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  1. Yong WL, Yusof N, Ithnin A, Shuib S, Tumian R, Yousuf R, et al.
    Malays J Pathol, 2020 Dec;42(3):469-476.
    PMID: 33361731
    INTRODUCTION: Mixed phenotype acute leukaemia (MPAL) is a rare entity of acute leukaemia.

    CASE REPORT: Here we report a case of a 39-year-old lady, with an incidental finding of hyperleukocytosis (white blood cells count: 139.2 x 109/L). Her peripheral blood film revealed 36% of blasts and a bone marrow aspiration showed 53% of blasts. Immunophenotyping showed a population of blasts exhibiting positivity of two lineages, myeloid lineage and B-lymphoid lineage with strong positivity of CD34 and terminal deoxynucleotidyl transferase (Tdt). A conventional karyotyping revealed the presence of Philadelphia chromosome. She was diagnosed with MPAL with t(9,22), BCR ABL1, which carried a poor prognosis. She was treated with acute lymphoblastic leukaemia (ALL) chemotherapy protocol coupled with a tyrosine kinase inhibitor and was planned for an allogeneic stem cells transplant.

    CONCLUSION: This MPAL case was diagnosed incidentally in an asymptomatic patient during medical check-up. We highlight this rare case report to raise the awareness about this rare disease. Understanding the pathogenesis of the disease with the underlying genes responsible for triggering the disease, uniform protocols for diagnosis and targeted treatment will help for proper management of these patients.

  2. Wong FL, Ithnin A, Othman A, Cheah FC
    J Paediatr Child Health, 2017 Jul;53(7):705-710.
    PMID: 28376293 DOI: 10.1111/jpc.13509
    AIM: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a recognised cause of severe neonatal hyperbilirubinaemia, and identifying which infants are at risk could optimise care and resources. In this study, we determined if G6PD enzyme activity (EA) and certain gene variants were associated with neonatal hyperbilirubinaemia requiring phototherapy during the first week after birth.
    METHODS: Newborn infants with G6PD deficiency and a group with normal results obtained by the fluorescent spot test were selected for analyses of G6PD EA and the 10 commonly encountered G6PD mutations in this region, relating these with whether the infants required phototherapy before discharge from the hospital in the first week.
    RESULTS: A total of 222 infants with mean gestation and birth weight of 38.3 ± 1.8 weeks and 3.02 ± 0.48 kg, respectively, were enrolled. Of these, n = 121 were deficient with EA ≤6.76 U/g Hb, and approximately half (43%) received phototherapy in the first week after birth. The mean EA level was 3.7 U/g Hb. The EA had good accuracy in predicting phototherapy use, with area under the receiver-operating-characteristic curve of 0.81 ± 0.05. Infants on phototherapy more commonly displayed World Health Organization Class II mutations (<10% residual EA). Logistic regression analysis showed that deficiency in EA and mutation at c.1388G>A (adjusted odds ratio, 1.5 and 5.7; 95% confidence interval: 1.31-1.76 and 1.30-25.0, respectively) were independent risk factors for phototherapy.
    CONCLUSION: Low G6PD EA (<6.76 U/g Hb) and the G6PD gene variant, c.1388G>A, are risk factors for the need of phototherapy in newborn infants during the first week after birth.
    Study site: Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
  3. Ithnin A, Zubir A, Awang N, Mohamad Sulaiman NN
    Pak J Biol Sci, 2019 Jan;22(3):143-147.
    PMID: 30972984 DOI: 10.3923/pjbs.2019.143.147
    BACKGROUND AND OBJECTIVE: Welding fume exposure has led to the respiratory problems among welders including cough, phlegm, chest illnesses, nausea and fatigue. Inadequate ventilation during welding works causes the situation to worsen. Welding fumes can cause a decrease in lung function among welders. Chronic exposure will lead to other health effects especially COPD (Chronic Obstructive Pulmonary Disease). The objective of this study is to determine the exposure of welding fumes (Cd, Fe, Pb and Zn) towards respiratory health including lung function test (FEV1, FVC, FEV1/FVC, PEFR) of workers in Lumut shipyard, Perak.

    MATERIAL AND METHODS: This research study the relationship between exposures of welding fumes towards lung function test among workers in Lumut shipyard, Perak. Lung function test was measured by spirometry among 30 welders and 31 non-welders. The concentration welding fume exposure was measured using OSHA ID-121 method. Sociodemographic data, respiratory symptoms and smoking habit data was analyzed based on the ATS 1987 questionnaire.

    RESULTS: The mean concentration for Pb in welding fumes was 2.752 mg m-3 which is above 0.5 mg m-3 PEL-TWA. The FEV1 and FVC readings showed significant different between welders and non-welders (p = 0.001). Cough and phlegm symptoms showed significant different between welders and non-welders (p = 0.001). Welders had higher prevalence in smoking habit than the non-welders. Chest illnesses symptom showed an association with the smoking habit (p = 0.01).

