Genotype and Phenotype of Adenosine Deaminase 2 Deficiency: a Report from Saudi Arabia.

Adenosine deaminase 2 deficiency (DADA2), a rare and potentially fatal systemic autoinflammatory disease, is characterized by low or lack of ADA2 activity due to ADA2 mutations. DADA2 symptoms are variable and include vasculitis, immunodeficiency, and cytopenia. Minimal data are available from Saudi Arabia. This retrospective study conducted at seven major tertiary medical centers examined the phenotypic and genotypic variabilities, clinical and diagnostic findings, and treatment outcomes among 20 Saudi patients with DADA2 from 14 families. The median age of the study cohort was 9.5 years (4-26 years). The clinical presentation was before the age of 5 months in 25% of patients. Homozygous c.1447-1451del mutation was the most frequent ADA2 alteration (40%), followed by c.882-2A:G (30%). All tested patients exhibited absent or near-absent ADA2 activity. Phenotypic manifestations included stroke (40%), hematological abnormalities (95%), lymphoproliferation (65%), and recurrent infection (45%). Five and three patients had extracranial vasculitis features and Hodgkin lymphoma, respectively. Atypical manifestations included growth retardation (30%) and transverse myelitis. Anti-tumor necrosis factor (anti-TNF) therapy was the main treatment. Some patients underwent blood transfusion, splenectomy, cyclosporine and colony-stimulating factor therapies, and hematopoietic stem cell transplantation due to anti-TNF therapy failure. Fulminant hepatitis and septic multiorgan failure caused mortality in three patients. Thus, this study revealed the variability in the molecular and clinical characteristics of DADA2 in the study cohort with predominant aberrant hematological and immunological characteristics. Consensus diagnostic criteria will facilitate early diagnosis and treatment. Additionally, disease registries or large prospective studies are needed for evaluating rare disease complications, such as cancer.

Biallelic ZNFX1 variants are associated with a spectrum of immuno-hematological abnormalities.

Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense-mediated decay, and two frameshift changes that likely introduce a truncation. Our findings (i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, (ii) expand the genetic and clinical spectrum of ZNFX1-related disease, and (iii) illustrate the utility of large, well-curated, and continually updated genotype-phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings.

Clinicopathologic features and therapy outcome in childhood Hodgkin's lymphoma: a report from tertiary care center in Saudi Arabia.

BACKGROUND: Hodgkin lymphoma (HL) is lymphoid neoplasm usually affecting lymphatic system; it accounts 3.6% of cancers in Saudi Arabia. Modern treatment protocols had shown particular success rates in overall-survival (OS) and event-free-survival (EFS). In our study, we reviewed the medical records of 80 pediatric and young adolescent patients diagnosed HL from January 2006 to July 2020, treated at tertiary care hospital in Riyadh, Saudi Arabia. Demographic, clinical, and pathological data were explored. First line therapy was ABVD, COG, COPP, R-CHOP, or radiotherapy alone in 53/80 (66.4%), 24/80 (30%), 1/80 (1.2%), 1/80 (1.2%), or 1/80 (1.2%) patients; respectively. Response assessment was done by CT + / - PET scan after first 2 cycles then every 2 cycle and end of therapy. Another assessment was done if any clinical suspicion of recurrence. RESULTS: Median age 11 (range 3-16) years. Males to females 1.3:1. Seventy-two out of eighty (90%) patients showed first complete remission (CR1) and maintained remission for median 40 (range 7-136) months. Eight out of eighty (10%) patients showed refractory disease. Nineteen patients received salvage therapy (ICE or ESHAP/brentuximab vedotin or gemcitabine/brentuximab vedotin), 14/19 (73.7%) had 2nd complete remission (CR2) for median time 24 (ranged 9-78) months, while 5/19 (26.3%) did not show any response. Five-year OS and EFS were 95% and 75%. Two patients had 2ry malignant neoplasms, one had AML and died, the other had malignant fibrous histocytoma and still alive. None of our patients had fertility problem. Also, they did not experience chronic pulmonary or cardiotoxicity. Classic Hodgkin's lymphoma: nodular sclerosis subtype was more prominent (55%) than mixed cellularity subtype (22.5%), which is similar to several European and US studies, lymphocyte rich (11.25%) and lymphocyte depleted (0%), while nodular lymphocyte predominant Hodgkin's lymphoma (11.25%). CONCLUSIONS: Our study provided unique descriptive study of childhood HL, in Saudi Arabia, with valuable insight into the long-term outcome and late toxicity. Our results are comparable to other studies in the Middle East and European countries.

