Thrombocytopenia-absent radius syndrome: a clinical genetic study.

The thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterised by bilateral absence of the radii and a thrombocytopenia. The lower limbs, gastrointestinal, cardiovascular, and other systems may also be involved. Shaw and Oliver in 1959 were the first to describe this condition, but it was Hall et al in 1969 who reported the first major series of patients. Since then most reports have been based on single or small numbers of cases. We report the results of a clinical study looking at the phenotype of 34 patients with TAR syndrome. All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies. Congenital anomalies not previously described in association with TAR syndrome included facial capillary haemangiomata, intracranial vascular malformation, sensorineural hearing loss, and scoliosis. Karyotype analysis, chromosome breakage studies including premature centromeric separation and fluorescence in situ hybridisation studies looking for a deletion of chromosome 22q11 were undertaken. Two abnormal karyotypes were identified.

Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease.

Severe congenital neutropenia (SCN) was originally described as an autosomal recessive disorder. Subsequently, autosomal dominant and sporadic forms of the disease have been recognized. All forms are manifest by persistent severe neutropenia and recurrent bacterial infection. In contrast, cyclical hematopoiesis is characterized by periodic neutropenia inter-spaced with (near) normal neutrophil counts. Recently, linkage analysis on 13 affected pedigrees identified chromosome 19p13.3 as the likely position for mutations in cyclical hematopoiesis. Heterozygous mutations in the ELA2 gene encoding neutrophil elastase were detected in all families studied. Further work also demonstrated mutations in ELA2 in sporadic and autosomal dominant SCN. However, all mutations described to date are heterozygous and thus appear to act in a dominant fashion, which is inconsistent with an autosomal recessive disease. Therefore, the current study investigated whether mutations in ELA2 could account for the disease phenotype in classical autosomal recessive SCN and in the sporadic and autosomal dominant types. All 5 exons of ELA2 and their flanking introns were studied in 18 patients (3 autosomal recessive, 5 autosomal dominant [from 3 kindreds], and 10 sporadic) using direct automated sequencing. No mutations were found in the autosomal recessive families. A point mutation was identified in 1 of 3 autosomal dominant families, and a base substitution was identified in 8 of 10 patients with the sporadic form, though 1 was subsequently shown to be a low-frequency polymorphism. These results suggest that mutations in ELA2 are not responsible for classical autosomal recessive Kostmann syndrome but provide further evidence for the role of ELA2 in SCN.

Trigger factors for prophylactic platelet transfusion.

The level of 20x10(9)/L for prophylactic platelet transfusion has rightly been challenged over the last few years, with some units recommending a level as low as 5x10(9)/L. The higher levels are usually based on retrospective data from the 1950s. We examined the more recent data and came to the conclusion that a threshold of 10x10(9)/L is safe in the stable patient; higher levels are recommended for specific clinical circumstances. This threshold will reduce donor exposure, costs and possibly donor alloimmunization. The dearth of prospective controlled clinical trials in the literature also presents an opportunity for both in-house and national audit.

Technetium (99mTc)-labelled white cell scanning, 51Cr-EDTA and 14C-mannitol-labelled intestinal permeability studies: non-invasive methods of diagnosing acute intestinal graft-versus-host disease.

We describe a case of a 38-year-old female who presented with diarrhoea and abdominal pain 27 days after a second 'top-up' allogeneic marrow infusion for acute myeloid leukaemia (AML) in first remission. A clinical diagnosis of gut graft-versus-host disease (GVHD) was made. Technetium (99mTc)-labelled white cell scanning and intestinal permeability studies using 51Cr-EDTA and 14C-mannitol were undertaken to confirm the diagnosis. The 99mTc white cell scan showed extensive uptake in the small bowel and the urinary excretion of 51Cr-EDTA was increased, the results being consistent with intestinal inflammation and gut GVHD. 99mTc white cell scanning and intestinal permeability studies may assist in the diagnosis of gut GVHD and in assessing its extent and response to treatment.