    CONCLUSION: There is relationship between welding fumes exposure on lung function test of workers in Lumut shipyard. Pb in welding fumes has high concentration and exceeded PEL-TWA level. The FEV1 and FVC in welders are lower than non-welder due to the fumes exposure. Welders showed higher respiratory symptoms than non-welders. Smoking habit is a contributing factor towards respiratory problem.
  4. Cheah FC, Peskin AV, Wong FL, Ithnin A, Othman A, Winterbourn CC
    FASEB J, 2014 Jul;28(7):3205-10.
    PMID: 24636884 DOI: 10.1096/fj.14-250050
    Erythrocytes require glucose-6-phosphate dehydrogenase (G6PD) to generate NADPH and protect themselves against hemolytic anemia induced by oxidative stress. Peroxiredoxin 2 (Prx2) is a major antioxidant enzyme that requires NADPH to recycle its oxidized (disulfide-bonded) form. Our aims were to determine whether Prx2 is more highly oxidized in G6PD-deficient erythrocytes and whether these cells are able to recycle oxidized Prx2 after oxidant challenge. Blood was obtained from 61 Malaysian neonates with G6PD deficiency (average 33% normal activity) and 86 controls. Prx2 redox state was analyzed by Western blotting under nonreducing conditions. Prx2 in freshly isolated blood was predominantly reduced in both groups, but the median level of oxidation was significantly higher (8 vs 3%) and the range greater for the G6PD-deficient population. When treated with reagent H2O2, the G6PD-deficient erythrocytes were severely compromised in their ability to recycle oxidized Prx2, with only 27 or 4% reduction after 1 h treatment with 0.1 or 1 mM H2O2 respectively, compared with >97% reduction in control erythrocytes. The accumulation of oxidized Prx2 in oxidatively stressed erythrocytes with common G6PD variants suggests that impaired antioxidant activity of Prx2 could contribute to the hemolysis and other complications associated with the condition.-Cheah, F.-C., Peskin, A. V., Wong, F.-L., Ithnin, A., Othman, A., Winterbourn, C. C. Increased basal oxidation of peroxiredoxin 2 and limited peroxiredoxin recycling in glucose-6-phosphate dehydrogenase deficient erythrocytes from newborn infants.
  5. Jalil N, Azma RZ, Mohamed E, Ithnin A, Alauddin H, Baya SN, et al.
    EXCLI J, 2016;15:155-62.
    PMID: 27103895 DOI: 10.17179/excli2015-604
    Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is the commonest cause of neonatal jaundice in Malaysia. Recently, OSMMR2000-D G6PD Assay Kit has been introduced to quantitate the level of G6PD activity in newborns delivered in Universiti Kebangsaan Malaysia Medical Centre (UKMMC). As duration of sample storage prior to analysis is one of the matters of concern, this study was conducted to identify the stability of G6PD enzyme during storage. A total of 188 cord blood samples from normal term newborns delivered at UKMMC were selected for this study. The cord bloods samples were collected in ethylene-diamine-tetra-acetic acid (EDTA) tubes and refrigerated at 2-8 °C. In addition, 32 out of 188 cord blood samples were spotted on chromatography paper, air-dried and stored at room temperature. G6PD enzyme activities were measured daily for 7 days using the OSMMR2000-D G6PD Assay Kit on both the EDTA blood and dried blood samples. The mean value for G6PD activity was compared between days of analysis using Student Paired T-Test. In this study, 172 out of 188 cord blood samples showed normal enzyme levels while 16 had levels corresponding to severe enzyme deficiency. The daily mean G6PD activity for EDTA blood samples of newborns with normal G6PD activity showed a significant drop on the fourth day of storage (p < 0.005) while for samples with severely deficient G6PD activity, significant drop was seen on third day of storage (p = 0.002). Analysis of dried cord blood showed a significant reduction in enzyme activity as early as the second day of storage (p = 0.001). It was also noted that mean G6PD activity for spotted blood samples were lower compared to those in EDTA tubes for all days (p = 0.001). Thus, EDTA blood samples stored at 2-8 °C appeared to have better stability in terms of their G6PD enzyme level as compared to dried blood samples on filter paper, giving a storage time of up to 3 days.
  6. Wong YY, Alauddin H, Raja Sabudin RZA, Ithnin A, Jalil N, Abdul Latiff Z, et al.
    Malays J Pathol, 2021 Apr;43(1):95-100.
    PMID: 33903312
    The Siriraj I Gγ(Aγδβ)0-thalassaemia is a novel mutation involving a 118kb deletion of the β-globin gene cluster. It was first reported in 2012 in two unrelated families from the southern part of Thailand. The carriers in the heterozygous state are clinically asymptomatic. Nonetheless, its complex interaction with other β-thalassaemia could give rise to different clinical phenotypes, ranging from mild thalassaemia intermedia to thalassaemia major. We report here a case of a six-year-old Malay boy, presented with pallor, growth failure and hepatosplenomegaly. His haemoglobin at presentation was 9.2g/dL with a mean cell haemoglobin of 22.6pg and a mean cell volume of 69.9fl. His peripheral blood smear showed features of thalassaemia intermedia. Haemoglobin (Hb) analysis revealed markedly raised Hb F (83%), normal HbA2 levels and absent HbA. Deoxyribonucleic acid (DNA) analysis showed compound heterozygous IVS1-1 (G→T) β-globin gene mutation and Siriraj I Gγ(Aγδβ)0-deletion (genotype βIVS1-1/ β Siriraj I deletion). Both his father and elder sister are carriers of Siriraj I Gγ(Aγδβ)0-thalassaemia while his mother carries IVS1-1 (G→T) gene mutation. Clinically, the patient is transfusion dependent on six weekly regime. To the best of our knowledge, this is the first reported case in Malaysia involving unique Siriraj I Gγ(Aγδβ)0-thalassaemia and IVS1-1 (G→T) in a compound heterozygous state. In summary, detection of Siriraj I Gγ(Aγδβ)0-thalassaemia is essential as this deletion can lead to severe disease upon interaction with a β-thalassemia point mutation as demonstrated in our case. The establishment of effective carrier screening and genetic counselling is important to prevent its adverse consequences.
  7. Jamali NS, Raja Sabudin RZA, Alauddin H, Ithnin A, Tumian NR, Jalil N, et al.
    Malays J Pathol, 2021 Apr;43(1):63-68.
    PMID: 33903307
    INTRODUCTION: The advent of BCR-ABL1-targeted therapy with the tyrosine kinase inhibitor (TKI), for example, imatinib and nilotinib, marked a turning point in the therapy of chronic myeloid leukaemia (CML). However, a substantial proportion of patients experience primary or secondary disease resistance to TKI. There are multifactorial causes contributing to the treatment failure of which BCR-ABL1 kinase domain mutation being the most common. Here, we describe a case of a CML patient with H396P mutation following treatment with nilotinib.

