dRTA and hemolytic anemia: first detailed description of SLC4A1 A858D mutation in homozygous state.

Mutations in the anion exchanger 1 (AE1) gene encoding the erythroid and kidney anion (chloride-bicarbonate) exchanger 1 may result in familial distal renal tubular acidosis (dRTA) in association with membrane defect hemolytic anemia. Seven children presenting with hyperchloremic normal anion gap metabolic acidosis, failure to thrive, and compensated hemolytic anemia were studied. Analysis of red cell AE1/Band 3 surface expression by Eosin 5'-maleimide (E5M) was performed in patients and their family members using flow cytometry. Genetic studies showed that all patients carried a common SLC4A1 mutation, c.2573C>A; p.Ala858Asp in exon 19, found as homozygous (A858D/A858D) mutation in the patients and heterozygous (A858D/N) in the parents. Analysis by flowcytometry revealed a single uniform fluorescence peak, with the mean channel fluorescence (MCF) markedly reduced in cases with homozygous mutation, along with a left shift of fluorescence signal but was only mildly reduced in the heterozygous state. Red cell morphology showed striking acanthocytosis in the homozygous state [patients] and only a mild acanthocytosis in heterozygous state [parents]. In conclusion, this is the first description of a series of homozygous cases with the A858D mutation. The E5M flowcytometry test is specific for reduction in the Band 3 membrane protein and was useful in conjunction with a careful morphological examination of peripheral blood smears in our patient cohort.

Susceptibility to invasive bacterial infections in children with sickle cell disease.

Individuals with sickle cell disease (SCD) demonstrate an increased susceptibility to invasive bacterial infections (IBI). The most common organisms causing IBI are Streptococcus pneumoniae, nontyphi Salmonella species and Haemophilus influenzae type b (Hib). IBI are the most common causes of death in children below 5 years of age with SCD. Increased susceptibility to IBI is because of several factors including dysfunctional antibody production and opsonophagocytosis as well as defective splenic clearance. Early diagnosis of Hib and pneumococcal infections combined with antibiotic prophylaxis and immunization programs, could lead to significant improvements in mortality, especially in Africa.

Orbital infarction in sickle cell disease.

PURPOSE: To determine the role of hematological and genetic factors in the development of orbital infarction in sickle cell disease. DESIGN: Retrospective, noncomparative case series. METHODS: Fourteen sickle cell disease patients were diagnosed with orbital infarction during a vaso-occlusive crisis. Clinical and radiological findings were reviewed retrospectively. Sickle cell disease patients without orbital infarction were recruited as controls after matching for disease severity. Sickle haplotypes were determined for all patients. Differences between groups were evaluated statistically. RESULTS: Patients with orbital infarction in sickle cell disease presented with acute periorbital pain and swelling with or without proptosis, ophthalmoplegia, and visual impairment during a vaso-occlusive crisis. Radiological findings included orbital soft tissue swelling (100%), hematoma (orbital, 36%; intracranial, 21%), and abnormal bone marrow intensities. Severity of orbital involvement was unrelated to that of the systemic disease (Pearson correlation coefficient, -0.1567). Affected patients predominantly had the Benin haplotype (P < .00782). CONCLUSIONS: Orbital infarction is a potential threat to vision in sickle cell disease patients. Magnetic resonance imaging is more specific than computed tomography or nuclear scintigraphy in the evaluation of orbital changes. The degree of severity of the orbital manifestations appears unrelated to the severity of sickle cell disease. Patients with the Benin haplotype are more likely to develop orbital infarction during vaso-occlusive crises.

Serum transferrin receptor status of healthy adult Arabs.

Several studies have provided reference ranges for the concentration of serum transferrin receptor (sTfR) in various white populations, but there is a dearth of relevant reference sTfR data in non-whites. The aim of this investigation was to establish sTfR reference ranges and mean values for a healthy non-white Arab population that could be used also for Arabs worldwide. sTfR and serum ferritin concentrations were estimated by immunoassays and blood counts were determined by conventional methods. Analysis of the data of 114 volunteer Arab blood donors (91 male, 23 female) revealed a higher mean sTfR concentration in males of 22.6+/-8.1 nmol/L (range 10.9-38.7 nmol/L) compared to that in females of 18.7+/-4.4 nmol/L (range 10.7-25.8 nmol/L, p=0.001). There was no significant correlation of sTfR concentration with age, serum ferritin level, or blood haemoglobin level, but a strong inverse correlation was demonstrated with mean cell volume and mean cell haemoglobin of red cells. Iron-replete volunteer subjects with alpha-thalassaemia trait appear to have relatively high mean sTfR concentration. We recommend the use of gender-dependent sTfR reference values for Arabs.

