Publications by authors named "Abdulrahman Alsultan"

55 Publications

Current practice of oral care for hematopoietic stem cell transplant patients: A survey of the Eastern Mediterranean Blood and Marrow transplantation group.

Hematol Oncol Stem Cell Ther 2021 Feb 11. Epub 2021 Feb 11.

Oncology Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

Introduction: The oral cavity is one of the most common sites impacted by hematopoietic stem cell transplantation (HSCT) with acute complications including mucositis, bleeding, salivary gland dysfunction, infection, and taste alteration. These complications may result in significant morbidity and can negatively impact outcomes such as length of stay and overall costs. As such, oral care during HSCT for prevention and management of oral toxicities is a standard component of transplant protocols at all centers. The objective of this study was to evaluate the current oral care practices for patients during HSCT at different transplant centers within the Eastern Mediterranean region.

Material And Methods: An internet-based survey was directed to 30 transplant centers in the Eastern Mediterranean region. The survey included five sections asking questions related to (1) transplant center demographics; (2) current oral care protocol used at the center and type of collaboration (if any) with a dental service; (3) use of standardized oral assessment tools and grading systems for mucositis; (4) consultations for management of oral complications; and (5) oral health needs at each center. Data are presented as averages and percentages.

Results: A total of 16 responses from 11 countries were collected and analyzed, indicating a response rate of 53%. Eight centers reported that a dentist was part of the HSCT team, with four reporting oral medicine specialists specifically being part of the team. Almost all centers (15/16; 93%) had an affiliated dental service to facilitate pre-HSCT dental clearance with an established dental clearance protocol at 14 centers (87%). Dental extraction was associated with the highest concern for bleeding and the need for platelet transfusion. With respect to infection risk, antibiotic prophylaxis was considered in the setting of low neutrophil counts with restorative dentistry and extraction. All centers provide daily reinforcement of oral hygiene regimen. The most frequently used mouth oral rinses included sodium bicarbonate (68%) and chlorhexidine gluconate (62%), in addition to ice chips for dry mouth (62%). The most frequently used mucositis assessment tools were the World Health Organization scale (7/16; 43%) and visual analogue scale for pain (6/16; 37%). Mucositis pain was managed with lidocaine solution (68.8%), magic mouth wash (68.8%) and/or systemic pain medications (75%).

Conclusions: Scope and implementation of oral care protocols prior to and during HSCT varied between transplant centers. The lack of a universal protocol may contribute to gaps in oral healthcare needs and management for this group of patients. Further dissemination of and education around available oral care guidelines is warranted.

Clinical Relevance: Considering oral care during HSCT a standard component of transplant protocols, the current study highlights the common oral care practices for patients at centers within the Eastern Mediterranean region.
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http://dx.doi.org/10.1016/j.hemonc.2021.01.006DOI Listing
February 2021

Dietary Practices and Barriers to Adherence to Healthy Eating among King Faisal University Students.

Int J Environ Res Public Health 2020 12 1;17(23). Epub 2020 Dec 1.

Department of Family & Community Medicine, College of Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia.

Proper dietary practices should be developed during the student years that will continue into the future. This study aimed to identify the eating habits and dietary practices among King Faisal University (KFU) students, explore the barriers to adherence to healthy eating, associate the understanding of healthy diets with students' characteristics, and determine the association between body mass index (BMI) and awareness of the concept of healthy diets, academic discipline, and enrollment in a nutrition course. In this cross-sectional study, students were selected randomly and a questionnaire was distributed using an electronic platform through KFU email. Out of 564 students, nearly half (45.7%) reported eating snacks as their main food, and some (38.3%) reported eating with their family twice daily. The students rarely reported eating with friends (73%) or eating dates (48.8%). Furthermore, many reported that they were not consuming a balanced diet (42.6%). Some students (46.3%) reported taking breakfast daily, and 49.1% reported eating meals regularly. There was low consumption of vegetables (29.3%) and fruits (26.2%) among the students. The barriers to adherence to healthy eating were the availability of fast food (73.2%), high cost of healthy food (72.7%), limited time (59%), and laziness (57.1%). Statistically significant data indicated that the students with a normal BMI were more aware of the concept of healthy diets, studied medical and applied sciences, and were enrolled in KFU nutrition courses.
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http://dx.doi.org/10.3390/ijerph17238945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731134PMC
December 2020

Travel burden and geographic access to health care among children with cancer in Saudi Arabia.

East Mediterr Health J 2020 Nov 11;26(11):1355-1362. Epub 2020 Nov 11.

Department of Oncology, Princess Noorah Oncology Center, King Saud Bin Abdulaziz University and King Abdulaziz Medical City, Jeddah, Saudi Arabia.

Background: Travel burden has a substantial psychosocial impact and financial strain on childhood cancer patients and their families.

Aims: To study the geographic distribution of childhood cancer and assess the travel burden for care in Saudi Arabia.

Methods: This was a cross-sectional multi-institutional study that enrolled 1657 children with cancer who were diagnosed between 2011 and 2014. Cancer type/stage, city/region of residence, and city/region of treating centre were recorded. Travel burden was measured based on a 1-way distance in kilometres from the city centre to the treatment institution. This study was supported by Sanad Children's Cancer Support Association.

