idade de Início , Anemia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Anticorpos Antinucleares/imunologia , Artralgia/tratamento farmacológico , Artralgia/genética , Artralgia/imunologia , Sedimentação Sanguínea , Bronquiectasia/diagnóstico , Bronquiectasia/tratamento farmacológico , Bronquiectasia/genética , Bronquiectasia/imunologia , Proteína C-Reativa/imunologia , Pré-Escolar , Tosse , Insuficiência de Crescimento , Feminino , Febre/tratamento farmacológico , Febre/genética , Febre/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoglobulina G/imunologia , Imunossupressores/uso terapêutico , Lactente , Interferon Tipo I , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Nódulos Pulmonares Múltiplos/diagnóstico , Nódulos Pulmonares Múltiplos/tratamento farmacológico , Nódulos Pulmonares Múltiplos/genética , Nódulos Pulmonares Múltiplos/imunologia , Osteoartropatia Hipertrófica Primária , Análise de Sequência de DNA , Proteína Amiloide A Sérica , Dermatopatias Vasculares/tratamento farmacológico , Dermatopatias Vasculares/genética , Dermatopatias Vasculares/imunologia , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/genética , Doenças Vasculares/imunologiaRESUMO
OBJECTIVE: Individuals with deficiency of adenosine deaminase 2 (DADA2), a recently recognized autosomal recessive disease, present with various systemic vascular and inflammatory manifestations, often with young age at disease onset or with early onset of recurrent strokes. Their clinical features and histologic findings overlap with those of childhood-onset polyarteritis nodosa (PAN), a primary "idiopathic" systemic vasculitis. Despite similar clinical presentation, individuals with DADA2 may respond better to biologic therapy than to traditional immunosuppression. The aim of this study was to screen an international registry of children with systemic primary vasculitis for variants in ADA2. METHODS: The coding exons of ADA2 were sequenced in 60 children and adolescents with a diagnosis of PAN, cutaneous PAN, or unclassifiable vasculitis (UCV), any chronic vasculitis with onset at age 5 years or younger, or history of stroke. The functional consequences of the identified variants were assessed by ADA2 enzyme assay and immunoblotting. RESULTS: Nine children with DADA2 (5 with PAN, 3 with UCV, and 1 with antineutrophil cytoplasmic antibody-associated vasculitis) were identified. Among them, 1 patient had no rare variants in the coding region of ADA2 and 8 had biallelic, rare variants (minor allele frequency <0.01) with a known association with DADA2 (p.Gly47Arg and p.Gly47Ala) or a novel association (p.Arg9Trp, p.Leu351Gln, and p.Ala357Thr). The clinical phenotype varied widely. CONCLUSION: These findings support previous observations indicating that DADA2 has extensive genotypic and phenotypic variability. Thus, screening ADA2 among children with vasculitic rash, UCV, PAN, or unexplained, early-onset central nervous system disease with systemic inflammation may enable an earlier diagnosis of DADA2.
Assuntos
Adenosina Desaminase/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Poliarterite Nodosa/genética , Adenosina Desaminase/deficiência , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Masculino , Mutação , Dermatopatias Vasculares/genética , Vasculite Sistêmica/genéticaAssuntos
Hipoplasia Dérmica Focal/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Mosaicismo , Dermatopatias Vasculares/congênito , Aciltransferases/genética , Adulto , Biópsia , Análise Mutacional de DNA , Dermoscopia , Diagnóstico Diferencial , Feminino , Hipoplasia Dérmica Focal/sangue , Hipoplasia Dérmica Focal/genética , Hipoplasia Dérmica Focal/patologia , Mutação da Fase de Leitura , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Proteínas de Membrana/genética , Pele/diagnóstico por imagem , Pele/patologia , Dermatopatias Vasculares/diagnóstico , Dermatopatias Vasculares/genética , Dermatopatias Vasculares/patologiaRESUMO
A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA-mutation is described. This case is an example of the clinical diversity of the PIK3CA-Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly-Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term.
