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1.
Postgrad Med ; 131(7): 445-452, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31443616

RESUMO

Given the complexity of neurocutaneous syndromes, a multidisciplinary approach has been advocated in order to provide optimum care. Subjects and Methods: Retrospective analysis of a cohort of 157 patients during a 3-year period, seen at a newly developed neurocutaneous clinic in a pediatric tertiary care hospital in Athens (Greece); and systematic chart review of the patients diagnosed with neurofibromatosis type 1 during this time period. Results: The most frequent neurocutaneous syndromes were neurofibromatosis type 1 (NF1) in 89 patients and tuberous sclerosis complex in 17. In 20.38% of patients a neurocutaneous syndrome was not confirmed. Approximately 2/3 of the NF1 patients underwent genetic analysis, and for 76.67% of them, a pathogenic mutation on the NF1 gene was revealed. Eighty-one patients manifested with generalized NF1 and eight with mosaic NF1. Dermatological manifestations included café-au-lait macules in all patients, followed by axillary and/or inguinal freckling (n = 57), external plexiform neurofibromas (n = 17), and cutaneous and subcutaneous neurofibromas (n = 11). Approximately half of patients had learning disabilities and attention deficit hyperactivity disorder, followed by mental retardation (n = 9), autistic spectrum disorders (n = 4), headaches (n = 3) and seizures (n = 2). Neuroimaging showed characteristic areas of hyperintensity on T2-weighted images in 74.07% of patients and optic pathway glioma in 19.75%. Two patients developed malignant peripheral sheath nerve tumor. Conclusions: Neurocutaneous syndromes are clinically heterogeneous and the surveillance of potential clinical complications is challenging. The availability of genetic diagnosis and novel imaging methods in this group of disorders is likely to further expand their clinical spectrum. Guidelines for assessment and management will need to be modified based on new available data.


Assuntos
Neurofibromatose 1/fisiopatologia , Equipe de Assistência ao Paciente , Esclerose Tuberosa/fisiopatologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Espectro Autista/complicações , Manchas Café com Leite/complicações , Criança , Pré-Escolar , Estudos de Coortes , Dermatologistas , Feminino , Genes da Neurofibromatose 1 , Testes Genéticos , Genética Médica , Grécia , Humanos , Lactente , Deficiência Intelectual/complicações , Transtornos de Aprendizagem/complicações , Masculino , Mosaicismo , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/fisiopatologia , Síndromes Neurocutâneas/terapia , Neurofibroma Plexiforme/complicações , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Neurofibromatose 1/terapia , Neurologistas , Neuropsicologia , Oncologistas , Oftalmologistas , Cirurgiões Ortopédicos , Ambulatório Hospitalar , Pediatras , Radiologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/fisiopatologia , Neoplasias Cutâneas/terapia , Esclerose Tuberosa/complicações , Esclerose Tuberosa/genética , Esclerose Tuberosa/terapia
2.
Medicina (Kaunas) ; 55(3)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934652

RESUMO

The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediak⁻Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival.


Assuntos
Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/genética , Doenças Raras/diagnóstico , Doenças Raras/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/imunologia , Anormalidades Múltiplas/patologia , Adulto , Síndrome de Chediak-Higashi/diagnóstico , Síndrome de Chediak-Higashi/genética , Síndrome de Chediak-Higashi/imunologia , Síndrome de Chediak-Higashi/patologia , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/imunologia , Anormalidades Craniofaciais/patologia , Diagnóstico Diferencial , Feminino , Cabelo/anormalidades , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/imunologia , Perda Auditiva Neurossensorial/patologia , Humanos , Hipertricose/induzido quimicamente , Iris/anormalidades , Masculino , Mutação , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/imunologia , Síndromes Neurocutâneas/patologia , Piebaldismo/diagnóstico , Piebaldismo/genética , Piebaldismo/imunologia , Piebaldismo/patologia , Transtornos da Pigmentação/imunologia , Transtornos da Pigmentação/patologia , Qualidade de Vida , Doenças Raras/imunologia , Doenças Raras/patologia , Anormalidades da Pele , Proteínas rab27 de Ligação ao GTP/genética
3.
Mol Genet Genomic Med ; 7(5): e625, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30891959