Results: Diagnosis was leukaemia (45.2%), non-CNS solid tumours (30.2%), lymphoma (12.3%), CNS tumours (11.8%) and histiocytosis (0.5%). Childhood cancer centres were in the same city as where the patients lived in 652 (39.3%) cases, same region but different city in 308 (18.6%), different regions in 613 (37%), and not known in 84 (5.1%). The mean 1-way travel distance for patients who lived in different regions was 790 (range, 116-1542) km. A total of 536 (32%) patients lived ≥ 400 km and 216 (13%) > 1000 km from the treatment centre. Among 642 patients with acute lymphoblastic leukaemia who required 2-3 years of therapy, 197 (31%) lived ≥ 400 km and 94 (15%) >1000 km from the treatment centre.

Conclusions: Nearly two thirds of patients with childhood cancer lived in different cities than the treatment centres, including one third of patients who lived ≥ 400 km away. There is a need to develop strategies to improve access to childhood cancer care.
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http://dx.doi.org/10.26719/emhj.20.020DOI Listing
November 2020

Effect of on Urinary Biochemical Parameters among Patients with Kidney Stones in Saudi Arabia.

Nutrients 2020 Oct 30;12(11). Epub 2020 Oct 30.

Department of Nursing, College of Applied Medical Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia.

The study purpose was to investigate the effect of (PV) on urinary biochemical parameters among patients with kidney stones. We conducted a randomized controlled study among 60 patients with kidney stones (size < 10 mm) in the nephrology unit of both government and private hospitals, Al-Ahsa. Urinary volume, calcium, magnesium, potassium, oxalate, uric acid, and power of hydrogen (pH) were assessed before and after the intervention of giving 250 g of PV consumption as an extract thrice weekly (2.2 L to 2.5 L per week) for 6 weeks, which was compared with control. A 't' test was used with the significance at 5%. Mean score of age was 44.5 ± 10.16 in PV group and 43.73 ± 9.79 in control. Four (13.3%) and two (6.7%) had family history of kidney stones. Body mass Index (BMI) mean was 26.44 ± 2.7 and 26.36 ± 2.65 in pre and post-test, respectively, which were significant ( = 0.01017). There were significant changes ( = 0.000) in urine volume from 1962 ± 152.8 to 2005 ± 148.8, calcium 205.4 ± 11.99 to 198.4 ± 12.52, potassium 44.07 ± 3.66 to 52.15 ± 4.37, oxalate 37.12 ± 5.38 to 33.02 ± 5.71, and uric acid 6.88 ± 0.7 to 6.31 ± 0.58. In conclusion, PV is effective management for the patients with kidney stones as it increases the urinary volume and enhances the elimination of small kidney stones.
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http://dx.doi.org/10.3390/nu12113346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692137PMC
October 2020

Orbital extramedullary leukemia relapse in a pediatric patient post-CART cell therapy-Case report.

Pediatr Transplant 2020 Sep 30:e13852. Epub 2020 Sep 30.

Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

CART therapy is an approved therapy in advanced ALL. The mechanism of relapse post-CART therapy is under vigorous research. We report a 9-year-old boy who received CD19-CART therapy after BM ALL relapse post-HSCT. He presented with unilateral eye swelling which was initially managed as orbital cellulitis. Later on, it was proven to be an isolated ALL orbital relapse without peripheral blood B-cell detection or BM involvement. Despite radiotherapy, he subsequently developed refractory CD19 positive ALL BM relapse. This case highlights the possibility of unusual relapse sites after CART-therapy and that regular peripheral B-cell monitoring is not enough to assure remission status. Better monitoring tools are needed to detect early disease relapse. Further understanding of the pathophysiology of isolated extramedullary relapse post-CART therapy is warranted to improve the management of such challenging presentations.
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http://dx.doi.org/10.1111/petr.13852DOI Listing
September 2020

Screening for pre-leukemia TEL-AML1 chromosomal translocation in banked cord blood units: cord blood bank perspective.

Cell Tissue Bank 2020 Dec 18;21(4):625-630. Epub 2020 Aug 18.

Department of Pediatric, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

Acute lymphocytic leukemia is the most common leukemia in children. Many studies suggest the existence of two subsequent hits in order for the disease to occur. TEL-AML1 (ETV6-RUNX1) is considered an initial genetic hit that occurs prenatally and generates a pre-leukemia clone. In cord blood (CB) stem cell transplantation, donor cell leukemia (DCL) is one of the complications associated with the presence of the pre-leukemic clone. The aim of this study was to identify the prevalence of ETV6-RUNX1 translocation in CB units and the feasibility in implementing such a screening test, to ensure the safety of the CB units. A total of 424 CB samples were tested from the CB units banked at KAIMRC-CBB. RNA was extracted and cDNA synthesis was performed on 1 ug input RNA using Reverse Transcriptase RT-PCR methodology. Chromosomal translocation ETV6-RUNX1 was tested using real time quantitative PCR methodology. Our study showed undetectable levels of ETV6-RUNX1 in all tested CB samples. The samples were analyzed for the chromosomal translocation ETV6-RUNX1 under controlled conditions, using control and fusion genes with known concentrations. The result of this study does not rule out the importance of this screening test in predicting and/or preventing DCL. Moreover, the outcome strengthens the adopted system in our CBB for mother medical history screening prior to donation. We propose adding this test during the verification testing stage, prior to the release of CB units selected for transplantation rather than at the banking stage.
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http://dx.doi.org/10.1007/s10561-020-09855-yDOI Listing
December 2020

Mapping COVID-19 related research from Saudi Arabia, a scoping review. Between reality and dreams.

Saudi Med J 2020 Aug;41(8):791-801

Department of Medicine, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia. E-mail.