Assessment of Health-related Quality of Life in Saudi Children with Cancer.

Advances in pediatric cancer treatment and dramatic improvement in long-term survival have made health-related quality of life (HRQOL) a priority. This study describes the HRQOL of Saudi children on cancer treatment, given the paucity of data on the subject. Parents of children undergoing cancer treatment between the ages of 2 and 12 years enrolled to answer the Arabic version of the parent proxy report PedsQL™ 3.0 cancer module. The module items were reverse-scored to a linear scale from 0 to 100, in which higher scores indicated a better HRQOL. Of the 95 study participants, 61 (64.2%) were hematological malignancies and 34 (35.8%) solid malignancies. The mean score of our sample's total HRQOL was 72.3, which is in line with the results of similar studies worldwide. The lowest scores were observed for procedural anxiety (60.14), perceived physical appearance (67.37), and treatment anxiety (67.58), while the highest were for communication (80.21), nausea (78.32), and cognitive problems (78.32). Significant associations were reported between the patients aged younger than 5 years and procedural anxiety, those aged 5 years or older and perceived physical appearance, and frequent hospital visits and worry. Healthcare professionals should consider the poor HRQOL sub-scales and their associated risks to improve treatment outcomes.

Diagnostic accuracy of reticulocyte parameters on the sysmex XN 1000 for discriminating iron deficiency anaemia and thalassaemia in Saudi Arabia.

INTRODUCTION: Iron deficient erythropoiesis and Thalassaemia are both associated with microcytic erythropoiesis albeit from different pathological mechanisms. Given the high prevalence of Hemoglobinopathies in the Mediterranean region, discriminating these two conditions is important. Several algorithms using conventional red cell indices have been developed to facilitate diagnosis, however, their diagnostic accuracy is low. The new generation haematology analyzers enabled the use of more innovative parameters such as reticulocyte parameters. We aimed to evaluate the diagnostic performance of the reticulocyte parameters on the Sysmex XN 1000 to distinguish between IDA and Thalassemia in our population. METHODS: We performed a retrospective analysis of blood samples sent to our laboratory for haemoglobin electrophoresis screening. We categorized our cohort into Thalassemia and Iron Deficient patients based on known diagnostic criteria. We analyzed the reticulocyte parameters using receiver operator curve analysis (ROC) and determined the cut off value for each parameter. RESULTS: Reticulocyte parameters most accurate for discriminating IDA from Thalassemia patients was: RET, RET-HE and IRF. The RET-HE had the best statistical significance for IDA patients with AUC = 0.69 for cut off 22.25. The RET-HE for dual positive patients was more accurate with AUC = 0.78 for cut off 21.25. The IRF had the best statistical significance for Alpha Thalassemia with AUC = 0.66 for cut off value 18. CONCLUSION: An IRF cut off below 15.5 and RET-HE cut off below 22.25 was the most accurate variable in predicting IDA with a sensitivity of 59.4% and 68.3%.

Unusual presentation of COVID-19 in a child complicated by massive acute pulmonary embolism and lung infarction.

The Novel Coronavirus 2019 (SARSCoV- 2), which was first reported on in Wuhan, China, in late December 2019, causes a respiratory illness called COVID- 19 Disease. COVID-19 is most likely causing a hypercoagulable state, however the prevalence of acute venothromboembolism is still unknown. Limited data suggest pulmonary microvascular thrombosis may play a role in progressive respiratory failure. Here, we report a case of a child with an unusual presentation of COVID-19 presented initially by dry cough without fever and complicated by massive acute pulmonary embolism and lung infarction and treated successfully by hydroxychloroquine and azithromycin, in addition to anticoagulant therapy.

Wolman's disease presenting with secondary hemophagocytic lymphohistiocytosis: a case report from Saudi Arabia and literature review.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal syndrome that is characterized by strong activation of the immune system from hyperinflammatory cytokines. Symptoms of HLH patients include fever, hepatosplenomegaly, cytopenia, and hyperferritinemia. Inherited HLH is classified as primary, whereas secondary HLH (sHLH) occurs when acquired from non-inherited reasons that include severe infection, immune deficiency syndrome, autoimmune disorder, neoplasm, and metabolic disorder. Wolman's disease (WD) is a rare and fatal infantile metabolic disorder caused by lysosomal acid lipase deficiency, that exhibits similar clinical signs and symptoms as HLH. This paper reports the case of an infant diagnosed with WD and who presented with sHLH. CASE PRESENTATION: A 4-month-old infant presenting with hepatosplenomegaly, failure to thrive, and other abnormalities. WD diagnosis was confirmed by the presence of the LIPA gene homozygous deletion c.(428 + 1_967-1)_(*1_?)del. The infant also met the HLH-2004 diagnostic criteria. CONCLUSIONS: Metabolic disorder such as WD should be investigated in infants fulfilling the HLH criteria to diagnose the underlying condition. More studies are needed to understand the link between WD and sHLH and to identify appropriate therapies.