RESUMO

BACKGROUND: Postzygotic KRAS, HRAS, NRAS, and FGFR1 mutations result in a group of mosaic RASopathies characterized by related developmental anomalies in eye, skin, heart, and brain. These oculocutaneous disorders include oculoectodermal syndrome (OES) encephalo-cranio-cutaneous lipomatosis (ECCL), and Schimmelpenning-Feuerstein-Mims syndrome (SFMS). Here, we report the results of the clinical and molecular characterization of a novel cohort of patients with oculocutaneous mosaic RASopathies. METHODS: Two OES, two ECCL, and two SFMS patients were ascertained in the study. In addition, two subjects with unilateral isolated epibulbar dermoids were also enrolled. Molecular analysis included PCR amplification and Sanger sequencing of KRAS, HRAS, NRAS, and FGFR1 genes in DNA obtained from biopsies (skin/epibulbar dermoids), buccal mucosa, and blood leukocytes. Massive parallel sequencing was employed in two cases with low-level mosaicism. RESULTS: In DNA from biopsies, mosaicism for pathogenic variants, including KRAS p.Ala146Thr in two OES subjects, FGFR1 p.Asn546Lys and KRAS p.Ala146Val in ECCL patients, and KRAS p.Gly12Asp in both SFMS patients, was demonstrated. No mutations were shown in DNA from conjunctival lesions in two subjects with isolated epibubar dermoids. CONCLUSION: Our study allowed the expansion of the clinical spectrum of mosaic RASopathies and supports that mosaicism for recurrent mutations in KRAS and FGFR1 is a commonly involved mechanism in these rare oculocutaneous anomalies.


Assuntos
Cisto Dermoide/genética , Displasia Ectodérmica/genética , Oftalmopatias/genética , Lipomatose/genética , Síndromes Neurocutâneas/genética , Nevo Sebáceo de Jadassohn/genética , Fenótipo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Cisto Dermoide/patologia , Displasia Ectodérmica/patologia , Oftalmopatias/patologia , GTP Fosfo-Hidrolases/genética , Humanos , Lipomatose/patologia , Proteínas de Membrana/genética , Mosaicismo , Síndromes Neurocutâneas/patologia , Nevo Sebáceo de Jadassohn/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética
4.
Brain Tumor Pathol ; 35(4): 217-223, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30145692

RESUMO

Primary melanocytic tumors of central nervous system represent rare tumors arising from melanocytes of the leptomeninges. These neoplasms include focal forms like melanocytoma and primary malignant melanoma and diffuse forms like leptomeningeal melanocytosis and primary leptomeningeal melanomatosis. The clinical diagnosis remains challenging, with clinical and radiologic features overlapping with other more common diseases. Here we present a case of a 38 years old male with primary diffuse leptomeningeal melanomatosis with presence of a NRASQ61K mutation without features of neurocutaneous melanosis.


Assuntos
GTP Fosfo-Hidrolases/genética , Melanoma/genética , Melanoma/patologia , Proteínas de Membrana/genética , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Mutação , Adulto , Autopsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Evolução Fatal , Humanos , Imagem por Ressonância Magnética , Masculino , Melanoma/diagnóstico por imagem , Melanose/genética , Neoplasias Meníngeas/diagnóstico por imagem , Síndromes Neurocutâneas/genética , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia
5.
Actas dermo-sifiliogr. (Ed. impr.) ; 108(9): e57-e62, nov. 2017.
Artigo em Espanhol | IBECS | ID: ibc-168144