Assuntos
Anormalidades Múltiplas/diagnóstico , Classe I de Fosfatidilinositol 3-Quinases/genética , Lipoma/diagnóstico , Megalencefalia/diagnóstico , Anormalidades Musculoesqueléticas/diagnóstico , Nevo/diagnóstico , Dermatopatias Vasculares/diagnóstico , Telangiectasia/congênito , Malformações Vasculares/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/terapia , Sequência de Bases , Broncodilatadores/uso terapêutico , Diagnóstico Diferencial , Nutrição Enteral , Humanos , Imunossupressores/uso terapêutico , Recém-Nascido , Lipoma/genética , Lipoma/terapia , Masculino , Megalencefalia/genética , Megalencefalia/terapia , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/terapia , Mutação , Nevo/genética , Nevo/terapia , Fenótipo , Respiração Artificial/métodos , Sirolimo/uso terapêutico , Dermatopatias Vasculares/genética , Dermatopatias Vasculares/terapia , Telangiectasia/diagnóstico , Telangiectasia/genética , Telangiectasia/terapia , Malformações Vasculares/genética , Malformações Vasculares/terapiaAssuntos
Malformações Arteriovenosas/diagnóstico por imagem , Capilares/anormalidades , Mancha Vinho do Porto/diagnóstico por imagem , Diagnóstico Pré-Natal , Dermatopatias Vasculares/diagnóstico por imagem , Adulto , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/patologia , Capilares/diagnóstico por imagem , Capilares/patologia , Feminino , Testes Genéticos , Humanos , Recém-Nascido , Mancha Vinho do Porto/genética , Mancha Vinho do Porto/patologia , Gravidez , Dermatopatias Vasculares/genética , Dermatopatias Vasculares/patologiaAssuntos
Fator V/genética , Vasculite por IgA/genética , Dermatopatias Vasculares/genética , Aspirina/administração & dosagem , Azatioprina/administração & dosagem , Biópsia , Pré-Escolar , Humanos , Vasculite por IgA/diagnóstico , Vasculite por IgA/tratamento farmacológico , Vasculite por IgA/patologia , Imunossupressores/administração & dosagem , Extremidade Inferior , Masculino , Necrose/tratamento farmacológico , Necrose/etiologia , Inibidores da Agregação Plaquetária/administração & dosagem , Dermatopatias Vasculares/tratamento farmacológico , Dermatopatias Vasculares/patologiaAssuntos
Lipoma/genética , Anormalidades Musculoesqueléticas/genética , Mutação de Sentido Incorreto/genética , Nevo/genética , Fosfatidilinositol 3-Quinases/genética , Malformações Vasculares/genética , Classe I de Fosfatidilinositol 3-Quinases , Extremidades , Heterozigoto , Humanos , Lipoma/congênito , Mosaicismo , Nevo/congênito , Dermatopatias Vasculares/congênito , Dermatopatias Vasculares/genéticaAssuntos
Hemangioma/classificação , Hemangioma/genética , Dermatopatias Vasculares/classificação , Dermatopatias Vasculares/genética , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/genética , Malformações Vasculares/classificação , Malformações Vasculares/genética , Testes Genéticos , Hemangioma/patologia , Humanos , Dermatopatias Vasculares/patologia , Neoplasias Cutâneas/patologia , Malformações Vasculares/patologiaRESUMO
OBJECTIVES: Rheumatoid arthritis is a polygenically controlled systemic autoimmune disease. Rheumatoid vasculitis is an important extra-articular phenotype of rheumatoid arthritis that can result in deep cutaneous ulcers. The objective of this study was to establish a correlation between the frequency of major histocompatibility complex class I/II alleles and killer immunoglobulin-like receptor genotypes in patients with cutaneous rheumatoid vasculitis. METHODS: Using the Scott & Bacon 1984 criteria to diagnose rheumatoid vasculitis and after excluding any other causes such as diabetes, atherosclerosis, adverse drug reactions, infection, and smoking, patients who met the criteria were selected. All of the selected rheumatoid vasculitis patients presented deep cutaneous ulcers. Identification of the major histocompatibility complex class I/II and killer immunoglobulin-like receptor genotypes was performed by polymerase chain reaction assays of samples collected from the 23 rheumatoid vasculitis patients as well as from 80 controls (40 non-rheumatoid vasculitis RA control patients and 40 healthy volunteers). RESULTS: An association between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and cutaneous lesions in rheumatoid vasculitis patients and a correlation between the inhibitor KIR2DL3 and the HLA-C*0802 ligand in rheumatoid vasculitis patients were found. CONCLUSION: An association was found between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and the development of cutaneous lesions in rheumatoid vasculitis patients. Additionally, the HLA-C*0802 ligand protects these individuals from developing cutaneous lesions.
