RESUMO
BACKGROUND AND OBJECTIVES: Severe congenital neutropenia (SCN) or Kostmann syndrome was originally reported to be an autosomal recessive disease of neutrophil production causing recurrent, life-threatening infections. Mutations in the neutrophil elastase gene (ELA-2) have previously been identified in patients with sporadic or autosomal dominant SCN. DESIGN AND METHODS: We studied 14 individuals (four patients with SCN and ten close relatives) belonging to the original Kostmann family in northern Sweden for mutations in the ELA-2 and the granulocyte colony-stimulating factor (G-CSF) receptor genes. RESULTS: One patient belonging to the original Kostmann family harbored a novel heterozygous ELA-2 mutation (g.2310T-->A;Leu92His) that was not inherited from her parents. The mutation was identified in DNA isolated from both whole blood and skin fibroblasts, suggesting a sporadic de novo mutation. As a young adult this patient sequentially acquired two mutations in the gene for the G-CSF receptor (G-CSFR) and therefore recently received a hematopoietic stem cell transplant, due to the risk of evolution to leukemia. Moreover, another patient developed acute leukemia and was treated with transplantation. No pathogenic ELA-2 or G-CSFR gene mutations were found in this patient or the other two patients, nor in any healthy relative. INTERPRETATION AND CONCLUSIONS: Our data are the first to document leukemia evolution and G-CSFR gene mutations in the original Kostmann kindred. In addition, our findings indicate that ELA-2 mutations are not the primary cause of SCN in the Swedish Kostmann family.
Assuntos
Elastase de Leucócito/genética , Proteínas de Neoplasias/genética , Neutropenia/congênito , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Pré-Leucemia/genética , Receptores de Fator Estimulador de Colônias de Granulócitos/genética , Adulto , Substituição de Aminoácidos , Diferenciação Celular/genética , Criança , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Genes Recessivos , Transplante de Células-Tronco Hematopoéticas , Humanos , Cariotipagem , Masculino , Mutação de Sentido Incorreto , Neutropenia/epidemiologia , Neutropenia/genética , Neutropenia/cirurgia , Linhagem , Mutação Puntual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiologia , Pré-Leucemia/epidemiologia , Estrutura Terciária de Proteína , Análise de Sequência de DNA , Suécia/epidemiologia , Síndrome , Fatores de Transcrição/genética , Proteína da Síndrome de Wiskott-Aldrich/genéticaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) embraces the frequently indistinguishable conditions of familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hemophagocytic syndrome (VAHS). Without therapy FHL is invariably fatal, but successful therapy, including chemotherapy and immunotherapy followed by bone marrow transplantation (BMT), has been presented. To clarify the outcome of HLH in a developing country, with regard to clinical, laboratory, and genetic features, a nationwide study on all patients diagnosed with HLH in Oman during the 5-year period 1997-2001 was performed. In 5 patients and their families, mutational analysis was made. Thirteen patients with HLH were identified, 5 of whom had clinical manifestations of central nervous system involvement at presentation. In none of the patients could an infectious cause be identified. Ten children were referred late in the disease course, and the concern about starting chemotherapy before exclusion of an acute viral infection resulted in delayed treatment in some patients. Two children were started early on the HLH-94-therapy followed by successful BMT in one child. In the successfully transplanted child, the response to intrathecal hydrocortisone appeared to be better than standard therapy with intrathecal methotrexate. Finally, a novel missense mutation in the perforin gene was identified in 2 patients and their family members, causing a transition of proline to threonine at codon 89. Early diagnosis and treatment is important to improve outcome. Intrathecal corticosteroids may be considered, in addition to intrathecal methotrexate, in certain patients. Since the novel perforin mutation has been reported in only 2 patients from Oman, and since similar polymorphism in the sequencing data of the members of their families has been identified, a founder effect is possible in this population.
Assuntos
Histiocitose de Células não Langerhans , Transplante de Medula Óssea , Quimioterapia Combinada , Evolução Fatal , Feminino , Histiocitose de Células não Langerhans/diagnóstico , Histiocitose de Células não Langerhans/genética , Histiocitose de Células não Langerhans/terapia , Humanos , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Masculino , Glicoproteínas de Membrana/genética , Mutação , Omã , Perforina , Proteínas Citotóxicas Formadoras de Poros , Análise de SobrevidaRESUMO
Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disorder of immune regulation. Mutations in the gene encoding perforin were previously identified in a subset of FHL patients. The present analysis of two novel candidate genes, granzyme B and granulysin, by direct sequencing in a total of 16 FHL families, disclosed several sequence variations. However, none of these sequence variations were associated with the manifestations of FHL. These data do not support the notion that granulysin and granzyme B are candidate genes for FHL.
