Splenectomy for haematological disorders: a single center study in 150 patients from Oman.

BACKGROUND: Haematological disorders, in particular sickle cell disease (SCD) and thalassaemia, are relatively common in Oman. We report our experience of splenectomy for haematological disorders and review the literature on splenectomy role in their management. OBJECTIVES: To review our experience in the management of 150 patients with haematological disorders undergoing splenectomy with emphasis on indications and outcome. To compare our experience with those reported from outside this region. METHODS: The records of 150 patients who underwent splenectomy over a thirteen year period were reviewed retrospectively, analyzing the age and sex of the patients, indication for splenectomy, operative procedures, complications, peri-operative management and outcome. RESULTS: Of the 150 patients, 96 (64%) had SCD and 34 (22.6%) had beta-thalassaemia; the rest comprised patients with refractory idiopathic thrombocytopenic purpura (ITP) n=12, hereditary spherocytosis (HS) n=6, and auto-immune haemolytic anaemia (AHA) n=2. In SCD patients, the main indications for splenectomy were recurrent splenic sequestration (60.4%) and hypersplenism (36.4%), whereas in thalassaemic patients it was increased requirement of packed red blood cells (PRBC) transfusion (mean 310 ml, range 242-372 of PRBC/kg/year). All patients received prophylactic antibiotics and vaccination against pneumococcal infection and when the vaccine was available for Haemophilus influenzae. PRBC and platelet concentrates as well as intravenous fluids were infused preoperatively as per protocol. Concomitant procedures at laparotomy included liver biopsy (14.6%) and cholecystectomy (8.6%). The postoperative morbidity was low (8.6%) and there was no mortality. All patients were maintained on long term penicillin and proguanil, and the mean follow-up was 4.6 years. In SCD patients splenectomy eliminated the risks of life threatening acute splenic sequestration and improved significantly the blood counts of the hypersplenic cases, while in thalassaemic patients it reduced significantly the mean transfusion requirement by 100ml PRBC/kg/year (p<0.0001). Of the patients with refractory ITP, two thirds had a good response to splenectomy (p<0.0001). All HS and AHA patients benefited from splenectomy. CONCLUSION: The predominant indications for splenectomy were recurrent acute splenic sequestration and hypersplenism in SCD patients, and increased transfusion demand in the thalassaemics. Overall, splenectomy proved beneficial in eliminating the risk of splenic sequestration in SCD patients, in improving the blood counts in SCD with hypersplenism and in reducing transfusion requirement in thalassaemic patients, while in ITP group two thirds of the patients benefited.

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.

Cytogenetic, morphological, and immunophenotypic patterns in Omani patients with de novo acute myeloid leukemia.

Chromosome aberrations observed at diagnosis are considered to be the most valuable prognostic factors in acute myeloid leukemia (AML). Some specific aberrations vary in frequency among different geographical areas and ethnic groups. There are only limited studies on the role of such variability in AML patients. Here, we report the results of a cytogenetic study on 63 ethnic Omani patients with de novo AML: 18 children (

Cytogenetic profile of childhood acute lymphoblastic leukemia in Oman.

BACKGROUND: Chromosomal abnormalities have important diagnostic and prognostic significance in acute lymphoblastic leukemia (ALL). The purpose of this study was to define and classify the frequency and type of chromosomal abnormalities among newly diagnosed children with ALL and compare the results with those reported from other geographical regions of the world. METHODS: Bone marrow chromosomal studies with GTG banding were performed in untreated ALL pediatric patients aged from 7 days to 14 years. RESULTS: Among Omani children examined with ALL, 47 (81%) patients yielded results, with 26 (55.3%) showing an abnormal karyotype [10 (21.3%) pseudodiploid, 2 (4.3%) hypodiploid and 14 (29.7%) hyperdiploidy] and 21 (44.6%) had normal diploidy. Structural abnormalities were observed in 16 (34%), of which 11 (23.4%) cases were translocations, the most frequent being t(9;22) observed in three (6.4%) of our patients. Uncommon translocations such as t(9;15)(p11;q10), t(3;6)(p12;q11), t(1;6)(?31;?q23), t(1;19)(q12;q12), der(18)t(12;18)(q11;p11), and other structural aberrations add(2)(q22), add(6)(q16), add(18)(q22), add(14)(q32) along with deletions del(10)(q22), del(12)(p11), del(12)(p12), del(18)(q11) were also observed. CONCLUSIONS: The study showed a good correlation and concordance between the ploidy distribution by cytogenetics and flow cytometry. The patterns of chromosomal anomalies in our patients showed some variations in the frequency of aberrations reported. It is therefore necessary that newer techniques like fluorescence in situ hybridization (FISH) along with reverse transcriptase polymerase chain reaction (RT-PCR) and spectral karyotyping will help us identify chromosomal aberrations not detected by conventional cytogenetic methods in the near future. To our knowledge, this is the first report from the Middle East of a cytogenetic study on childhood ALL.

