RESUMEN
Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive lethal condition characterized by fever, cytopenia, hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defect apoptosis triggering and lymphocyte cellular cytotoxicity. Thus far three disease-causing genes (PRF1, UNC13D, STX11) have been identified. We performed a genotype-phenotype study in a large, multi-ethnic cohort of 76 FHL patients originating from 65 unrelated families. Biallelic mutations in PRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%) and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed for all three genes, no molecular diagnosis was established. STX11 mutations were most common in Turkish families (7/28, 25%), whereas in Middle East families, PRF1 mutations were most frequent (6/13, 46%). No biallelic mutation was identified in most families of Nordic origin (13/14, 93%). Patients carrying PRF1 mutations had higher risk of early onset (age <6 months) compared to patients carrying STX11 mutations [adjusted odds ratio 8.23 (95% confidence interval [CI] = 1.20-56.40), P = 0.032]. Moreover, patients without identified mutations had increased risk of pathological cerebrospinal fluid (CSF) at diagnosis compared to patients with STX11 mutations [adjusted odds ratio 26.37 (CI = 1.90-366.82), P = 0.015]. These results indicate that the disease-causing mutations in FHL have different phenotypes with regard to ethnic origin, age at onset, and pathological CSF at diagnosis.
Asunto(s)
Linfohistiocitosis Hemofagocítica/genética , Proteínas de la Membrana/genética , Mutación , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Qa-SNARE/genética , Edad de Inicio , Preescolar , Estudios de Cohortes , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Modelos Logísticos , Linfohistiocitosis Hemofagocítica/líquido cefalorraquídeo , Linfohistiocitosis Hemofagocítica/etnología , Masculino , Oportunidad Relativa , Omán/etnología , Perforina , Fenotipo , Medición de Riesgo/métodos , Suecia/etnología , Turquía/etnologíaRESUMEN
In the present study, DNA sequencing of the genes SRGN, ARF6, AP3B1, and SH2D1A was performed in a well defined cohort of 18 families with familial hemophagocytic lymphohistiocytosis (FHL). A heterozygous nucleotide change (C > T) in the 3'untranslated region of the SRGN gene and a monoallelic 3-base pair deletion (c.2409_2411delGAA) in exon 21 of the AP3B1 gene were observed in two different families. Additionally, two novel polymorphisms, one in intron 17 of AP3B1 and another in intron 2 of SH2D1A were identified. We conclude that mutations in SRGN, ARF6, and AP3B1 are not likely to be common in patients fulfilling the FHL criteria.
Asunto(s)
Factores de Ribosilacion-ADP/genética , Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Linfohistiocitosis Hemofagocítica/genética , Polimorfismo Genético/genética , Proteoglicanos/genética , Proteínas de Transporte Vesicular/genética , Regiones no Traducidas 3'/genética , Factor 6 de Ribosilación del ADP , Niño , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Exones/genética , Femenino , Humanos , Lactante , Masculino , Mutación/genética , Proteína Asociada a la Molécula de Señalización de la Activación LinfocitariaRESUMEN
UNLABELLED: Congenital neutropenia in man was first reported 50 years ago by the Swedish paediatrician Rolf Kostmann. He coined the term 'infantile genetic agranulocytosis' for this condition, which is now known as Kostmann syndrome. Recent studies have revealed mutations in ELA-2, encoding the neutrophil granule protease, neutrophil elastase, in autosomal dominant neutropenia, and mutations in HAX-1, encoding an anti-apoptotic protein, in autosomal recessive neutropenia. CONCLUSION: Future studies should aim to clarify the mechanisms underlying the evolution of secondary malignancies in these patients.
Asunto(s)
Neutropenia/genética , Proteínas Adaptadoras Transductoras de Señales , Apoptosis/genética , Proteínas de Unión al ADN/genética , Genes Recesivos , Factor Estimulante de Colonias de Granulocitos , Humanos , Lactante , Leucemia/genética , Elastasa de Leucocito/genética , Mutación , Células Progenitoras Mieloides/fisiología , Neoplasias Primarias Secundarias/etiología , Neutropenia/congénito , Linaje , Proteínas/genética , Receptores de Factor Estimulante de Colonias de Granulocito/genética , Síndrome , Factores de Transcripción/genéticaRESUMEN
Chronic neutropenia comprises several different diseases that vary in degree of severity and management. We analysed the levels of the neutrophil-derived protein pro-LL-37 in plasma of patients with chronic neutropenia to assess whether it could be used to differentiate different categories of chronic neutropenia. All patients with severe congenital neutropenia were pro-LL-37 deficient. This was in contrast to patients with autoimmune or idiopathic neutropenia, who exhibited normal pro-LL-37 levels while patients with cyclic neutropenia displayed an oscillation of pro-LL-37 in plasma. Plasma levels of pro-LL-37 may thus prove useful for differential diagnosis of chronic neutropenia.