Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies (original) (raw)
Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies
- E Rudd1,
- K Göransdotter Ericson1,
- C Zheng1,
- Z Uysal1,
- A Özkan4,
- A Gürgey5,
- B Fadeel6,
- M Nordenskjöld2,
- J-I Henter1
- 1Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
- 2Clinical Genetics Unit, Department of Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
- 3Division of Paediatric Haematology, Ankara University School of Medicine, Ankara, Turkey
- 4Department of Paediatric Haematology, University of Istanbul, Cerrahpasa Medical Faculty, Istanbul, Turkey
- 5Department of Paediatric Haematology, Hacettepe University, Ankara, Turkey
- 6Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Correspondence to: Dr Jan-Inge Henter Childhood Cancer Research Unit, Karolinska University Hospital Q6:05, SE-171 76 Stockholm, Sweden; jan-inge.henter{at}ki.se
Abstract
Objective: To determine the frequency and spectrum of mutations in the gene encoding syntaxin 11 (STX11) in familial haemophagocytic lymphohistiocytosis (FHL), a rare autosomal recessive disorder of immune dysregulation characterised by a defect in natural killer cell function.
Methods: Mutational analysis of STX11 by direct sequencing was done in 28 FHL families that did not harbour perforin mutations, previously identified in some FHL patients. A detailed investigation of clinical features of these patients was also undertaken.
Results: Two different STX11 mutations were identified, one nonsense mutation and one deletion, affecting six of 34 children in four of 28 unrelated PRF1 negative families. Both mutations have been reported before. Three patients experienced long periods (⩾1 year) in remission without specific treatment, which is very uncommon in this disease. Despite the milder phenotype, some children with STX11 mutations developed severe psychomotor retardation. Two of the six patients harbouring STX11 gene defects developed myelodysplastic syndrome (MDS) or acute myelogenous leukaemia (AML).
Conclusions:STX11 gene mutations were found in 14% of the PRF1 negative FHL families included in the present cohort. These results suggest that STX11 gene mutations may be associated with secondary malignancies (MDS/AML), and that there is segregation of specific clinical features in FHL patients with an underlying genotype.
- AML, acute myelogenous leukaemia
- CTL, cytotoxic T lymphocyte
- FHL, familial haemophagocytic lymphohistiocytosis
- MDS, myelodysplastic syndrome
- NK, natural killer
- PRF1, perforin
- SCT, stem cell transplantation
- STX11, syntaxin
- familial haemophagocytic lymphohistiocytosis
- syntaxin
- acute myelogenous leukaemia
- myelodysplastic syndrome
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