Assuntos
Anemia/diagnóstico , Betacoronavirus , Infecções por Coronavirus/diagnóstico , Hemoglobinopatias/diagnóstico , Pneumonia Viral/diagnóstico , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/epidemiologia , COVID-19 , Criança , Pré-Escolar , Infecções por Coronavirus/epidemiologia , Feminino , Hemoglobinopatias/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , SARS-CoV-2 , Adulto JovemAssuntos
Medula Óssea/patologia , Grânulos Citoplasmáticos/ultraestrutura , Imunofenotipagem , Leucemia Promielocítica Aguda/patologia , Complicações Neoplásicas na Gravidez/patologia , Adulto , Antígenos CD34/análise , Biomarcadores Tumorais/sangue , Testes de Coagulação Sanguínea , Núcleo Celular/ultraestrutura , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 17/ultraestrutura , Grânulos Citoplasmáticos/química , Feminino , Antígenos HLA-DR/análise , Humanos , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Proteínas Nucleares/sangue , Gravidez , Complicações Neoplásicas na Gravidez/diagnóstico , Proteína da Leucemia Promielocítica , Fatores de Transcrição/sangue , Translocação Genética , Proteínas Supressoras de Tumor/sangueRESUMO
Perforin, a pore-forming toxin released from secretory granules of NK cells and CTLs, is essential for their cytotoxic activity against infected or cancerous target cells. Bi-allelic loss-of-function mutations in the perforin gene are invariably associated with a fatal immunoregulatory disorder, familial haemophagocytic lymphohistiocytosis type 2 (FHL2), in infants. More recently, it has also been recognized that partial loss of perforin function can cause disease in later life, including delayed onset FHL2 and haematological malignancies. Herein, we report a family in which a wide range of systemic inflammatory and neoplastic manifestations have occurred across three generations. We found that disease was linked to two missense perforin gene mutations (encoding A91V, R410W) that cause protein misfolding and partial loss of activity. These cases link the partial loss of perforin function with some solid tumors that are known to be controlled by the immune system, as well as haematological cancers. Our findings also demonstrate that perforin gene mutations can contribute to hereditary cancer predisposition.