Objectives: To map research production by Saudi-affiliated investigators in order to identify areas of strength and weakness. Method: We followed the Arksey and O'Malley (2005) framework. Medline and Cochrane databases were searched with a focus on identifying articles related to COVID-19 and Saudi Arabia following the PRISMA protocol. The study was conducted at King Saud University, Riyadh, Saudi Arabia between March and May 2020. Results: A total of 53 articles were ultimately included. Most of the research production from Saudi Arabia was opinion and narrative reviews related to the clinicopathological features of COVID-19 as well as control and prevention of virus spread.  Conclusion: The results of this scoping review identify a relative deficiency in original research, which requires further investigation.
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http://dx.doi.org/10.15537/smj.2020.8.25163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502955PMC
August 2020

Incidence trends of childhood acute lymphoblastic leukemia in Saudi Arabia: Increasing incidence or competing risks?

Cancer Epidemiol 2020 08 16;67:101764. Epub 2020 Jun 16.

Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

Introduction: The incidence of childhood acute lymphoblastic leukemia (cALL) varies between countries likely as a result of competing risks including infections, access-to-care, socioeconomic influences, and/or ethnicity. However, little is known about disease burden in high-income Arab countries offering free-of-charge healthcare. The hypothesis was that, due to population characteristics (young age, high fertility and parental consanguinity rate), the incidence of cALL in Saudi Arabia is equal or higher than that observed in high-income Western countries.

Methods: Saudi databases were used to calculate the incidence of cALL from 2001 to 2014. Incidence trends over time of children with ALL, 14-years of age or younger, were analyzed and compared with those reported in USA.

Results: The age-adjusted incidence over the years was lower in Saudi Arabia compared to USA. However, the incidence trend of cALL in Saudi Arabia was increasing at a rate higher than that observed in USA (p < 0.001). The overall incidence of cALL in Saudi Arabia increased from 1.58/100,000 in 2001 to 2.35/100,000 population in 2014. The median annual increase was 4.58 %. The incidence in males increased from 1.88 to 2.71/100,000, and from 1.21 to 1.86/100,000 population in females.

Conclusions: The reported incidence of cALL in Saudi Arabia is rapidly increasing. The increasing trend may reflect evolving socioeconomic structure, improved access-to-cancer care, and improved diagnosis/ reporting capacity. This highlights the need for better understanding of cALL causes and the need for the formation of separate national pediatric cancer registries in different countries to monitor childhood cancer incidence trends.
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http://dx.doi.org/10.1016/j.canep.2020.101764DOI Listing
August 2020

Frequency of pathogenic/likely pathogenic germline variants in cancer-related genes among children with acute leukemia in Saudi Arabia.

Pediatr Blood Cancer 2020 07 2;67(7):e28340. Epub 2020 May 2.

Department of Oncology, Princess Noorah Oncology Center, King Saud Bin Abdulaziz University and King Abdulaziz Medical City, Jeddah, Saudi Arabia.

Background: The frequency of pathogenic/likely pathogenic (P/LP) germline mutations in cancer-related genes among children with cancer in highly consanguineous populations is not well studied.

Methods: Whole-exome sequencing of germline DNA was performed in 60 children with acute leukemia. We used the St. Jude Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE) data portal for the classification of germline variants by the St. Jude Medal Ceremony pipeline.

Results: Fifty-seven patients had acute lymphoblastic leukemia (ALL) and three patients had acute myeloid leukemia. Parental consanguinity was present in 27 (45%) patients. All patients were of Arab ancestry. Three patients (5%) had a history of cancer in their siblings. Five patients (8.3%) had P/LP germline mutations in cancer-related genes. Three patients with B-ALL had heterozygous pathogenic mutations in TP53, BRCA1, and BRCA2; one patient with B-ALL had homozygous pathogenic mutation in PMS2; and one patient with T-ALL had LP homozygous mutation in AK2 that was associated with reticular dysgenesis. Among patients who had history of parental consanguinity, three (11%) had P/LP germline mutations compared with two (8%) in the absence of parental consanguinity. Fourteen (23%) patients had gold medal variants in cancer-related genes, 13 were heterozygous, and one was homozygous. Silver medal variants were present in 35 (58%) patients; all were heterozygous except one homozygous.

Conclusions: Children with acute leukemia in Saudi Arabia had low frequency of P/LP mutations in cancer-related genes despite the high rate of consanguinity. Larger studies using whole-genome sequencing are needed to further explore the heritability of childhood leukemia.
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http://dx.doi.org/10.1002/pbc.28340DOI Listing
July 2020

Population pharmacokinetics of busulfan in Saudi pediatric patients undergoing hematopoietic stem cell transplantation.

Int J Clin Pharm 2020 Apr 5;42(2):703-712. Epub 2020 Mar 5.

Pharmaceutical Analysis Section, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.