Assuntos
Antígenos HLA-C/genética , Complexo Principal de Histocompatibilidade/imunologia , Receptores KIR2DL3/genética , Receptores KIR/genética , Vasculite Reumatoide/imunologia , Dermatopatias Vasculares/imunologia , Adolescente , Adulto , Idoso , Alelos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Brasil , Feminino , Citometria de Fluxo , Genótipo , Cadeias HLA-DRB1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Vasculite Reumatoide/genética , Dermatopatias Vasculares/genética , Adulto JovemRESUMO
OBJECTIVES: Rheumatoid arthritis is a polygenically controlled systemic autoimmune disease. Rheumatoid vasculitis is an important extra-articular phenotype of rheumatoid arthritis that can result in deep cutaneous ulcers. The objective of this study was to establish a correlation between the frequency of major histocompatibility complex class I/II alleles and killer immunoglobulin-like receptor genotypes in patients with cutaneous rheumatoid vasculitis. METHODS: Using the Scott & Bacon 1984 criteria to diagnose rheumatoid vasculitis and after excluding any other causes such as diabetes, atherosclerosis, adverse drug reactions, infection, and smoking, patients who met the criteria were selected. All of the selected rheumatoid vasculitis patients presented deep cutaneous ulcers. Identification of the major histocompatibility complex class I/II and killer immunoglobulin-like receptor genotypes was performed by polymerase chain reaction assays of samples collected from the 23 rheumatoid vasculitis patients as well as from 80 controls (40 non-rheumatoid vasculitis RA control patients and 40 healthy volunteers). RESULTS: An association between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and cutaneous lesions in rheumatoid vasculitis patients and a correlation between the inhibitor KIR2DL3 and the HLA-C*0802 ligand in rheumatoid vasculitis patients were found. CONCLUSION: An association was found between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and the development of cutaneous lesions in rheumatoid vasculitis patients. Additionally, the HLA-C*0802 ligand protects these individuals from developing cutaneous lesions. .
Assuntos
Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antígenos HLA-C/genética , Complexo Principal de Histocompatibilidade/imunologia , Receptores KIR/genética , /genética , Vasculite Reumatoide/imunologia , Dermatopatias Vasculares/imunologia , Alelos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Brasil , Citometria de Fluxo , Genótipo , Cadeias HLA-DRB1/genética , Reação em Cadeia da Polimerase , Vasculite Reumatoide/genética , Dermatopatias Vasculares/genéticaRESUMO
IMPORTANCE: The type I interferonopathies comprise a recently recognized group of mendelian diseases characterized by an upregulation of type I interferon signaling. These monogenic phenotypes include classic Aicardi-Goutières syndrome and syndromic forms of systemic lupus erythematosus, including familial chilblain lupus and spondyloenchondrodysplasia. Dermatologic features provide a major diagnostic clue to this disease grouping, as exemplified by the recently described stimulator of interferon genes-associated vasculopathy with onset in infancy (SAVI) caused by gain-of-function mutations in TMEM173. OBSERVATIONS: We describe a male child who, from the age of 2 months, had significant cutaneous disease that manifested as red violaceous plaques of the cheeks, nose, ears, fingers, and toes that progressed to gangrenous necrosis. In addition to his severe cutaneous vasculopathy, he experienced recurrent fevers, interstitial lung disease, and failure to thrive. His clinical syndrome was refractory to multiple immunosuppressive therapies. Evidence of marked upregulation of type I interferon signaling was observed in peripheral blood, and genetic testing identified a de novo germline mutation in TMEM173, confirming a diagnosis of SAVI 7 years after the onset of his disease. CONCLUSIONS AND RELEVANCE: This observational report describes a new case of SAVI, a recently defined monogenic inflammatory phenotype, that exemplifies an emerging group of disorders related to primary upregulation of type I interferon signaling.