RESUMO

El síndrome del nevus melanocítico congénito (SNMC) consiste en la proliferación anormal de melanocitos en la piel y el sistema nervioso central, y se debe a mutaciones de las células progenitoras durante el desarrollo embrionario. En muchas de estas células se han detectado mutaciones en el gen NRAS. Se exponen 5 casos de nevus melanocítico congénito gigante, 3 de ellos asociados al SNMC, en los que se ha estudiado dicha mutación. Hasta hace unos años la cirugía era el tratamiento de elección, sin embargo, sus resultados son insatisfactorios, con cirugías agresivas que no mejoran el aspecto estético y reducen mínimamente el riesgo de malignización. En el año 2013 se aprobó el trametinib en el uso del melanoma avanzado con mutaciones de NRAS. Dicho fármaco, que participa en la cascada intracelular de RAS-RAF-MEK-pERK-MAPK, podría ser útil en pacientes pediátricos con SNMC. El conocimiento más amplio de esta enfermedad permitirá crear nuevas estrategias (AU)


Congenital melanocytic nevus syndrome (CMNS) is the result of an abnormal proliferation of melanocytes in the skin and central nervous system caused by progenitor-cell mutations during embryonic development. Mutations in the NRAS gene have been detected in many of these cells. We present 5 cases of giant congenital melanocytic nevus, 3 of them associated with CMNS; NRAS gene mutation was studied in these 3 patients. Until a few years ago, surgery was the treatment of choice, but the results have proved unsatisfactory because aggressive interventions do not improve cosmetic appearance and only minimally reduce the risk of malignant change. In 2013, trametinib was approved for use in advanced melanoma associated with NRAS mutations. This drug, which acts on the intracellular RAS/RAF/MEK/pERK/MAPK cascade, could be useful in pediatric patients with CMNS. A better understanding of this disease will facilitate the development of new strategies (AU)


Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Nevo Pigmentado/congênito , Melanose/genética , Síndromes Neurocutâneas/genética , Síndrome do Hamartoma Múltiplo/congênito , Mutação/genética , Marcadores Genéticos , Melanócitos
6.
J AAPOS ; 21(5): 426-429.e1, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28867399

RESUMO

Evaluation for intracranial lesions in a patient with retinal cavernous hemangiomas is vital for early recognition of this heritable and potentially life-threatening disease. We report a case of a highly penetrant but variably expressed form of cerebral cavernous malformation syndrome with cerebral, cutaneous, and retinal cavernomas in a family found to harbor a nonsense mutation of the CCM1 gene.


Assuntos
Códon sem Sentido , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso/genética , Proteína KRIT1/genética , Síndromes Neurocutâneas/genética , Neoplasias da Retina/genética , Neoplasias Cutâneas/genética , Criança , Análise Mutacional de DNA , Feminino , Angiofluoresceinografia , Hemangioma Cavernoso/patologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Síndromes Neurocutâneas/patologia , Linhagem , Neoplasias da Retina/patologia , Neoplasias Cutâneas/patologia , Tomografia de Coerência Óptica
7.
Interv Neuroradiol ; 23(6): 572-576, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28814167

RESUMO

A novel hypothesis proposes that "cardio-cephalic neural crest (NC) syndrome," i.e. cephalic NC including cardiac NC, contributes to the concurrent occurrence of vascular diseases in the cardio- and cerebrovascular regions. NC is a transient structure present in early embryogenesis. Cephalic NC provides mesenchymal cells to the vascular media in these regions. Concurrent cardio- and cerebrovascular lesions have been reported in PHACE syndrome, ACTA2 mutation syndrome, and less frequently in the spontaneous occlusion of the circle of Willis (so-called moyamoya disease). Cardiovascular lesions in these syndromes include coarctation of the aorta, persistent truncus arteriosus, patent ductus arteriosus, and coronary artery disease, and cerebrovascular lesions include agenesis and stenosis/occlusion of the internal carotid arteries, and moyamoya phenomenon. These concurrent vascular lesions both in the cardio- and cerebrovascular regions might be related to cephalic NC. This hypothesis, although not proven, may facilitate a better understanding of the above-mentioned NC-related vascular pathologies and lead to appropriate diagnostic and therapeutic approaches for clinicians and chart future direction for researchers.


