Angiofibroma nasofaríngeo: revisão dos aspectos genéticos e moleculares / Nasopharyngeal angiofibroma: review of the genetic and molecular aspects

Introdução: O angiofibroma nasofaríngeo juvenil (ANJ) é um tumor fibrovascular raro de etiologia desconhecida, com poucos estudos que analisam sua patogênese. Objetivo: Revisar a patogênese do ANJ, com ênfase nos aspectos genéticos e moleculares. Método: Foram revisados todos os artigos pertinentes indexados no PUBMED e LILACS e capítulos de livros de referência publicados entre 1959 e 2007. Resultados: A seletividade do ANJ em relação ao sexo pode ser explicada por acúmulos intranucleares do receptor androgênico e de beta-catenina, um coativador que aumenta a sensibilidade do tumor a andrógenos. As alterações genéticas observadas no ANJ acometem mais freqüentemente cromossomos sexuais. Inúmeros fatores de crescimento parecem estar implicados na patogênese do tumor. O fator II de crescimento símile a insulina é altamente expresso, enquanto que o fator de crescimento endotelial vascular e o fator beta transformador do crescimento são liberados por células estromais e podem influenciar o crescimento e a vascularização do ANJ. Conclusão: Apesar da escassez de dados sobre a etiologia e patogênese do ANJ, fatores genéticos e moleculares parecem colaborar para o entendimento de muitas características morfológicas e clínicas da doença. O conhecimento sobre estes fatores específicos pode contribuir futuramente para o estabelecimento de potenciais alvos terapêuticos.

Introduction: Juvenile nasopharyngeal angiofibroma (JNA) is a rare fibrovascular tumor of unknown etiology, with few studies analyzing its pathogenesis. Objective: Reviewing JNA's pathogenesis, emphasizing genetic and molecular aspects. Method: All the relevant articles indexed in PUBMED and LILACS, besides reference book chapters, published between 1959 and 2007 were reviewed. Results: The sex selectivity seen in JNA may be explained by intranuclear accumulation of androgen receptor and beta-catenin, a co-activator which increases the tumor sensitivity to androgynous. The genetic alterations seen in JNA are most frequently located in sexual chromosomes. A number of growth factors seem to be related to the tumor pathogenesis. The insulin-like growth factor II is highly expressed while the vascular endothelial growth factor and the transforming growth factor beta are released by stromal cells and may influence the JNA's growth and vascularization. Conclusion: In spite of the scarce data describing the JNA etiology and pathogenesis, genetic and molecular factors seem to collaborate to the understanding of the disease's many clinical and morphological features. Knowledge regarding these specific issues could contribute for the establishment of potential therapeutic targets in the future.

Tuberous sclerosis complex: advances in diagnosis, genetics, and management

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome characterized by the development of multiple hamartomas distributed throughout the body, skin, brain, heart, kidneys, liver, and lungs. Two-thirds of patients represent sporadic mutations. The classic triad is seizures, mental retardation, and cutaneous angiofibromas. However, the full triad occurs in only 29 por cento of patients; 6por cento of them lack all three of them. Two tumor suppressor genes responsible for TSC have been identified: TSC1 gene on chromosome 9 and TSC2 on chromosome 16. This article highlights the most recent significant advances in the diagnosis and genetics of TSC, along with a discussion on the limitations and the usefulness of the revised 1998 clinical criteria for the tuberous sclerosis complex. The [quot ]ash leaf[quot ] macule often comes in other shapes, such as round; most are polygonal, usually 0.5 cm to 2.0 cm in diameter, resembling a thumbprint. Since the death of its describer, Thomas Fitzpatrick, we call each a [quot ]Fitzpatrick patch.[quot ] Special attention is paid in this work to TSC treatment options, including therapeutic trials with rapamycin, also known as sirolimus. LEARNING OBJECTIVE: After completing this learning activity, participants should familiar with tuberous sclerosis complex, its cutaneous signs and systemic findings stratified by patient age, its genetics, and the potential for meaningful therapeutic intervention.

Genetic alterations in Ki-ras and Ha-ras genes in juvenile nasopharyngeal angiofibromas and head and neck cancer

Context: Ras gene mutations have been associated to a wide range of human solid tumors. Members of the ras gene family (Ki-ras, Ha-ras and N-ras) are structurally related and code for a protein (p21) known to play an important role in the regulation of normal signal transduction and cell growth. The frequency of ras mutations is different from one type of tumor to another, suggesting that point mutations might be carcinogen-specific. Objectives: To study the occurrence of Ki-ras and Ha-ras mutations. We also studied the relative level of Ha-ras mRNA in 32 of the head and neck tumors. Design: Case series. Setting: University referral unit. Participants: 60 head and neck tumors and in 28 Juvenile Nasopharyngeal Angiofibromas (JNA). Diagnostic test: Using PCR-SSCP we examined the occurence of Ki-ras and Ha-ras mutations. The relative level of Ha-ras mRNA was examined by Northern blot analysis. Results: None of the head and neck tumors or JNA samples showed evidence of mutations within codons 12,13,59 and 61 of Ki-ras or Ha-ras genes. However, 17 (53 per cent) of the tumors where gene expression could be examined exhibited increased levels of Ha-ras mRNA compared with the normal tissue derived from the same patient. Conclusions: Our results demonstrate for the first time that mutations of Ki-ras and Ha-ras genes are not associated with the development of JNA and confirm previous reports indicating that activating ras mutations are absent or rarely invloved in head and neck tumors from western world patients. Furthermore, our findings suggest that overexpression of Ha-ras, rather than mutations, might be an important factor in the development and progression of head and neck tumors.