The Impact of COVID-19 Pandemic in Children With Cancer: A Report From Saudi Arabia.

In January 2020, the WHO declared the novel coronavirus (2019-nCoV) outbreak as a public health emergency of international concern. Due to the rapid spread of 2019-nCoV, all countries started preventive and precautionary measures to prevent COVID-19 infection spread. These measures limited the population mobility and services provided, which subsequently Impact of on children with cancer and cancer care delivery in the many health centers in Saudi Arabia. We did a cross-sectional study to assess the impact of this outbreak on children with cancer concerning all aspects of life including medical services provided, the specific precautions to prevent spread in cancer patients, mental, psychological effects, and its effect on the quality of life. We collected 204 responses during a survey that assessed the impact on the treatment of cancer children at a tertiary institution during the COVID-19 pandemic. The majority of patients were receiving ongoing chemotherapy for leukemia/lymphoma. The majority of these patients (60.5%) reported a delay in treatment received due to hospital cancellation of appointments due to the pandemic. Although the majority of patients in our cohort complained of delayed treatment, fortunately, none of the delays led to fatalities. In the context of global lockdowns and physical distancing to help flatten the COVID-19 curve, telemedicine has proved fundamental to keeping patients and their healthcare providers connected and safe. Children also faced multiple other difficulties such as psychosocial issues during the COVID-19 pandemic. Our long-term goals are to develop new programs that will enable children with cancer to emerge successfully during a pandemic.

Routine Preoperative Coagulation Tests in Children Undergoing Elective Surgery or Invasive Procedures: Are They Still Necessary?

INTRODUCTION: Preoperative coagulation screening tests in pediatric patients was once routine clinical practice globally and still used as standard practice in some countries before surgical procedures to assess of perioperative bleeding risk. OBJECTIVE: The study aimed to evaluate unselected routine preoperative coagulation testing in children undergoing elective or invasive surgery to predict abnormal perioperative bleeding. The study also aimed to provide a rational approach of determining bleeding and family history of coagulation disorders as a predictive risk for bleeding. METHODS: This retrospective study conducted between 2014 and 2015 (1 year) on normal healthy children aged under 15 years admitted to the hospitals for elective mild to intermediate surgery or invasive procedures. We reviewed and collected the details of the clinical history, previous surgery, trauma, family history, detail of anti-thrombotic medication and coagulation tests performed (prothrombin time (PT), the activated partial prothrombin time (APTT), and international normalized ratio (INR)) at the time of admission. RESULTS: Among 2078 cases, 1940 cases had normal coagulation tests (93.4%), 77 cases had abnormal coagulation results (3.7%), and 61 patients underwent surgery without preoperative coagulation screening (2.9%). In 15 of 77 patients, coagulation tests were normal on repeat testing. A total of 52 were confirmed to have abnormal screening testing. Among these 52 cases, 45 had normal factors assay; where seven patients had abnormal factors assay. Postoperative bleeding occurred only in three cases (0.14%), two cases due to surgical procedures with normal preoperative testing and one due to hemophilia A which was detected postoperatively as no preoperative testing was performed. CONCLUSIONS: Routine coagulation screening before surgery or invasive procedures to predict perioperative bleeding in unselected patients is not recommended. Our study emphasizes that selective preoperative testing is more appropriate. Selective criteria for consideration of the latter includes physical examination, type of surgery, family and bleeding history, and concomitant use of antiplatelet and anti-thrombotic therapy.