Assuntos
Coartação Aórtica/diagnóstico por imagem , Transtornos Cerebrovasculares/diagnóstico por imagem , Anormalidades do Olho/diagnóstico por imagem , Doença de Moyamoya/diagnóstico por imagem , Crista Neural/anormalidades , Síndromes Neurocutâneas/diagnóstico por imagem , Actinas , Adenosina Trifosfatases , Coartação Aórtica/genética , Circulação Cerebrovascular , Transtornos Cerebrovasculares/genética , Anormalidades do Olho/genética , Humanos , Doença de Moyamoya/genética , Mutação de Sentido Incorreto , Síndromes Neurocutâneas/genética , Fenótipo , Ubiquitina-Proteína Ligases
8.
Am J Med Genet A ; 173(5): 1378-1382, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28371479

RESUMO

CHIME syndrome is a rare autosomal recessive neuroectodermal disorder associated with biallelic mutations in PIGL. To date, six molecularly confirmed cases of CHIME syndrome have been reported. Here, we report the seventh patient with biallelic PIGL mutations associated with CHIME syndrome and describe the first characterization of an intragenic deletion in PIGL. Our characterization of the deletion breakpoint junction demonstrated that the breakpoints occurred within Alu repeats and the deletion was most likely mediated by a microhomology event. Analysis of PIGL genomic sequences for repetitive elements demonstrated that Alu repeats represent ∼34% of its intronic sequence, suggesting that the genomic architecture may predispose the gene to disease-causing copynumber changes. Taken together, these findings indicate that patients with a clinical diagnosis of CHIME syndrome and a single identifiable mutation in PIGL warrant further investigation for copynumber changes involving PIGL.


Assuntos
Elementos Alu/genética , Coloboma/genética , Perda Auditiva Condutiva/genética , Cardiopatias Congênitas/genética , Ictiose/genética , Deficiência Intelectual/genética , N-Acetilglucosaminiltransferases/genética , Síndromes Neurocutâneas/genética , Deleção de Sequência/genética , Alelos , Pré-Escolar , Coloboma/fisiopatologia , Perda Auditiva Condutiva/fisiopatologia , Cardiopatias Congênitas/fisiopatologia , Humanos , Ictiose/fisiopatologia , Deficiência Intelectual/fisiopatologia , Íntrons , Masculino , Síndromes Neurocutâneas/fisiopatologia
9.
Actas Dermosifiliogr ; 108(9): e57-e62, 2017 Nov.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28110826

RESUMO

Congenital melanocytic nevus syndrome (CMNS) is the result of an abnormal proliferation of melanocytes in the skin and central nervous system caused by progenitor-cell mutations during embryonic development. Mutations in the NRAS gene have been detected in many of these cells. We present 5 cases of giant congenital melanocytic nevus, 3 of them associated with CMNS; NRAS gene mutation was studied in these 3 patients. Until a few years ago, surgery was the treatment of choice, but the results have proved unsatisfactory because aggressive interventions do not improve cosmetic appearance and only minimally reduce the risk of malignant change. In 2013, trametinib was approved for use in advanced melanoma associated with NRAS mutations. This drug, which acts on the intracellular RAS/RAF/MEK/pERK/MAPK cascade, could be useful in pediatric patients with CMNS. A better understanding of this disease will facilitate the development of new strategies.