Background Busulfan is an antineoplastic drug that is used widely as part of a conditioning regimen in pediatric patients undergoing hematopoietic stem cell transplantation. It has a narrow therapeutic index and highly variable pharmacokinetics; therefore therapeutic drug monitoring is recommended to optimize busulfan dosing. Objective To study the population pharmacokinetics of busulfan in Saudi pediatric patients to optimize its dosing. Settings King Abdullah Specialist Children's Hospital in Riyadh, Saudi Arabia. Methods This pharmacokinetic observational study was conducted between January 2016 and December 2018. All pediatric patients receiving IV busulfan and undergoing routine therapeutic drug monitoring were included. Population pharmacokinetics modeling was conducted using Monolix2019R1. Pharmacokinetic data of busulfan in children. Results The study included 59 patients and 513 samples. The mean ± SD age was 6.10 ± 3.17 years, and the dose administered was 0.994 ± 0.15 mg/kg. The mean ± SD Cmax and area under the curve (AUC) were 900.60 ± 402.8 ng/mL and 1031.14 ± 300.75 µM min, respectively. Based on our simulations, the European Medicines Agency recommended dose were adequate for most patient's groups to achieve the conventional target of an AUC of 900-1350 µM min. For patients in the lower weight group < 9 kg, higher doses were need at 1.2 mg/kg. With regards to the newly proposed target of AUC 78-101 mg h/mL, all of the doses we tested had low probability of achieving it. Conclusions Most of our patients had less than a proportional increase in busulfan concentration suggesting autoinduction. The high interindividual variability and autoinduction make dose adjustments challenging and AUC at steady state difficult to predict from the first dose. One approach to improve dose predictions is to use Bayesian dosing software. Based on our simulations, the European Medicines Agency recommended doses were adequate for most patient groups, except those in the lower (< 9 kg) and higher weight groups (> 34 kg).
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http://dx.doi.org/10.1007/s11096-020-00989-3DOI Listing
April 2020

Successful hematopoietic stem cell transplant in leukocyte adhesion deficiency type III presenting primarily as malignant infantile osteopetrosis.

Clin Immunol 2020 04 21;213:108365. Epub 2020 Feb 21.

Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

Leukocyte adhesion deficiency type III (LAD-III) is caused by mutations in FERMT3 that encodes Kindlin-3 which regulates integrins activation. LAD-III predisposes to infections and bleeding. Osteopetrosis was reported in some cases. We report three patients who presented as malignant infantile osteopetrosis. One had recurrent infections and none had bleeding. Exome sequencing revealed a novel homozygous mutation in FERMT3 c.1555C > T (p.Gln519Ter). Two patients underwent successful hematopoietic stem cell transplant (HSCT) from matched siblings with resolution of osteopetrosis. The third patient died secondary to sepsis prior to HSCT. Our results support early HSCT in LAD-III prior to the occurrence of life-threatening complications.
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http://dx.doi.org/10.1016/j.clim.2020.108365DOI Listing
April 2020

Children and Adults with Refractory Acute Graft-versus-Host Disease Respond to Treatment with the Mesenchymal Stromal Cell Preparation "MSC-FFM"-Outcome Report of 92 Patients.

Cells 2019 12 5;8(12). Epub 2019 Dec 5.

Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt am Main, 60590 Frankfurt, Germany.

(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
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http://dx.doi.org/10.3390/cells8121577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952775PMC
December 2019

Identifying Prognostic Factors That Influence Outcome of Childhood Acute Myeloid Leukemia in First Relapse in Saudi Arabia: Results of the Multicenter SAPHOS Study.

Clin Lymphoma Myeloma Leuk 2018 12 12;18(12):773-780. Epub 2018 Sep 12.

King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; Faculty of Medicine, Alfaisal University, Riyadh, Saudi Arabia.

Background: The outcome of childhood acute myeloid leukemia (AML) in first relapse (rAML) remains poor. Reported overall survival (OS) rates vary between high-income developed countries and those with fewer resources. The OS of rAML in high-income developing countries (HIDCs) has not been reported.

Patients And Materials: A multicenter study was performed in an HIDC. The outcome of patients with relapsed non-M3/non-Down syndrome AML was evaluated. Three-year OS was computed using the Kaplan-Meier method, and predictors of OS were analyzed using a Cox proportional hazards model.

Results: A total of 88 patients with non-M3/non-Down syndrome AML diagnosed between January 2005 and December 2012 with a first relapse were identified. Their 3-year OS was 22.6% ± 5.4%. Patients with inv(16) and t(8;21) had an OS of 75.0% ± 21.7% and 36.0% ± 16.1%, respectively. Worse outcomes were associated with "other intermediate" and 11q23 rearrangement AML (OS of 9.4% ± 8.7% and 10.7% ± 9.6%, respectively). Patients experiencing time to relapse (TTR) less than 1 year had shorter OS than those with a longer TTR (14.6% ± 5.4% vs. 41.1% ± 11.5%; P = .006). The outcome of patients after stem cell transplantation (SCT) in second complete remission (CR2) was superior compared with no SCT (50.9% ± 11.2% vs. 7.7% ± 4.6%; P = .001). TTR, risk group, CR2, and SCT in CR2 were the most significant predictors for survival.

Conclusions: rAML remains a clinical challenge. Genetic variability in outcomes was observed. A majority of patients with inv(16) were successfully salvaged post-relapse, whereas patients with 11q23 rearrangement had a poor prognosis. Only one-third of those with t(8;21) rAML survived. Better access to SCT in HIDCs is needed.
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http://dx.doi.org/10.1016/j.clml.2018.09.001DOI Listing
December 2018

Utilizing Whole-Exome Sequencing to Characterize the Phenotypic Variability of Sickle Cell Disease.

Genet Test Mol Biomarkers 2018 Sep 5;22(9):561-567. Epub 2018 Sep 5.

4 Department of Pediatrics, King Abdullah Specialist Children's Hospital , King Abdullah International Medical Research Centre, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia .

Background: Sickle cell disease (SCD) is a monogenic disease that has wide variety of phenotypes with both and environmental factors contributing to its severity.

