Transition of care from paediatric to adult services in haematology.

The need for adequate preparation for transition for young people with health care needs who require long term follow-up in the adult sector has long been recognised and is a required part of the national service framework for children. The Royal College of Paediatrics and Child Health and the Royal College of Nursing have endorsed this need for improvement in services for adolescents. In 2006 the Department of Health launched guidelines with a wealth of recommendations. Despite these initiatives only slow progress has been made (usually by enthusiasts) and much work is needed to develop good programmes in many specialties, including non-malignant haematology.     

Combined glucose-6-phosphate dehydrogenase and glucosephosphate isomerase deficiency can alter clinical outcome

Glucosephosphate isomerase (GPI) deficiency in humans is an autosomal recessive disorder, which results in nonspherocytic hemolytic anemia of variable clinical expression. A 4-year-old female with severe congenital hemolytic anemia had low red cell GPI activity of 15.5 IU/g Hb (50% of normal mean) indicating GPI deficiency. Subsequent DNA sequence analysis revealed a novel homozygous 921C to G mutation in the GPI gene sequence, predicting a Phe307 to Leu replacement. Strikingly, the red cell GPI activity in this patient was higher than that found in a second patient expressing the same GPI variant, with a more severe clinical phenotype. We propose that the hemolysis in the first patient may be modified by an accompanying deficiency of glucose-6-phosphate dehydrogenase (G6PD). The proband's red cell G6PD activity was reduced at 4.5 IU/g Hb (50% of normal mean) and molecular studies revealed heterozygosity for the G6PD Viangchan mutation and a skewed pattern of X-chromosome inactivation, producing almost exclusive expression of the mutated allele. The G6PD Viangchan variant is characterised by severe enzyme deficiency, but not chronic hemolysis. This study suggests that the metabolic consequences of a combined deficiency of GPI and G6PD might be responsible for a different clinical outcome than predicted for either defect in isolation.     

Evidence-based treatment of haemophilia

Summary.  Haemophilia care is effective but therapy is expensive. Despite concentrates being available in some areas for more than 30 years, many scientific questions concerning the management of haemophilia, such as what doses and duration of factor are required for different bleeding episodes or for surgical procedures, remain inadequately answered. Modern rigorous methods of assessment of the evidence both assist in determining what facts are available, how reliable the evidence is, and also help to define what studies need to be done. Cochrane methodology can be applied to haemophilia, and an assessment of prophylaxis provides an example. International collaborative studies would be valuable and require enthusiastic participants.     

Haemophilias A and B

The haemophilias are inherited disorders in which one of the coagulation factors is deficient. Although deficiencies of factor VIII (haemophilia A) and factor IX (haemophilia B) are well recognised, von Willebrand's disease is much more common. Rare defects can occur in any of the coagulation factors. In the past, men with haemophilia were likely to die in their youth. With advances in diagnosis, and especially with development of safe and effective treatment, affected individuals can now look forward to a normal life expectancy. Complications of the disorder, particularly the development of antibodies that make treatment ineffective, and of treatment, such as transfusion-transmitted infections, have taken a severe toll on these patients. The future holds the realistic possibility of gene therapy. However, we must not forget that haemophilia is a worldwide disorder that requires significant economic resources not available for the majority.     

Mucosa associated lymphoma of the lung.

Two cases of mucosa associated lymphoma (pseudolymphoma) of the lung are described which highlight the varied clinical and radiological features of this rare pulmonary condition. Following chemotherapy with prednisolone and chlorambucil, both patients are disease free three years later.     

Idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura in children usually a self limiting disorder. It may follow a viral infection or immunisation and is caused by an inappropriate response of the immune system. About 20-30% of children will fail to remit over six months (chronic idiopathic thrombocytopenic purpura). This is more likely in older children, especially girls. The disease is reviewed with reference to diagnosis, investigation, and management options.     

Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by complete absence of detectable fibrinogen. We previously identified the first causative mutations for this disease: a homozygous deletion of approximately 11 kb of the fibrinogen alpha-chain gene (FGA). Subsequent studies revealed that the great majority of afibrinogenemia mutations are localized in FGA, but mutations were also found in FGG and FGB. Apart from 3 missense mutations identified in the C-terminal portion of FGB, all fibrinogen gene mutations responsible for afibrinogenemia are null. In this study, a young boy with afibrinogenemia was found to be a compound heterozygote for 2 mutations in FGB: an N-terminal nonsense mutation W47X (exon 2) and a missense mutation (G444S, exon 8). Coexpression of the FGB G444S mutant cDNA in combination with wild-type FGA and FGG cDNAs demonstrated that fibrinogen molecules containing the mutant beta chain are able to assemble but are not secreted into the media, confirming the pathogenic nature of the identified mutation.     

Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C

We report a kindred in which two siblings suffered spontaneous venous thromboses in the second decade of life. Further investigation showed reduced coagulation factor V (FV) activity and activated protein C resistance (APCR) ratio but no other thrombophilic abnormalities. The reduction in APCR ratio persisted in a modified APCR assay in which FV activity was normalized between test and control plasmas. Analysis of the FV gene showed that the thrombotic individuals had a complex genotype that included two novel point mutations c.529G>T and c.1250T>C resulting in FV E119X and FV I359T substitutions inherited on different alleles. Individuals in the kindred with FV E119X or FV I359T substitutions alone were asymptomatic. We suggest that the FV I359T substitution confers pro-thrombotic risk and APCR, but that this is only clinically manifest when co-inherited with the FV E119X allele. The FV I359T substitution creates a new consensus sequence for N-linked glycosylation within the FV heavy chain and we speculate that this abnormal glycosylation may disrupt activated protein C-mediated proteolysis of the variant FV and FVa.     

Bilateral avascular necrosis of the capitate. A case report and a review of the literature

A case of bilateral avascular necrosis of the capitate is presented. A review of the literature has identified a clear-cut clinical syndrome. The aetiology and pathology of this syndrome is discussed and a new method of treatment is proposed.     

Total ankle arthroplasty. A long-term review of the London Hospital experience

We report a retrospective study of 62 total ankle arthroplasties performed between 1972 and 1981. Forty-one of these have been reviewed clinically after an average follow-up of five and a half years; only 13 can be described as satisfactory. The complications encountered in all 62 arthroplasties are detailed, the most significant being superficial wound healing problems, talar collapse, and loosening of the components; 13 prosthetic joints have already been removed and arthrodesis attempted. The management of the complications is discussed. In view of the high complication rate and the generally poor long-term clinical results, we recommend arthrodesis as the treatment of choice for the painful stiff arthritic ankle, regardless of the underlying pathological process.