Assuntos
Granulomatose com Poliangiite/diagnóstico , Interferon Tipo I/genética , Proteínas de Membrana/genética , Dermatopatias Vasculares/diagnóstico , Humanos , Lactente , Masculino , Mutação , Fenótipo , Dermatopatias Vasculares/genética , Dermatopatias Vasculares/patologia , Regulação para CimaRESUMO
The name capillary malformation has caused much confusion because it is presently used to designate numerous quite different disorders such as naevus flammeus, the salmon patch, the vascular naevus of the hereditary 'megalencephaly-capillary malformation syndrome' and the skin lesions of non-hereditary traits such as 'capillary malformation-arteriovenous malformation' and 'microcephaly-capillary malformation'. To avoid such bewilderment, the present review describes the distinguishing clinical and genetic criteria of 20 different capillary malformations, and a specific name is given to all of them. The group of capillary naevi includes naevus flammeus, port-wine naevus of the Proteus type, port-wine naevus of the CLOVES type, naevus roseus, rhodoid naevus, cutis marmorata telangiectatica congenita, congenital livedo reticularis, segmental angioma serpiginosum, naevus anaemicus, naevus vascularis mixtus and angiokeratoma circumscriptum. Capillary lesions that perhaps represent naevi are the mesotropic port-wine patch, Carter-Mirzaa macules, unilateral punctate telangiectasia and unilateral naevoid telangiectasia of the patchy type. Capillary malformations that do not represent naevi include X-linked angiokeratoma corporis diffusum (Fabry disease), autosomal dominant angiokeratoma corporis diffusum, hereditary haemorrhagic telangiectasia, hereditary angioma serpiginosusm and the salmon patch. In this way, we are able to discriminate between various non-hereditary capillary naevi such as naevus roseus and the hereditary rhodoid naevus and several hereditary traits that do not represent naevi such as angiokeratoma corporis diffusum and hereditary haemorrhagic telangiectasia; between four different types of port-wine stains, three of them being lateralized and one being mesotropic; between cutis marmorata telangiectatica congenita and congenital livedo reticularis; between telangiectatic naevi and the vasoconstrictive naevus anaemicus; and between two different types of angiokeratoma corporis diffusum. Finally, arguments are presented why the salmon patch ('stork bite', 'naevus simplex') cannot be categorized as a naevus.
Assuntos
Capilares/anormalidades , Anormalidades da Pele/classificação , Anormalidades da Pele/patologia , Dermatopatias Vasculares/classificação , Dermatopatias Vasculares/patologia , Terminologia como Assunto , Humanos , Anormalidades da Pele/genética , Dermatopatias Vasculares/genéticaRESUMO
Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactyly--thus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A>G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (>100 × coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (>1000 × coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G>A; p.(Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Variação Genética , Mutação em Linhagem Germinativa , Megalencefalia/diagnóstico , Megalencefalia/genética , Fosfatidilinositol 3-Quinases/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Dermatopatias Vasculares/diagnóstico , Dermatopatias Vasculares/genética , Telangiectasia/congênito , Criança , Classe I de Fosfatidilinositol 3-Quinases , Hibridização Genômica Comparativa , Consanguinidade , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Modelos Biológicos , Linhagem , Fenótipo , Telangiectasia/diagnóstico , Telangiectasia/genéticaRESUMO
BACKGROUND: The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS: We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-ß, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS: We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients' lymphocytes was reduced by JAK inhibitors. CONCLUSIONS: STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.).