Yasser Wali

Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive lethal condition characterized by fever, cytopenia, hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defect apoptosis triggering and lymphocyte cellular cytotoxicity. Thus far three disease‐causing genes (PRF1, UNC13D, STX11) have been identified. We performed a genotype‐phenotype study in a large, multi‐ethnic cohort of 76 FHL patients originating from 65 unrelated families. Biallelic mutations in PRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%) and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed for all three genes, no molecular diagnosis was established. STX11 mutations were most common in Turkish families (7/28, 25%), whereas in Middle East families, PRF1 mutations were most frequent (6/13, 46%). No biallelic mutation was identified in most families of Nordic origin (13/14, 93%). Patients carrying PRF1 mutations had higher risk of early onset (age <6 months) compared to patients carrying STX11 mutations [adjusted odds ratio 8·23 (95% confidence interval [CI] = 1·20–56·40), P = 0·032]. Moreover, patients without identified mutations had increased risk of pathological cerebrospinal fluid (CSF) at diagnosis compared to patients with STX11 mutations [adjusted odds ratio 26·37 (CI = 1·90–366·82), P = 0·015]. These results indicate that the disease‐causing mutations in FHL have different phenotypes with regard to ethnic origin, age at onset, and pathological CSF at diagnosis.

Pulsed high-dose dexamethasone therapy in children with chronic idiopathic thrombocytopenic purpura

The effectiveness of pulsed high-dose oral dexamethasone therapy in children with refractory chronic idiopathic thrombocytopenic purpura (ITP) is evaluated. Thirteen children with severe chronic ITP were enrolled in the study from an outpatient pediatric hematology clinic (ages 2-14 years), 5 boys and 7 girls. They did not maintain a response to other forms of therapy (IVIg, Anti-D, conventional steroids, danazol) and one girl relapsed after splenectomy. Dexamethasone was administered orally at a dosage of 40 mg/M2/day (maximum 40 mg/day) for 4 consecutive days. The cycle was repeated once a month for 6 months. The immediate response to therapy was excellent as the mean platelet count at day 1 was 15 2 10 9 /L, while mean platelet count at day 4 was 158 2 10 9 /L. At the end of 6 cycles 3 patients maintained a platelet count of >150 2 10 9 /L and 4 patients showed partial response. At the end of the first year and second year (12 and 24 months after onset of treatment) 3 patients still had complete response, 3 patients had partial response, and 7 patients were failures. Six of the failures underwent splenectomy and one was shifted to dapsone, had no response, and refused splenectomy. Side effects were tolerable. They included bloating, nausea, vomiting, insomnia, anxiety, and depression, and transient glucosuria; however, they were not severe enough to discontinue the cycles. Mean duration of illness prior to start of dexamethasone was not significantly different in between responders and nonresponders. Dexamethasone given orally in high doses is an effective drug in achieving short-term platelet responses. Long-term remission is obtained in nearly half the patients with well-established chronic ITP. Its effectiveness in almost half the patients, minimal side effects, and low cost indicate that this treatment should be considered in patients with chronic ITP who do not tolerate the disease well before considering splenectomy.

Efficacy and safety of a novel combination of two oral chelators deferasirox/deferiprone over deferoxamine/deferiprone in severely iron overloaded young beta thalassemia major patients.

Minimal data are available on the combined two oral iron chelators in β‐thalassemia major (β‐TM). Comparison of safety, efficacy, compliance, treatment satisfaction, and quality of life (QoL) of two regimens: deferiprone (DFP) and deferoxamine (DFO) versus DFP and deferasirox (DFX) were studied.

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.

A Comparison of Two Transfusion Regimens in the Perioperative Management of Children with Sickle Cell Disease Undergoing Adenotonsillectomy

Adenotonsillar hypertrophy and chronic tonsillitis are common findings in patients with sickle cell disease (SCD). Various preoperative transfusion regimens have been suggested to reduce the population of sickle erythrocytes and correct the anemia, ranging from conservative (correcting the anemia) to aggressive (lowering the level of HbS to less than 30%). A total of 39 patients with SCD were included in the study. They were divided into 2 groups. Fourteen patients in group 1 were assigned aggressive exchange transfusion and 25 patients in group 2 were assigned a conservative (simple) transfusion. The 2 groups were compared for possible operative and postoperative complications. Thirty percent of patients in both groups had postoperative complications. They ranged from mild local infection to acute chest syndrome. Simple transfusion was not associated with higher incidence of complications and resulted in only one-third as many transfusion requirements.