Cytogenetic Profile and FLT3 Gene Mutations of Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent genetic aberrations. The identification of those abnormalities is clinically important because they are considered significant risk-stratifying markers. AIMS: There are insufficient data of cytogenetic profiles in Saudi Arabian patients with childhood ALL leukemia. We have examined a cohort of 110 cases of ALL to determine the cytogenetic profiles and prevalence of FLT3 mutations and analysis of the more frequently observed abnormalities and its correlations to other biologic factors and patient outcomes and to compare our results with previously published results. MATERIALS AND METHODS: Patients-We reviewed all cases from 2007 to 2016 with an established diagnosis of childhood ALL. Of the 110 patients, 98 were B-lineage ALL and 12 T-cell ALL. All the patients were treated by UKALL 2003 protocol and risk stratified according previously published criteria. Cytogenetic analysis-Chromosome banding analysis and fluorescence in situ hybridization were used to detect genetic aberrations. Analysis of FLT3 mutations-Bone marrow or blood samples were screened for FLT3 mutations (internal tandem duplications, and point mutations, D835) using polymerase chain reaction methods. RESULT: Cytogenetic analysis showed chromosomal anomalies in 68 out of 102 cases with an overall incidence 66.7%. The most frequent chromosomal anomalies in ALL were hyperdiploidy, t(9;22), t(12;21), and MLL gene rearrangements. Our data are in accordance with those published previously and showed that FLT3 mutations are not common in patients with ALL (4.7%) and have no prognostic relevance in pediatric patients with ALL. On the contrary, t(9;22), MLL gene rearrangements and hypodiploidy were signs of a bad prognosis in childhood ALL with high rate of relapse and shorter overall survival compared with the standard-risk group (P = .031).The event-free survival was also found to be worse (P = .040). CONCLUSIONS: Our data are in accordance with those published previously, confirming the overall frequency of cytogenetic abnormalities and their prognostic relevance.

Underlying undiagnosed inherited marrow failure syndromes among children with cancer.

To study the prevalence of pediatric cancer patients who have underlying inherited bone marrow failure syndrome (IBMFS), we retrospectively reviewed the medical records of newly diagnosed pediatric cancer patients at The Hospital for Sick Children from June 2009 to May 2010, focusing on clinical, laboratory, and treatment-related findings which may indicate underlying IBMFS. We found five (1.8%) patients out of 276 who had two or more findings suggestive of IBMFS. We conclude that a small fraction of patients with cancer have clinical features that indicate investigations to rule out underlying IBMFSs. A prospective study is needed to determine their prevalence.

Hemophagocytic Lymphohistiocytosis: Single-Center Series of 12 Cases from Saudi Arabia.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease that commonly appears in infancy, although it has been reported in adults. Chemoimmunotherapy-based treatments have improved the survival of patients with HLH; however, overall survival is still poor. We retrospectively analyzed the data of 12 HLH patients who were admitted between 2005 and 2014. All patients were Saudi Arabia in origin with a female predominance (75%) and a median age of onset of 9.5 months. The consanguinity rates were significantly high (75%) with a positive family history in 41% of cases. Of the 12 patients, nine were defined as primary HLH patients and three were confirmed to be secondary HLH patients. All patients fulfilled the 2004 diagnostic criteria for HLH and received HLH-2004 treatment. Six of these patients showed a good response to chemotherapy, while the remainder of the patients showed partial or no response to chemotherapy. Five patients in this cohort received stem cell transplant, and these patients are currently in remission. The mortality rate of this cohort is currently 50%. Genetic mutational analysis showed a positive STX11 mutation in five patients and a PRF1 (perforin) mutation in two patients. To the best of our knowledge, this is the first case series of HLH from Saudi Arabia.

FLT3 Internal Tandem Duplication and D835 Mutations in Patients with Acute Lymphoblastic Leukemia and its Clinical Significance.

The fms-like tyrosine kinase 3 (FLT3) gene is a member of the class III receptor tyrosine kinase family. Mutations of FLT3 were first described in 1997 and account for the most frequent molecular mutations in acute myeloid leukemia. Currently, there is no published data on FLT3 mutations in Saudi acute lymphoblastic leukemia (ALL) patients. In this retrospective study, we have examined a cohort of 77 ALL patients to determine the prevalence of FLT3 mutations and the possible prognostic relevance of these mutations in ALL patients. Correlations to other biologic factors such as karyotype, molecular mutations, and leukocyte count were also considered. FLT3 internal tandem duplication (ITD) mutations and point mutation in tyrosine kinase domain (D835) were analyzed in ALL patients, at diagnosis, by polymerase chain reaction (PCR). Two cases (2.6%, 2/77) were positive for FLT3 mutations; one was found to have FLT3/ITD and the other FLT3/D835. Our findings suggest that FLT3 mutations are not common in Saudi ALL and do not affect clinical outcome.