Methods: We performed whole-exome sequencing (WES) in 22 Saudi SCD patients to identify variants that could explain differences in disease phenotypes. All variants, except those that were benign and likely benign, described in the ClinVar database, were considered in our analysis. Gene-based association testing using sequence kernel association optimal unified test (SKAT-O) with small sample adjustment was performed to evaluate the effect of multiple variants in genes on SCD phenotypes.

Results: The mean age of participants was 28 (range, 10-48 years). All patients were homozygous for the sickle cell mutation. The Benin haplotype was present in 15 patients and the Arab-Indian haplotype in 7 patients. One patient who had both SCD and CHARGE association was heterozygous for pathogenic mutation p.Arg987Ter in the CHD7 gene. One SCD individual who had a stroke was a carrier of the pathogenic variant p.Asp36Tyr in the VKORC1 gene which is, associated with warfarin resistance. Two patients with steady hemoglobin levels of 7.5 and 7.1 g/dL were carriers of the pathogenic mutation p.Gly140Ser in the RPL5 gene that is associated with Diamond-Blackfan anemia. None of the patients were transfusion dependent. A heterozygous pathogenic mutation in the LDLR gene associated with autosomal dominant familial hypercholesterolemia was present in one patient with deep venous thrombosis, although their cholesterol level was normal. One individual with stroke was a carrier for the p.Arg284Ter variant in the NLRP12 gene, which is associated with familial cold autoinflammatory syndrome 2. Another patient with stroke and a pulmonary embolism was heterozygous for the p.Pro106Leu variant of the MPL gene, which has been associated with thrombocytosis. Coding variants in the GOLGB1, ENPP1, and PON1 genes showed no association with stroke in our study. SKAT-O analysis did not explain SCD heterogeneity.

Conclusion: WES provided limited information to explain the severity of SCD. Whole genome sequencing, epigenetic studies, and assessment of environmental factors might expand our knowledge of SCD heterogeneity.
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http://dx.doi.org/10.1089/gtmb.2018.0058DOI Listing
September 2018

Prevalence of hereditary cancer susceptibility syndromes in children with cancer in a highly consanguineous population.

Cancer Epidemiol 2018 08 30;55:88-95. Epub 2018 May 30.

Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Consultant Pediatric Hematology/Oncology/BMT, Department of Pediatric Hematology/Oncology, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia.

Background & Aim: Hereditary cancer susceptibility syndromes (HCSS) are reported in up to one-third of children with cancer. Diagnosis of HCSS is crucial for implementation of surveillance protocols. We identified children who fulfilled criteria for HCSS in Saudi Arabia using the American College of Medical Genetics and Genomics (ACMG) guidelines, addressing the utility of these guidelines in a highly consanguineous population.

Methods: This multi-center cross-sectional study recruited 1858 children with cancer between January 2011 and December 2014. HCSS criteria were based on the ACMG guidelines.

Results: Seven hundred and four (40.4%) out of 1742 eligible patients fulfilled criteria for HCSS. Consanguinity was reported in 629 (38%) patients, with 50 (2.9%) first-degree, 535 (30.7%) second-degree, and 272 (15.6%) third-degree relatives affected with cancer. Two hundred and eighty eight (17.4%) leukemia and 87 (5.3%) brain tumour patients fulfilled HCSS criteria, with parental consanguinity being the most frequent criterion in both (leukemia 85.4%, brain tumors 83.9%). However, leukemia was less frequent in patients of consanguineous parents (p = 0.023).

Conclusion: Four out of 10 children with cancer fulfilled criteria for HCSS, most often due to consanguinity. This higher than expected prevalence suggests the need to validate consanguinity as a criterion for HCSS in highly consanguineous populations.
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http://dx.doi.org/10.1016/j.canep.2018.05.006DOI Listing
August 2018

Secondary Hemophagocytic Syndrome Associated with COG6 Gene Defect: Report and Review.

JIMD Rep 2018 15;42:105-111. Epub 2018 Feb 15.

King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease that is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes. Clinically, it is characterized by prolonged fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, pancytopenia, and hemophagocytosis in the bone marrow, spleen, or lymph nodes. It can be classified as primary if it is due to a genetic defect, or secondary if it is due to a different etiology such as severe infection, immune deficiency syndrome, rheumatological disorder, malignancy, and inborn errors of metabolism such as galactosemia, multiple sulfatase deficiency, lysinuric protein intolerance, Gaucher disease, Niemann-Pick disease, Wolman disease, propionic acidemia, methylmalonic acidemia, biotinidase deficiency, cobalamin C defect, galactosialidosis, Pearson syndrome, and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. For the first time in the literature, we report on a 5-year-old girl diagnosed with a Component of Oligomeric Golgi Complex 6 (COG6) gene defect complicated by HLH. Finally, we review the literature on inborn errors of metabolism associated with HLH and compare the previously reported patients of COG6 gene defect with our patient.
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http://dx.doi.org/10.1007/8904_2018_88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226399PMC
February 2018

Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM).

Bone Marrow Transplant 2018 07 29;53(7):852-862. Epub 2018 Jan 29.

Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt am Main, Germany.