SPLENIC FUNCTION IN OMANI CHILDREN WITH SICKLE CELL DISEASE: Correlation with Severity Index, Hemoglobin Phenotype, Iron Status, and α -Thalassemia Trait

The prevalence of functional asplenia in Omani children with sickle cell disease (SCD) has not been previously defined. In this study, the authors aim to compare the natural history of splenic dysfunction in their patients to other reports. The splenic function was studied in 72 Omani patients with sickle cell disease (50 homozygous for hemoglobin S (HbS-S), 11 double heterozygotes for HbS and g 0 -thalassemia (HbS- g 0 -thal), 5 HbS- g + -thal, 5 patients with hemoglobin S-D disease, and 1 child with hemoglobin S oman trait) aged 4.8-16 years, using 99m Tc-labeled tin colloid scintigraphy. The study revealed 4 groups according to their colloid uptake: group I included 20 patients (28%) with normal splenic function; group II, 6 patients (8%) with mild hyposplenism; group III, 20 (28%) with severe hyposplenism; and group IV, 26 (36%) patients with functional asplenia. Overall, more than 60% of them had preserved splenic function. Except for HbS- g + patients, the developmental pattern of hyposplenism was not different among the different Hb phenotypes. Factors associated with preservation of spleen function in these patients were larger splenic size ( p < .01), less clinical severity ( p < .05), lower MCH ( p < .01), higher HbF ( p < .001), and presence of f -thalassemia trait ( p < .05).

CRAVING FOR ICE AND IRON-DEFICIENCY ANEMIA: A Case Series from Oman

Pagophagia, or the practice of consuming ice, is a particular expression of the more general phenomenon of pica. Pagophagia is a complex behavioral phenomenal arising from the interplay of biochemical, hematological, psychological, and cultural factors. This compulsive dietary aberration is observed in many children and pregnant women worldwide. The authors report 3 cases of severe iron deficiency anemia with a serum ferritin level of 2–3 ng/mL, in which the patients were consuming 2 trays and many bags of ice per day. Following treatment with iron therapy, pagophagia spontaneously resolved within 2 weeks. It is a commonly missed problem. Pediatricians should be alert to this phenomena and its association with iron-deficiency anemia.

Case report. Successful outcome of invasive nasal sinus zygomycosis in a child with relapsed acute lymphoblastic leukaemia due to liposomal amphotericin B.

Summary.  We report a case of life‐threatening nasal sinus zygomycosis that developed during remission induction therapy for a relapsed acute lymphoblastic leukaemia. The patient was successfully treated with liposomal amphotericin B and granulocyte‐colony stimulating factor followed by surgical reconstruction of the resultant cutaneous defect.

Cardiovascular function in Omani children with sickle cell anaemia

Summary Systolic murmurs were detected in 22 (61%) of the 36 children with sickle cell anaemia (SCA) who completed the study. Cardiomegaly was detected in 14 (39%). Mean values of left and right ventricular dimensions were higher in SCA than in controls (p < 0.05). Left atrial chambers and aortic root dimensions followed the same pattern. The dilated cardiac chambers in SCA were not associated with any abnormality in systolic or diastolic left ventricular function nor with significant pulmonary hypertension.

Optimizing Hydroxyurea use in children with sickle cell disease: Low dose regimen is effective

Hydroxyurea (HU) is the standard treatment for severely affected children with sickle cell disease (SCD). Starting dose is 15–20 mg/kg/day that can be escalated up to 35 mg/kg/day. Ethnic neutropenia is common in this area of the world that requires judicious usage of myelosuppressive drugs. Aim was to assess the efficacy of a lower initial dose of HU and cautious dose escalation regimen in patients with SCD.