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Variações nos genes PTCH1, SUFU e PTCH2 e suas manifestações clínico-orais da síndrome de Gorlin-Goltz: uma revisão narrativa
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A Síndrome de Gorlin-Goltz (SGG), também designada síndrome do nevo basocelular, resulta de perturbações germinativas na via Hedgehog, sendo o gene PTCH1 responsável por cerca de 90% dos casos, enquanto mutações no gene SUFU e, mais raramente, no gene PTCH2, compõem um espectro genético complementar. Nas variantes truncadas do gene PTCH1 observa-se ativação constitutiva da via, o que favorece a formação precoce de queratocistos odontogénicos (QQO) mandibulares múltiplos, calcificações da foice do cérebro e múltiplos carcinomas basocelulares cutâneos. Portadores de mutações no gene SUFU manifestam fenótipo “Gorlin-like”, mas apresentam risco acrescido de meduloblastoma infantil, obrigando a vigilância neurológica intensiva. Já as variantes no gene PTCH2 permanecem controversas: estudos recentes documentam indivíduos homozigóticos assintomáticos, sugerindo penetrância muito reduzida ou ausência de implicação clínica direta. Do ponto de vista oro-maxilofacial, a assinatura patognomónica da SGG traduz-se em QQO extensos, alterações dentárias (hipodontia, retenção dentária, raízes curtas) e assimetrias faciais. A literatura indica que o número, dimensão e recidiva dos QQO correlacionam-se com o tipo de alelo afetado, sendo as mutações truncantes no gene PTCH1 as mais agressivas, enquanto mutações no gene SUFU geram quistos menos numerosos, mas associados a tumores centrais do sistema nervoso. Esta revisão narrativa sintetiza a evidência publicada entre 2014-2024, destacando as correlações genótipofenótipo que sustentam uma medicina dentária personalizada. A pesquisa bibliográfica foi realizada nas bases de dados PubMed/MEDLINE, ScienceDirect e Web of Science. Foram utilizados os filtros de artigos completos disponíveis online e o limite temporal de 2014 a 2025, assim como foram aplicados critérios de elegibilidade pré-estabelecidos. Foram então incluídos para análise 24 estudos que evidenciaram que as mutações no PTCH1 representam a maioria dos casos, estando fortemente associadas ao fenótipo clássico, enquanto as mutações em SUFU, embora menos frequentes, configuram maior risco de meduloblastoma pediátrico. O papel do PTCH2 permanece controverso, sugerindo um potencial efeito modificador. A análise das manifestações clínicas confirmou uma elevada prevalência de queratocistos mandibulares e recidivas frequentes, que variam consoante o tipo de abordagem cirúrgica. Conclui-se que a integração da genética, da vigilância clínica e de novas abordagens terapêuticas é essencial para melhorar a gestão e o prognóstico da SGG.
Gorlin-Goltz syndrome (GGS), also known as basal cell nevus syndrome, results from germline disorders in the Hedgehog pathway. The PTCH1 gene accounts for approximately 90% of cases, while mutations in the SUFU gene and, more rarely, the PTCH2 gene comprise a complementary genetic spectrum. Constitutive activation of the pathway is observed in truncated variants of the PTCH1 gene, favoring the early formation of multiple mandibular odontogenic keratocysts (KOCs), calcifications of the falx cerebri, and multiple cutaneous basal cell carcinomas. Carriers of mutations in the SUFU gene exhibit a "Gorlin-like" phenotype but are at increased risk of childhood medulloblastoma, requiring intensive neurological surveillance. Variants in the PTCH2 gene remain controversial: recent studies document asymptomatic homozygous individuals, suggesting very low penetrance or no direct clinical implications. From an oromaxillofacial perspective, the pathognomonic signature of GGS is extensive QQO, dental alterations (hypodontia, tooth retention, short roots), and facial asymmetries. The literature indicates that the number, size, and recurrence of QQO correlate with the type of allele affected, with truncating mutations in the PTCH1 gene being the most aggressive, while mutations in the SUFU gene generate fewer cysts but are associated with central nervous system tumors. This narrative review synthesizes the evidence published between 2014 and 2024, highlighting the genotype-phenotype correlations that support personalized dentistry. The literature search was conducted in the PubMed/MEDLINE, ScienceDirect, and Web of Science databases. Filters for full-text articles available online and the time limit of 2014 to 2025 were used, as well as preestablished eligibility criteria. Twenty-four studies were then included for analysis, showing that PTCH1 mutations account for most cases and are strongly associated with the classic phenotype, while SUFU mutations, although less frequent, represent a higher risk of pediatric medulloblastoma. The role of PTCH2 remains controversial, suggesting a potential modifying effect. Analysis of clinical manifestations confirmed a high prevalence of mandibular keratocysts and frequent recurrences, which vary depending on the type of surgical approach. It is concluded that the integration of genetics, clinical surveillance, and new therapeutic approaches is essential to improve the management and prognosis of GGS.
Gorlin-Goltz syndrome (GGS), also known as basal cell nevus syndrome, results from germline disorders in the Hedgehog pathway. The PTCH1 gene accounts for approximately 90% of cases, while mutations in the SUFU gene and, more rarely, the PTCH2 gene comprise a complementary genetic spectrum. Constitutive activation of the pathway is observed in truncated variants of the PTCH1 gene, favoring the early formation of multiple mandibular odontogenic keratocysts (KOCs), calcifications of the falx cerebri, and multiple cutaneous basal cell carcinomas. Carriers of mutations in the SUFU gene exhibit a "Gorlin-like" phenotype but are at increased risk of childhood medulloblastoma, requiring intensive neurological surveillance. Variants in the PTCH2 gene remain controversial: recent studies document asymptomatic homozygous individuals, suggesting very low penetrance or no direct clinical implications. From an oromaxillofacial perspective, the pathognomonic signature of GGS is extensive QQO, dental alterations (hypodontia, tooth retention, short roots), and facial asymmetries. The literature indicates that the number, size, and recurrence of QQO correlate with the type of allele affected, with truncating mutations in the PTCH1 gene being the most aggressive, while mutations in the SUFU gene generate fewer cysts but are associated with central nervous system tumors. This narrative review synthesizes the evidence published between 2014 and 2024, highlighting the genotype-phenotype correlations that support personalized dentistry. The literature search was conducted in the PubMed/MEDLINE, ScienceDirect, and Web of Science databases. Filters for full-text articles available online and the time limit of 2014 to 2025 were used, as well as preestablished eligibility criteria. Twenty-four studies were then included for analysis, showing that PTCH1 mutations account for most cases and are strongly associated with the classic phenotype, while SUFU mutations, although less frequent, represent a higher risk of pediatric medulloblastoma. The role of PTCH2 remains controversial, suggesting a potential modifying effect. Analysis of clinical manifestations confirmed a high prevalence of mandibular keratocysts and frequent recurrences, which vary depending on the type of surgical approach. It is concluded that the integration of genetics, clinical surveillance, and new therapeutic approaches is essential to improve the management and prognosis of GGS.
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Palavras-chave
Síndrome de Gorlin-Goltz PTCH1 SUFU PTCH2 Via Hedgehog Queratocisto odontogénico Carcinoma basocelular Gorlin-Goltz syndrome Hedgehog pathway Odontogenic keratocyst Basal cell carcinoma