RESUMEN
Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease of early childhood characterized by nonmalignant accumulation and multivisceral infiltration of activated T lymphocytes and histiocytes (macrophages). Cytotoxic T and natural killer (NK) cell activity is markedly reduced or absent in these patients, and mutations in a lytic granule constituent, perforin, were recently identified in a number of FHL individuals. Here, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutations, and one patient was a compound heterozygote. Four novel mutations were detected: one nonsense, two missense, and one deletion of one amino acid. In four families, a previously reported mutation at codon 374, causing a premature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mutations in 20% of all FHL patients investigated (7/34), with a somewhat higher prevalence, approximately 30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phenotype of the patients was evident from the present study. Our combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%-40% of the FHL cases and the FHL 1 locus on chromosome 9 for approximately 10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes.
Asunto(s)
Histiocitosis de Células no Langerhans/genética , Glicoproteínas de Membrana/genética , Mutación , Sustitución de Aminoácidos , Niño , Codón , Codón de Terminación , Marcadores Genéticos , Histiocitosis de Células no Langerhans/inmunología , Humanos , Macrófagos/inmunología , Datos de Secuencia Molecular , Mutación Missense , Perforina , Proteínas Citotóxicas Formadoras de Poros , Eliminación de Secuencia , Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunologíaRESUMEN
PURPOSE: The comparable health-care organizations and common Cancer Registry for childhood malignancies in the five Nordic countries offered an opportunity to conduct an epidemiological study on a reasonable number of childhood non-Hodgkin's lymphoma (NHL) cases collected in a population-based manner. MATERIAL AND METHODS: All childhood cases (0-14.9 years at diagnosis) reported during the 5-year period of 1985-1989 to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) Cancer Registry for childhood malignancies were reviewed and analyzed according to age, Murphy's stage, gender, site, and survival. RESULTS: The annual incidence of NHL is 0.7 per 100,000 children in the five Nordic countries, constituting 5% of all childhood malignancies. Age distribution was even; the male/female ratio was 3:1. Age and stage were shown by Cox regression analysis to be independent prognostic factors. Older age and lower stage affected outcome favorably. The stage and site distribution was similar to previous reports. Survival data were in accordance with those expected with modern treatment protocols. CONCLUSIONS: The incidence and relative frequency of NHL in childhood in the five Nordic countries is in agreement with previously reported data, but the even distribution of cases throughout childhood is a new finding. Older age at onset and stage of disease affect outcome favorably, whereas male gender contrary to acute lymphoblastic leukemia was not found to affect outcome.
Asunto(s)
Linfoma no Hodgkin/epidemiología , Adolescente , Factores de Edad , Niño , Preescolar , Dinamarca/epidemiología , Femenino , Finlandia/epidemiología , Humanos , Islandia/epidemiología , Masculino , Noruega/epidemiología , Estudios Prospectivos , Sistema de Registros , Factores Sexuales , Suecia/epidemiologíaRESUMEN
Fifteen 7-16-year-old patients, treated in 1981-1984 for acute lymphoblastic leukemia (ALL) in first complete remission, were studied. As a central nervous system prophylaxis, all the children were treated with repeated methotrexate (MTX) instillations, but none were irradiated. The study protocol included magnetic resonance (MR) and a battery of neuropsychological tests. Small, punctate white-matter lesions were found by MR in eight children, probably minor vascular lesions. All the children were within normal intelligence range with a mean total WISC-R IQ of 109. Minor neuropsychologic problems were found in two patients, while one child showed a more extensive specific learning disorder in school.