The inability to generate mesenchymal stromal cells (MSCs) of consistent potency likely is responsible for inconsistent clinical outcomes of patients with aGvHD receiving MSC products. We developed a novel MSC manufacturing protocol characterized by high in vitro potency and near-identity of individual doses, referred to as "MSC-Frankfurt am Main (MSC-FFM)". Herein, we report outcomes of the 69 patients who have received MSC-FFM. These were 51 children and 18 adults with refractory aGvHD grade II (4%), III (36%) or IV (59%). Patients were refractory either to frontline therapy (steroids) (29%) or to steroids and 1-5 additional lines of immunosuppressants (71%) were given infusions in four weekly intervals. The day 28 overall response rate was 83%; at the last follow-up, 61% and 25% of patients were in complete or partial remission. The median follow-up was 8.1 months. Six-month estimate for cumulative incidence of non-relapse mortality was 27% (range, 16-38); leukemia relapse mortality was 2% (range, 0-5). This was associated with a superior six-month overall survival (OS) probability rate of 71% (range, 61-83), compared to the outcome of patients not treated with MSC-FFM. This novel product was effective in children and adults, suggesting that MSC-FFM represents a promising therapy for steroid refractory aGvHD.
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http://dx.doi.org/10.1038/s41409-018-0102-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039391PMC
July 2018

Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis.

Pediatr Blood Cancer 2018 04 22;65(4). Epub 2017 Dec 22.

Department of Pediatrics, King Abdullah Specialist Children's Hospital and King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.

Adenosine deaminase-2 (ADA2) deficiency (DADA2) is associated with early onset polyarteritis nodosa and vasculopathy. Classic presentation includes livedo reticularis, vasculitis, and stroke. However, the phenotype and disease severity are variable. We present a 5-year-old female who presented with features that mimicked autoimmune lymphoproliferative syndrome (ALPS) in the absence of classic features of DADA2. Exome sequencing identified a novel homozygous splicing variant in ADA2 c.882-2A > G. Patient responded to anti- tumor necrosis factor medication and is in complete remission. Hematologists should be aware of various hematological presentations of DADA2, including ALPS-like disorder, that might lack vasculitis and livedo reticularis to prevent delay in initiating optimal therapy.
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http://dx.doi.org/10.1002/pbc.26912DOI Listing
April 2018

Clinical characteristics and outcome of childhood acute promyelocitic leukemia (APL) in Saudi Arabia: a multicenter SAPHOS leukemia group study.

Hematology 2018 Jul 7;23(6):316-323. Epub 2017 Dec 7.

j Faculty of Medicine Alfaisal University , Riyadh , Saudi Arabia.

Background: Acute promyelocytic leukemia (APL) is a rare form of acute myelogenous leukemia (AML). Survival rates exceed 80% in developed countries. Successful treatments rely on all-trans retinoic acid with anthracycline-based chemotherapy. Availability of modern care and public knowledge play important roles in pediatric APL survival.

Method: A cytogenetic diagnosis of APL was confirmed in 30 (14.5%) out of 207 children consecutively diagnosed with de novo AML between January 2005 and December 2012 at nine cancer care centers in Saudi Arabia. Patients were treated based on the standard protocol used by the center following the PETHEMA or the C9710 treatment protocols. We modeled 5-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) vs. treatment and potential covariates of age at diagnosis, involvement of central nervous system (CNS), and white blood cell (WBC) levels.

Results: The median age was 10.4 years with a male:female ratio of 1.9. WBC was 10 × 10/l or greater in 57% and CNS involvement was confirmed in 13%. OS, EFS, and CIR were 74 ± 12%, 55 ± 19%, and, 36 ± 17% respectively. No significant difference was found by treatment protocol. WBC levels were significantly prognostic for all negative events, but treatment with C9710 significantly ameliorated negative WBC effects. Overall outcomes were comparable to those reported in developed countries.

Conclusions: Access to modern care is likely to be a critical factor in successful and comparable outcomes of childhood APL across the globe. In the present study, utilizing a cytarabine-containing protocol improved outcome of high-risk pediatric patients with APL.
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http://dx.doi.org/10.1080/10245332.2017.1412380DOI Listing
July 2018

A phased SNP-based classification of sickle cell anemia HBB haplotypes.

BMC Genomics 2017 Aug 11;18(1):608. Epub 2017 Aug 11.

Department of Medicine, Boston University School of Medicine, 72 E. Concord St, Boston, MA, 02118, USA.

Background: Sickle cell anemia causes severe complications and premature death. Five common β-globin gene cluster haplotypes are each associated with characteristic fetal hemoglobin (HbF) levels. As HbF is the major modulator of disease severity, classifying patients according to haplotype is useful. The first method of haplotype classification used restriction fragment length polymorphisms (RFLPs) to detect single nucleotide polymorphisms (SNPs) in the β-globin gene cluster. This is labor intensive, and error prone.

Methods: We used genome-wide SNP data imputed to the 1000 Genomes reference panel to obtain phased data distinguishing parental alleles.

Results: We successfully haplotyped 813 sickle cell anemia patients previously classified by RFLPs with a concordance >98%. Four SNPs (rs3834466, rs28440105, rs10128556, and rs968857) marking four different restriction enzyme sites unequivocally defined most haplotypes. We were able to assign a haplotype to 86% of samples that were either partially or misclassified using RFLPs.

Conclusion: Phased data using only four SNPs allowed unequivocal assignment of a haplotype that was not always possible using a larger number of RFLPs. Given the availability of genome-wide SNP data, our method is rapid and does not require high computational resources.
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http://dx.doi.org/10.1186/s12864-017-4013-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553663PMC
August 2017

Genetic determinants of HbF in Saudi Arabian and African Benin haplotype sickle cell anemia.

Am J Hematol 2017 09 19;92(9):E555-E557. Epub 2017 Jul 19.

Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, 02118.

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http://dx.doi.org/10.1002/ajh.24822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546992PMC
September 2017

Treatment results in children with myeloid leukemia of Down syndrome in Saudi Arabia: A multicenter SAPHOS leukemia group study.

Leuk Res 2017 07 12;58:48-54. Epub 2017 Apr 12.

Faculty of Medicine, Alfaisal University, Riyadh, Saudi Arabia; King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.

Despite the high incidence of Down syndrome (DS) in Arab countires, the incidence and outcomes of myeloid leukemia of DS (ML-DS) have not been studied. We evaluated 206 pediatric acute myeloid leukemia (AML) patients diagnosed between 2005 and 2012 and identified 31 (15%) ML-DS. The incidence of ML-DS was 48 per 100,000 compared to 0.6 per 100,000 for AML in non-DS children. Thus, patients with DS had 80-fold increased risk of ML-DS compared to AML in non-DS children. The median age at diagnosis was 1.8 years, male/female ratio was 1.2, majority (84%) of patients had FAB-M7 subtype, and the cytogenetic abnormalities were normal karyotype (constitutional trisomy 21) in 48%, additional trisomy in 23%, and other aberrations in 29%. Complete remission, cumulative incidences of relapse (CIR), toxic-death, and 5-year event-free survival (EFS) rates were 96.8%, 19.4%, 13.1%, and 67.7±8.4%; respectively. In the present study, multivariate analysis revealed favorable outcome (5-year EFS 86.7±8.8%) for patients with normal karyotype. The incidence and clinical characteristics of ML-DS in Saudi patients were comparable to other reports. However, there is a need to optimize risk stratification and treatment intensity to reduce CIR and toxic death rates to further improve outcomes of patients with ML-DS.
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http://dx.doi.org/10.1016/j.leukres.2017.04.004DOI Listing
July 2017

A candidate transacting modulator of fetal hemoglobin gene expression in the Arab-Indian haplotype of sickle cell anemia.

Am J Hematol 2016 Nov 22;91(11):1118-1122. Epub 2016 Aug 22.

Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.

Fetal hemoglobin (HbF) levels are higher in the Arab-Indian (AI) β-globin gene haplotype of sickle cell anemia compared with African-origin haplotypes. To study genetic elements that effect HbF expression in the AI haplotype we completed whole genome sequencing in 14 Saudi AI haplotype sickle hemoglobin homozygotes-seven selected for low HbF (8.2% ± 1.3%) and seven selected for high HbF (23.5% ± 2.6%). An intronic single nucleotide polymorphism (SNP) in ANTXR1, an anthrax toxin receptor (chromosome 2p13), was associated with HbF. These results were replicated in two independent Saudi AI haplotype cohorts of 120 and 139 patients, but not in 76 Saudi Benin haplotype, 894 African origin haplotype and 44 AI haplotype patients of Indian origin, suggesting that this association is effective only in the Saudi AI haplotype background. ANTXR1 variants explained 10% of the HbF variability compared with 8% for BCL11A. These two genes had independent, additive effects on HbF and together explained about 15% of HbF variability in Saudi AI sickle cell anemia patients. ANTXR1 was expressed at mRNA and protein levels in erythroid progenitors derived from induced pluripotent stem cells (iPSCs) and CD34 cells. As CD34 cells matured and their HbF decreased ANTXR1 expression increased; as iPSCs differentiated and their HbF increased, ANTXR1 expression decreased. Along with elements in cis to the HbF genes, ANTXR1 contributes to the variation in HbF in Saudi AI haplotype sickle cell anemia and is the first gene in trans to HBB that is associated with HbF only in carriers of the Saudi AI haplotype. Am. J. Hematol. 91:1118-1122, 2016. © 2016 Wiley Periodicals, Inc.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072989PMC
http://dx.doi.org/10.1002/ajh.24527DOI Listing
November 2016

Clinical characteristics and outcome of childhood de novo acute myeloid leukemia in Saudi Arabia: A multicenter SAPHOS leukemia group study.

Leuk Res 2016 10 24;49:66-72. Epub 2016 Aug 24.

Department of Pediatric Hematology/Oncology, King Abdullah specialized Children's Hospital, King Abdulaziz Medical City - Riyadh, Saudi Arabia.

Geographic variation and ethnicity have been implicated to influence the outcome of pediatric acute myeloid leukemia (AML). Furthermore, survival outcomes from developing countries are reported to be inferior to developed nations. We hypothesized that risk- and response-based outcome in high-income resource-rich developing countries would be comparable to developed nations as access to care and supportive measures would be similar. A total of 193 children diagnosed with de novo AML between January 2005 and December 2012 were identified, of those 175 were evaluable for outcome. Patients were stratified into low-risk (LR), intermediate-risk (IR), or high-risk (HR) groups. The complete remission (CR), early death, and induction failure rates were: 85.7%, 2.3%, and 12%; respectively. The 5-year cumulative incidences of relapse (CIR) and non-relapse mortality (NRM) were 43.1% and 9.8% respectively; overall survival (OS) was 58.8±4% and event-free survival (EFS) 40.9±4.1%. The 5-year OS for LR, IR, and HR groups were 72.0±6.9%, 59.8±6.2%, and 45.1±7.4%; respectively (p=0.003); and EFS 50.5±8.0%, 46.3±6.4%, and 23.3±6.4%; respectively (p=0.001). This study demonstrated comparable outcomes to those reported from developed countries. This suggests that utilization of risk- and response-based protocols in developing countries can overcome ethnic and geographic variation, if access to care and supportive measures were similar.
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http://dx.doi.org/10.1016/j.leukres.2016.08.009DOI Listing
October 2016

Demands and challenges for patients with sickle-cell disease requiring hematopoietic stem cell transplantation in Saudi Arabia.

