Zakia Al-Lamki

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.

Orbital involvement in sickle cell disease: A report of five cases and review literature

Purpose To present five cases of orbital infarction in sickle cell disease and review relevant literature.Method We reviewed the hospital records of 5 patients with sickle cell disease who developed a periorbital swelling during a vaso-occlusive crisis and were managed at our hospital between April 1992 and June 2000.Results The 5 patients (4 with homozygous sickle cell disease and 1 with sickle cell-β-thalassaemia disease) were aged 6-15 years with a history of multiple admissions for vaso-occlusive crises. The periorbital swelling spread to the orbit in 4 cases and resulted in proptosis (2 cases), restriction of ocular motility and visual impairment. In all 4 cases, computed tomography and/or magnetic resonance imaging of the orbits showed a mass adjacent to the orbital wall. In 2 cases the mass was identified as a haematoma. Orbital wall infarction was demonstrated in 3 cases by bone/bone marrow scintigraphy. Epidural haematomas were detected by computed tomography in one case. All patients received intravenous fluids, analgesics, broad spectrum antibiotics and steroids, as well as simple or exchange transfusion, and responded well to medical management.Conclusions Infarction of orbital bones during vaso-occlusive crises in sickle cell disease presents acutely with a rapidly progressive periorbital swelling. Haematomas frequently complicate the condition and, along with the inflammatory swelling, may lead to orbital compression syndrome. The condition is therefore sight-threatening, and necessitates prompt diagnosis and appropriate management for resolution without adverse sequelae. Imaging techniques are invaluable in the evaluation of patients. The majority of cases resolve with conservative treatment that includes steps to combat the vaso-occlusive crisis and use of systemic steroids under antibiotic cover.

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).

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.

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.

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.

Childhood cancer: Quest for a complete cure

The priorities and needs to address the complete cure of children with cancer vary enormously on the global scale. Around 20% of children with cancer live in high-income countries (HIC) with ready access to comprehensive care. Their 5-year event free survival ranges from 75% to 79% [1,2]. Clinical oncology research in HIC emphasizes translational studies, novel approaches to refractory and relapsed patients, the amelioration of late effects, prospective studies exploring quality of life issues and the special needs of adolescents and young adults. The remainder of the world’s children who develop cancer and constitute a huge number, have limited or no access to cancer care. These patients more commonly present with advanced disease and experience higher rates of treatmentrelated morbidity and mortality because of inadequate supportive care, malnutrition or concurrent underlying serious illness such as malaria, tuberculosis, HIV or intestinal parasites. Cancer epidemiology studies by the International Agency for Cancer Research (IARC) estimate the incidence of cancer in children aged less than 15 years ranges from approximately 100 to 130 per million children yearly. The United Nations Population Division estimates the number of children aged less than 15 years in Asia was approximately 1.1 billion in 2005 and is expected to show a slow decline to just below 1.0 billion by 2050. (http://www.un.org/ esa/population/publications/wpp2006/FS_ageing.pdf). This means that about 130,000 children in Asia can be expected to develop cancer each year. Many of these cancers, for example, acute lymphoblastic leukemia, Hodgkin disease, Wilms tumor, and nonHodgkin lymphoma are potentially curable with low to intermediate intensity chemotherapy. The conference in Muscat, the Sultanate of Oman, was the first meeting of SIOP Asia in the Middle East and was combined with a meeting of the Middle East Childhood Cancer Alliance (MECCA) attracting over 150 participants from countries comprising the Gulf Cooperation Council (GCC, Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates), elsewhere from the Middle East, Asia, North America, Europe, and Australia. The meeting focused on the challenges in providing a ‘‘complete cure’’ to the children in the SIOP Asia region. However, the major themes of the meeting resonate world-wide among all pediatric oncology health care workers focusing on bridging the gap between HIC and middle or low income countries (MLIC), to find ways to transfer health care infrastructure, knowledge, supportive care, and empowerment to benefit those children with cancer who have limited or no access to potentially life-saving treatment. The SIOP Asia meeting emphasized understanding the needs of children with cancer, their families, and healthcare workers in MLIC in the context of their cultural, ethnic, religious, and environmental circumstances. The presentations by local and international speakers focused on four major themes: DEVELOPING PEDIATRIC CANCER UNITS (PCU) AND LOCAL NETWORKS