Clinical and molecular aspects of Turkish familial hemophagocytic lymphohistiocytosis patients with perforin mutations

Hacettepe University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, 06100-Sihhiye, Ankara, Turkey.
Leukemia Research (Impact Factor: 2.35). 07/2008; 32(6):972-5. DOI: 10.1016/j.leukres.2007.11.033
Source: PubMed


The aim of this study was to elucidate the pathologic sequence changes and associated clinical phenotypes in 9 new patients showing homozygosity for perforin gene among a total of 37 (24%) Turkish FHL families studied by linkage analysis. These 9 unrelated patients (5M/4F) were coming from consanguineous families and their presentation ages of systemic symptoms were ranged from birth to 15 years. Direct sequencing of coding exons of the perforin gene led to the identification of five different homozygous alterations. The nonsense W374X mutation was identified in three patients while four different missense mutations namely G149S, V50M, A91V and novel A523D were detected in the rest six patients.

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    • "In all, 3 patients (33%) carried the same nonsense W374X mutation in exon 3, and the 6 remaining patients (67%) had 4 different missense variations (G149S, V50M, A91V, and novel A523D). Among these missense changes, G149S S was detected in 2 patients, V50M in 1 patient, and A91V in 2 patients [18]. In contrast, 2 earlier studies reported that 30% and 44% of Turkish FHL patients had perforin mutations, of which, 67% and 86%, respectively, had W374X mutation [10,14]. "
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    ABSTRACT: Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous disease. Presentation of the disease such as primarily fever, hepatosplenomegaly, and cytopenia, which are the results of functional degradation in cytotoxic T-lymphocytes and natural killer cells, activation of macrophages and T-lymphocytes, over production of proinflammatory cytokines, and hemophagocytosis. In all, 5 genetic loci have been identified in FHL, and all known affected genes encode critical components of the granule exocytosis pathway, which is essential for the release of cytotoxic granules and proteases that are necessary for targeted cell death. Herein we present an FHL patient with a severe clinical course and a very rare perforin gene mutation. The patient was homozygous for A665G mutation. However, the child died in a short period of time. Prenatal diagnosis was performed in the family and the fetus was found to be heterozygous for the mutation.
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