Pediatr Transplant 2016 Sep 31;20(6):831-5. Epub 2016 Jul 31.

King Fahad Hospital, Hofuf, Saudi Arabia.

Allogeneic HSCT is the only curative treatment for SCD. In this study, we estimated the number of Saudi patients with SCD who are candidates for HSCT. We used the presence of overt stroke, recurrent ACS, and frequent severe pain crisis as indications for HSCT. We calculated the frequencies of these complications among a Saudi SCD cohort of 376 patients with SCD, 250 from SW and 126 from Eastern (E) provinces. We found that 59 (23.6%) of SW patients were transplant candidates compared to 22 (17.4%) from E province. It is estimated that about 61 000 patients with SCD live in Saudi Arabia. Thus, the projected number of Saudi patients with SCD who are candidates for HSCT is 10 536 patients. Of those, 2148 are children. The burden of SCD on HSCT centers in Saudi Arabia is substantial and is difficult currently to meet the demand. We recommend recruiting/training more transplant physicians and nurses, expand current capacity of centers if feasible, and open new transplant centers to make HSCT a practical therapeutic option for patients with severe SCD in Saudi Arabia.
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http://dx.doi.org/10.1111/petr.12767DOI Listing
September 2016

A lethal phenotype associated with tissue plasminogen deficiency in humans.

Hum Genet 2016 10 14;135(10):1209-11. Epub 2016 Jul 14.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

The role of plasminogen in preventing thrombosis requires activation by tissue plasminogen activator (t-PA) encoded by PLAT. While case-control associations have been pursued for common variants in PLAT, no disease-causing mutations have been reported. We describe a consanguineous family with two children who died shortly after birth due to complications related to severe hydranencephaly and diaphragmatic hernia. A combined exome/autozygome analysis was carried out with informed consent. We identified a homozygous null mutation in PLAT that abrogated t-PA level in patient cells. This is the first reported human knockout mutation of PLAT. The apparent association with hydranencephaly, diaphragmatic hernia and postnatal lethality requires further validation.
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http://dx.doi.org/10.1007/s00439-016-1711-5DOI Listing
October 2016

Activation-resistant homozygous protein C R229W mutation causing familial perinatal intracranial hemorrhage and delayed onset of thrombosis.

Thromb Res 2016 Jul 23;143:17-21. Epub 2016 Apr 23.

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.

Introduction: We describe a family with two first-degree cousins who presented with similar phenotypes characterized by neonatal intracranial hemorrhage and subsequent onset of thrombosis.

Patients/methods: We enrolled the two affected patients, five unaffected family members and fifty-five normal controls. Clinical, laboratory, and radiological characteristics of patients were obtained. Exome sequencing was performed for the older affected child. PROC c.811 C>T was genotyped by PCR in patients, family members, and controls. Protein C amidolytic activity and antigen were measured using the STACHROM® protein C kit and ELISAs. To define functional abnormalities caused by the patients' mutation, recombinant wildtype protein C and its mutants R229W, R229Q and R229A were studied.

Results: For the two cousins, protein C amidolytic activity was 61% and 59% and antigen was 57% and 73% (nl 70-140%), respectively. Exome sequencing revealed a homozygous variant in exon 9 of the protein C (PROC) gene c.811 C>T (R229W). The R229W mutation is located in the calcium binding loop of protein C's protease domain that mediates thrombomodulin interactions. Recombinant R229W-protein C mutant was strikingly defective in rate of activation by thrombin: thrombomodulin, suggesting an in vivo deficit in these children for generation of activated protein C.

Conclusions: These cases emphasize that protein C and activated protein C are important in maintaining the integrity of the brain vascular endothelium in humans. Moreover, routine protein C assays utilizing snake venom protease fail to detect protein C mutants that are resistant to thrombin:thrombomodulin activation.
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http://dx.doi.org/10.1016/j.thromres.2016.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943460PMC
July 2016

Clinical characteristics and genetic subtypes of Fanconi anemia in Saudi patients.

Cancer Genet 2016 Apr 15;209(4):171-6. Epub 2016 Feb 15.

Department of Pediatric Hematology/Oncology, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia; Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address:

We reviewed our institutional experience from 2011 to 2015 on new cases of Fanconi anemia (FA). Ten unrelated cases were diagnosed during this period. Four patients with severe aplastic anemia (SAA) had c.2392C > T (p.Arg798*) BRIP1/FANCJ mutation. Another child with SAA had novel c.1475T > C (p.Leu492Pro) FANCC mutation. One individual with SAA and acute myeloid leukemia had c.637_643del (p.Tyr213Lysfs*6) FANCG mutation. Three patients presented with early onset of cancer, two had BRCA2 mutation c.7007G > A (p.Arg2336His) and one had a novel c.3425del (p.Leu1142Tyrfs*21) PALB2 mutation. Another infant with c.3425del PALB2 mutation had clonal aberration with partial trisomy of the long arm of chromosome 17. Mutations in FA downstream pathway genes are more frequent in our series than expected. Our preliminary observation will be confirmed in a large multi-institutional study.
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http://dx.doi.org/10.1016/j.cancergen.2016.02.003DOI Listing
April 2016