Incidence and outcome of severe hyponatremia in children and young adults: a single institution experience.

OBJECTIVE: Our two main objectives are to assess the incidence and the outcome of severe hyponatremia in young hospitalized patients. METHOD: We retrospectively reviewed the incidence and outcome of severe hyponatremiac (Na <125 mmol/l) inpatients less than 18 years of age, admitted as consecutive admissions during one calender year. Psuedohyponatremia and artifactual hyponatremia were excluded. Patients' demographics, clinical features, laboratory, treatment and outcomes were recorded. RESULTS: Of 3561 admissions of patients less than 18 years of age, 20 developed severe hyponatremia. Nausea, vomiting, irritability, clouded sensorium and seizures were the most common symptoms and signs. Underlying central nervous system disease, pneumonia and malignancy were major co-morbid conditions. The initial volume status was determined as hypervolemia (n=7), hypovolemia (n=7) and euvolemia (n=6). Iatrogenic (diuretics 5 and hypotonic fluids 7) hyponatremia accounted for 60% of all cases. Mortality was 20%. CONCLUSION: Patients receiving intravenous hypotonic fluids should be closely monitored for the development of hyponatremia. The common etiology of hyponatremia in our studied cohort of patients is iatrogenic.

Identification of prognosis markers in pediatric high-risk acute lymphoblastic leukemia.

Gene expression profiling may improve the understanding of the biology behind relapse in pediatric acute lymphoblastic leukemia. Using suppression subtractive hybridization (SSH), cDNA concatenated sequencing (CCS), and reverse transcriptase real-time quantitative polymerase chain reaction (RT-RQ-PCR) on high-risk patient samples with nondeterminant chromosomal translocation, the authors identified 3 genes that were significantly overexpressed in the nonrelapsed patients: the calcium/calmodulin-dependent serine protein kinase (CASK), subunit 2 of the cofactor required for SP1 transcriptional activation (CRSP2), and granzyme K (GZMK). The level of expression of these biomarkers may help identify patients with potentially good prognosis within a group otherwise at high risk of relapse.

An inframe perforin gene deletion in familial hemophagocytic lymphohistiocytosis is associated with perforin expression.

Familial hemophagocytic lymphohistiocytosis is an autosomal recessive disease of early childhood manifested by hypercytokinemia and organ infiltration of macrophages and activated lymphocytes, and it is characterized by a fulminant clinical course. The molecular mechanism underlying this disease appears to be a deregulation of apoptosis of activated T cells and macrophages. Approximately 20-40% of patients with familial hemophagocytic lymphohistiocytosis reported worldwide had a perforin gene mutation. We report herein a novel perforin variant in the homozygous state in an Omani boy who was diagnosed 44 days after birth. Sequence analysis of the perforin gene coding region revealed a 12-base pair deletion (codon 284-287) resulting in the deletion of four amino acids in the membrane attack complex domain of the protein. This deletion maintains the reading frame of the perforin mRNA. Both parents were heterozygotes for this molecular defect. Flow-cytometric analysis revealed intracellular perforin expression at the lower end of the normal range in the cytotoxic T cells (CD3+/CD8+) and (CD3+/CD56+) and in around 50% of the natural killer cells (CD3-/CD56+). This is an additional example of a perforin variant which is associated with a significant level of cellular perforin expression and thus confirms that drastic reduction in its expression is not a constant feature in familial hemophagocytic lymphohistiocytosis type 2.

Relapsed acute leukemia in children: Oman experience.

Acute leukemia (AL) is the most common malignancy in children in Oman. It accounts for over one-third of all childhood cancers, most of which (approximately 75%) are acute lymphoblastic leukemia (ALL). Over a decade, a total of 128 cases of childhood acute leukemia have been diagnosed and managed at Paediatric Haematology/Oncology Unit, Sultan Qaboos University Hospital, which is the national referral center of pediatric leukemia cases. A retrospective review of case notes was used to study all children with a diagnosis of acute leukemia from January 1993 to January 2003. All the cases were diagnosed using a bone marrow aspirate with morphological and immunophenotypic classification. Over this period, 24 cases relapsed. They were classified as per BFM group as "very early," "early," and "late" according to the time from diagnosis to first relapse and were divided into isolated bone marrow (BM), extramedullary site, and combined relapse. Sixteen percent of ALL cases and 58.6% of acute myeloid leukemia (AML) cases so far relapsed. Most of the AML cases relapsed very early on in treatment. Eleven patients had combined relapse in BM and extramedullary site (9 in the central nervous system, 1 in the testicles, and 1 in the eye). The overall outcome of these patients is very poor, and only 6 patients out of 24 are still alive. In conclusion, the relapse rates of childhood AL are more or less similar to those of other reports but the overall outcome is very poor. A large majority of the patients in this study are either very early or early relapsers. Future studies including genetic and molecular analysis may be able to explain the difference in clinical outcome of these relapsed AL cases.