Assuntos
Nevo Pigmentado/congênito , Neoplasias Cutâneas/congênito , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Códon/genética , Síndrome de Dandy-Walker/diagnóstico por imagem , Síndrome de Dandy-Walker/etiologia , Síndrome de Dandy-Walker/cirurgia , Epilepsia do Lobo Temporal/etiologia , Paralisia Facial/etiologia , Evolução Fatal , Feminino , Genes ras , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Melanose/congênito , Melanose/diagnóstico por imagem , Melanose/genética , Melanose/patologia , Mutação de Sentido Incorreto , Síndromes Neurocutâneas/congênito , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/patologia , Neuroimagem , Nevo Pigmentado/genética , Nevo Pigmentado/patologia , Especificidade de Órgãos , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
14.
Pediatr Neurol ; 60: 71-4, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27131628

RESUMO

BACKGROUND: Encephalocraniocutaneous lipomatosis is a rare congenital neurocutaneous syndrome resulting from ectomesodermal dysgenesis and characterized by unique hairless scalp lesions in the form of nevus psiloliparus, ipsilateral ocular malformations, and central nervous system anomalies. According to the 2009 diagnostic criteria proposed by Moog et al., ocular abnormalities are supposed to be the most consistent feature of encephalocraniocutaneous lipomatosis. PATIENT DESCRIPTION: We describe an 18-year-old girl with most of the central nervous system manifestations of encephalocraniocutaneous lipomatosis, major skin alterations including nevus psiloliparus, but no ocular involvement. CONCLUSION: Our patient suggests more variability in clinical features and a more complex genetic/embryonic etiology of encephalocraniocutaneous lipomatosis.


Assuntos
Oftalmopatias/diagnóstico , Oftalmopatias/patologia , Lipomatose/diagnóstico , Lipomatose/patologia , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/patologia , Adolescente , Encéfalo/diagnóstico por imagem , Diagnóstico Diferencial , Olho/patologia , Oftalmopatias/etiologia , Oftalmopatias/genética , Feminino , Humanos , Lipomatose/etiologia , Lipomatose/genética , Síndromes Neurocutâneas/etiologia , Síndromes Neurocutâneas/genética , Fenótipo , Pele/patologia
16.
Clin Genet ; 90(4): 334-42, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26970110

RESUMO

Oculoectodermal syndrome (OES) and encephalocraniocutaneous lipomatosis (ECCL) are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor-like lesions, and others. About 20 cases with OES and more than 50 patients with ECCL have been reported. Both diseases were proposed to represent mosaic disorders, but only very recently whole-genome sequencing has led to the identification of somatic KRAS mutations, p.Leu19Phe and p.Gly13Asp, in affected tissue from two individuals with OES. Here we report the results of molecular genetic studies in three patients with OES and one with ECCL. In all four cases, Sanger sequencing of the KRAS gene in DNA from lesional tissue detected mutations affecting codon 146 (p.Ala146Val, p.Ala146Thr) at variable levels of mosaicism. Our findings thus corroborate the evidence of OES being a mosaic RASopathy and confirm the common etiology of OES and ECCL. KRAS codon 146 mutations, as well as the previously reported OES-associated alterations, are known oncogenic KRAS mutations with distinct functional consequences. Considering the phenotype and genotype spectrum of mosaic RASopathies, these findings suggest that the wide phenotypic variability does not only depend on the tissue distribution but also on the specific genotype.


Assuntos
Cisto Dermoide/genética , Displasia Ectodérmica/genética , Oftalmopatias/genética , Predisposição Genética para Doença , Lipomatose/genética , Síndromes Neurocutâneas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Criança , Pré-Escolar , Códon , Cisto Dermoide/patologia , Displasia Ectodérmica/patologia , Oftalmopatias/patologia , Humanos , Lactente , Lipomatose/patologia , Síndromes Neurocutâneas/patologia
17.
Am J Hum Genet ; 98(3): 579-587, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26942290

RESUMO

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.


Assuntos
Oftalmopatias/genética , Lipomatose/genética , Síndromes Neurocutâneas/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , Pré-Escolar , Exoma , Olho/fisiopatologia , Oftalmopatias/diagnóstico , Feminino , Humanos , Lactente , Lipomatose/diagnóstico , Masculino , Mutação , Mutação de Sentido Incorreto , Síndromes Neurocutâneas/diagnóstico , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Convulsões/genética , Análise de Sequência de DNA
18.
J Invest Dermatol ; 136(4): 770-778, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26778290

RESUMO

Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Gα subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11(R183C) and GNA11(Q209L) in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11(R183C) under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities.