Cytokine profile of sickle cell disease in Oman.

The aim of our study was to assess the cytokine profile of sickle cell disease (SCD) patients in steady state and in vaso-occlusive crisis (VOC). VOC has a complex nature, involving interactions between sickle red blood cells (RBC), the endothelium, and leucocytes. Endothelial damage due to recurrent adhesion of sickle RBCs may disrupt endothelial function, leading to altered cytokine release. It is therefore pertinent to study the cytokine profile of SCD patients in steady state and in crisis prior to exploring its contribution to vaso-occlusive manifestations, since it is believed that an altered balance of proinflammatory and anti-inflammatory cytokines plays an important role in painful crisis. Cytokines including IL-1beta, IL-2, IL-4, IL-6, IL-8, TNF-alpha, and IFN-gamma were measured by commercially available ELISA kits in SCD patients (n = 60); in steady state (n = 26) and in painful crisis (n = 34) and compared with nonanemic age- and sex-matched normal Omani controls (n = 20). SCD patients in crisis showed elevated levels of TNF-alpha (P < 0.092) and IL-6 (P < 0.024) when compared with steady state. It was also observed that SCD patients in steady state showed a significant elevation in IL-1beta (P < 0.04), IL-6 (P < 0.0001), and IFN-gamma (P < 0.02) as compared to normal subjects. It is thus evident that both type I and type II cytokines are significantly altered in SCD patients. In steady state, type II proinflammatory cytokines are elevated, whereas in crisis, an additional augmentation of type I cytokines occurs, with persistent elevation of type II cytokines, emphasizing the role of perturbed endothelium and activated monocytes in the pathophysiology of vaso-occlusion in sickle cell crisis.

Analysis of the immunophenotypes of de novo acute lymphoblastic leukaemia (ALL) in the Sultanate of Oman.

Acute lymphoblastic leukaemia (ALL) immmunophenotypes were analysed by flow cytometry in 65 Omani patients (46 children, 19 adults). Common ("CALLA-positive") ALL was the most frequently encountered (70%) B-cell lineage immunophenotype. Among T-cell lineage ALL patients, mature T-cell ALL was the least frequent (7%). Expression of certain surface markers including CD20 and CD6 appears to have an effect on some clinical and haematological features but FAB morphology was not useful in predicting cell lineage immunophenotypes. Other interesting findings, currently of uncertain significance, include the sizeable proportions of pre-B-ALL (group V) and cortical thymocytic ALL (stage III). Results of this study should help strengthen the emerging leukaemia database of the recently established Oman National Cancer Register and thereby contribute to a successful global attack against the haematological malignancies.

Colonic pseudo-obstruction in sickle cell disease.

A young Arab woman with sickle cell-beta0-thalassemia disease developed acute colonic pseudo-obstruction that became chronic but showed some response to hydroxyurea. There was no evidence of microvascular or macrovascular occlusion. We also report the case of an Arab man with sickle cell anemia who presented with acute colonic pseudo-obstruction from which he recovered completely within a few days. Although the development of pseudo-obstruction in these two cases seems to have been a complication of sickle cell disease, its pathogenesis remains unclear. There are several reports of ischemic and inflammatory disorders of the colon complicating sickle cell disease; however, these two cases represent the first descriptions of large-bowel pseudo-obstruction in this hemoglobinopathy [corrected].

Autoimmune haemolytic anaemia as the presenting manifestation of agnogenic myeloid metaplasia.

We report an unusual case of a 40-year-old female patient with a severe case of direct Coombs positive haemolytic anaemia, moderate hepatomegaly and marked splenomegaly. Her initial response to steroids was transient and was rapidly followed by a relapse. Therefore, she underwent splenectomy both as a therapeutic measure and to rule out an underlying lymphoproliferative disorder. Histopathological examination of the excised spleen, as well a liver biopsy, revealed extensive extramedullary haematopoiesis, while significant marrow fibrosis was noted in a trephine biopsy sample. These findings confirmed the concomitant diagnosis of agnogenic myeloid metaplasia with myelofibrosis.