Ten-year prospective study (clinical spectrum) of childhood Guillain-Barré syndrome in the Arabian peninsula: comparison of outcome in patients in the pre- and post-intravenous immunoglobulin eras.

A prospective study of Guillain-Barré syndrome from January 1992 to December 2001 was undertaken. Intravenous immunoglobulins were used in all patients. All patients were followed up until complete recovery. Various parameters, such as onset of weakness, duration of hospital stay, ventilation requirement, residual deficit, and mortality, were recorded. Acute relapses and fluctuations were also noted. The pattern of this group was compared with patients before 1992, who were not given intravenous immunoglobulins in the Sultanate of Oman. Our data were compared with a few studies prior to 1992 from the medical literature. Our study revealed a definite benefit with intravenous immunoglobulins. The disease course and hospital stay were shortened. Fewer patients needed ventilation. There was no mortality, and the residual deficit was less than 5%. Occasional relapses at a later stage in the course of illness have been noted in acute Guillain-Barré syndrome. However, acute relapse, a new phenomenon that was not seen in the pre-intravenous immunoglobulin era, stood at 11.9%. Intravenous immunoglobulins have made a significant difference in the outcome of Guillain-Barré syndrome, but one has to be aware of acute relapses, which usually occur in the first 2 to 3 weeks after administration.

Clinical and genetic studies of familial hemophagocytic lymphohistiocytosis in Oman: need for early treatment.

Hemophagocytic lymphohistiocytosis (HLH) embraces the frequently indistinguishable conditions of familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hemophagocytic syndrome (VAHS). Without therapy FHL is invariably fatal, but successful therapy, including chemotherapy and immunotherapy followed by bone marrow transplantation (BMT), has been presented. To clarify the outcome of HLH in a developing country, with regard to clinical, laboratory, and genetic features, a nationwide study on all patients diagnosed with HLH in Oman during the 5-year period 1997-2001 was performed. In 5 patients and their families, mutational analysis was made. Thirteen patients with HLH were identified, 5 of whom had clinical manifestations of central nervous system involvement at presentation. In none of the patients could an infectious cause be identified. Ten children were referred late in the disease course, and the concern about starting chemotherapy before exclusion of an acute viral infection resulted in delayed treatment in some patients. Two children were started early on the HLH-94-therapy followed by successful BMT in one child. In the successfully transplanted child, the response to intrathecal hydrocortisone appeared to be better than standard therapy with intrathecal methotrexate. Finally, a novel missense mutation in the perforin gene was identified in 2 patients and their family members, causing a transition of proline to threonine at codon 89. Early diagnosis and treatment is important to improve outcome. Intrathecal corticosteroids may be considered, in addition to intrathecal methotrexate, in certain patients. Since the novel perforin mutation has been reported in only 2 patients from Oman, and since similar polymorphism in the sequencing data of the members of their families has been identified, a founder effect is possible in this population.

Splenic function in Omani children with sickle cell disease: correlation with severity index, hemoglobin phenotype, iron status, and alpha-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 beta(0)-thalassemia (HbS-beta(0)-thal), 5 HbS-beta(+)-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-beta(+) 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 alpha-thalassemia trait (p < .05).

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 x 10(9)/L, while mean platelet count at day 4 was 158 x 10(9)/L. At the end of 6 cycles 3 patients maintained a platelet count of >150 x 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.

Visceral leishmaniasis and haemophagocytic syndrome in an Omani child.

The paper reports the case of a previously healthy 4-year-old-girl who presented with pallor, fever and hepatosplenomegaly. Laboratory findings included pancytopenia, hypertriglyceridemia and hyperferritinemia. Initial diagnosis of kala-azar could not be confirmed because of the absence of clinical evidence, negativity of bone marrow aspiration or specific serology for visceral leishmaniasis. Repeated marrow aspiration, performed due lack of clinical response, revealed histiocytes showing haemophagocytosis consistent with haemophagocytic lymphohistocytosis (HLH) and appropriate treatment was started. She continued to have high-grade fever, and a third bone marrow aspiration ultimately revealed presence of Leishmania amastigotes with evidence of active haemophagocytosis. The girl was treated with liposomal amphotericin (AmBisome) for 5 days, following which she recovered rapidly with definitive remission.