Search

The myelodysplastic syndromes (MDS) are heterogeneous and can evolve into acute myeloid leukaemia (AML). Rare familial cases are reported in which five disease genes have been identified to date (RUNX1, CEBPA, TERC, TERT and GATA2). Here we report the genetic categorization of 27 families with familial MDS/AML. All of these families were screened for RUNX1, CEBPA, TERC, TERT and GATA2 as well as TET2 and NPM1. Five of the 27 families had telomerase mutations; one had a RUNX1 mutation, while none were found to have TET2, CEBPA or NPM1 mutations. We identified four families with heterozygous GATA2 mutations, each associated with a different phenotype. While one of these mutations is novel, three have been previously reported: one has been described in dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency and one is in a family that has been reported in a series with primary lymphoedema with a predisposition to AML (Emberger syndrome). In summary, genetic characterization was shown in 10 (four GATA2, three TERT, two TERC, one RUNX1) of these families; however 17 remain uncharacterized, highlighting marked genetic heterogeneity in familial MDS/AML and the scope for further functional pathways that could give rise to this group of disorders.

Dyskeratosis congenita (DC) is a heterogeneous bone marrow failure disorder with known mutations in components of telomerase and telomere shelterin. Recent work in a mouse model with a dyskerin mutation has implicated an increased DNA damage response as part of the cellular pathology, while mouse models with Terc and Tert mutations displayed a normal response. To clarify how these contradictory results might apply to DC pathology in humans, we studied the cellular phenotype in primary cells from DC patients of several genetic subtypes, focussing on T lymphocytes to remain close to the haematopoietic system. We observed novel cell cycle abnormalities in conjunction with impaired growth and an increase in apoptosis. Using flow cytometry and confocal microscopy we examined induction of the DNA damage proteins γ-H2AX and 53BP1 and the cell cycle protein TP53 (p53). We found an increase in damage foci at telomeres in lymphocytes and an increase in the basal level of DNA damage in fibroblasts, but crucially no increased response to DNA damaging agents in either cell type. As the response to induced DNA damage was normal and levels of global DNA damage were inconsistent between cell types, DNA damage may contribute differently to the pathology in different tissues.

To address the association between travel and deep vein thrombosis (DVT) we examined the risk factors for DVT in 568 consecutive patients with suspected DVT attending King's College Hospital in London. No significant link between DVT and long-haul travel was demonstrable in this cohort, with an odds ratio of 1.3 (CI 0.6-2.8). Risk of DVT was only increased in long-haul travellers if one or more additional risk factors were present, with an odds ratio of 3.0 (CI 1.1-8.2). Such individuals may benefit from prophylactic measures to minimize risk.

To address the association between travel and deep vein thrombosis (DVT) we examined the risk factors for DVT in 568 consecutive patients with suspected DVT attending King's College Hospital in London. No significant link between DVT and long-haul travel was demonstrable in this cohort, with an odds ratio of 1.3 (CI 0.6-2.8). Risk of DVT was only increased in long-haul travellers if one or more additional risk factors were present, with an odds ratio of 3.0 (CI 1.1-8.2). Such individuals may benefit from prophylactic measures to minimize risk.