Assuntos
Subunidades alfa de Proteínas de Ligação ao GTP/genética , Mancha Mongólica/genética , Mutação , Síndromes Neurocutâneas/genética , Dermatopatias/genética , Alelos , Animais , Animais Geneticamente Modificados , Sequência de Bases , Análise Mutacional de DNA , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP , Células HEK293 , Humanos , Lactente , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Fenótipo , Fosforilação , Transdução de Sinais , Peixe-Zebra
19.
J Invest Dermatol ; 136(3): 672-679, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26747696

RESUMO

Loss-of-function mutations in the synaptosomal-associated protein 29 (SNAP29) gene cause the cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome. In this study, we created total (Snap29(-/-)) as well as keratinocyte-specific (Snap29(fl/fl)/K14-Cre) Snap29 knockout mice. Both mutant mice exhibited a congenital distinct ichthyotic phenotype resulting in neonatal lethality. Mutant mice revealed acanthosis and hyperkeratosis as well as abnormal keratinocyte differentiation and increased proliferation. In addition, the epidermal barrier was severely impaired. These results indicate an essential role of SNAP29 in epidermal differentiation and barrier formation. Markedly decreased deposition of lamellar body contents in mutant mice epidermis and the observation of malformed lamellar bodies indicate severe impairments in lamellar body function due to the Snap29 knockout. We also found increased microtubule associated protein-1 light chain 3, isoform B-II levels, unchanged p62/SQSTM1 protein amounts, and strong induction of the endoplasmic reticulum stress marker C/EBP homologous protein in mutant mice. This emphasizes a role of SNAP29 in autophagy and endoplasmic reticulum stress. Our murine models serve as powerful tools for investigating keratinocyte differentiation processes and provide insights into the essential contribution of SNAP29 to epidermal differentiation.


Assuntos
Diferenciação Celular/genética , Regulação da Expressão Gênica , Ceratodermia Palmar e Plantar/patologia , Síndromes Neurocutâneas/patologia , Proteínas Qb-SNARE/genética , Proteínas Qc-SNARE/genética , Animais , Autofagia/genética , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Células Epidérmicas , Imuno-Histoquímica , Queratinócitos/metabolismo , Queratinócitos/patologia , Ceratodermia Palmar e Plantar/genética , Camundongos , Camundongos Knockout , Síndromes Neurocutâneas/genética , Distribuição Aleatória , Valores de Referência
20.
Am J Med Genet A ; 170(3): 688-93, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26774077

RESUMO

We report the case of a young girl who was presented with complex clinical symptoms caused by the deletion of contiguous genes: RASA1 and MEF2C, located on chromosome 5q14.3. Specifically, the diagnosis of her skin disorder and vascular malformations involving central nervous system is consistent with a RASopathy. The child's neurological manifestations are observed in most patients suffering from 5q14.3 by deletion or mutation of the MEF2C gene. A review of the literature allowed us to conclude that the contiguous deletion of genes RASA1 and MEF2C fulfills the criteria for the diagnosis of a Neurocutaneous syndrome as proposed by Carr et al. [2011]. We also assessed the penetrance of RASA1 and clinical manifestations of MEF2C according to the type of deletion. This child described presents the complete symptomatology of both deleted genes. We would also like to highlight the progression of the disorder.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/genética , Proteína p120 Ativadora de GTPase/genética , Vasos Sanguíneos/anormalidades , Vasos Sanguíneos/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Progressão da Doença , Feminino , Deleção de Genes , Humanos , Fatores de Transcrição MEF2/deficiência , Fatores de Transcrição MEF2/genética , Síndromes Neurocutâneas/patologia , Síndromes Neurocutâneas/fisiopatologia , Penetrância , Pele/irrigação sanguínea , Pele/metabolismo , Pele/patologia , Proteína p120 Ativadora de GTPase/deficiência
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