    CASE: A 60-year-old woman presented with abdominal discomfort and hyperleukocytosis. She was diagnosed as CML in the chronic phase with positive BCR-ABL1 transcripts. Due to the failure to obtain an optimal response with imatinib treatment, it was switched to nilotinib. She responded well to nilotinib initially and achieved complete haematological and cytogenetic responses, with undetectable BCR-ABL1 transcripts. However, in 4 years she developed molecular relapse. Mutation analysis which was done 70 months after commencement of nilotinib showed the presence of BCRABL1 kinase domain mutation with nucleotide substitution at position 1187 from Histidine(H) to Proline(P) (H396P). Currently, she is on nilotinib 400mg twice daily. Her latest molecular analysis showed the presence of residual BCR-ABL1 transcripts at 0.22%.

    DISCUSSION/CONCLUSION: This case illustrates the importance of BCR-ABL1 mutation analysis in CML patients with persistent BCR-ABL1 positivity in spite of treatment. Early detection and identification of the type of BCRABL1 mutation are important to guide appropriate treatment options as different mutation will have different sensitivity to TKI.

  8. Wee SY, Muhamed Said SS, Raja Sabudin RZA, Alauddin H, Ithnin A
    Malays J Pathol, 2020 Aug;42(2):195-201.
    PMID: 32860371
    INTRODUCTION: Differentiating between thalassaemia and iron deficiency anaemia (IDA) in hypochromic anaemia is a challenge to pathologists as it influences the choice of subsequent specialized confirmatory tests. In this study, we aimed to evaluate the performance of microcytic to hypochromic ratio (MicroR/ Hypo-He, M/H ratio) as a discriminant index in hypochromic anaemia.

    MATERIALS AND METHODS: A retrospective study was carried out on 318 subjects with hypochromic anaemia, which comprised 162 IDA and 156 thalassaemia trait subjects with α-thalassemia, β-thalassemia and HbE trait. Optimal cut-off value, sensitivity and specificity of M/H ratio for thalassaemia trait discrimination was determined using Receiver Operating Characteristic (ROC) analysis.

    RESULTS: Subjects with thalassaemia trait showed higher MicroR compared to IDA ( p< 0.001) while subjects with IDA demonstrated higher Hypo-He than thalassaemia trait (p < 0.001). M/H ratio was significantly higher in thalassaemia trait compared to IDA, with medians of 3.77 (interquartile range: 2.57 - 6.52) and 1.73 (interquartile range: 1.27 - 2.38), respectively (p < 0.001). M/H ratio ≥ 2.25 was the optimal cut-off value for discriminating thalassaemia trait from IDA in hypochromic anaemia, with the area under ROC curve (AUC) of 0.83, sensitivity of 80.8% and specificity of 71.6%.

    CONCLUSIONS: M/H ratio is a useful discriminant index to distinguish thalassaemia trait from IDA in hypochromic anaemia prior to diagnostic analysis for thalassaemia confirmation. High M/H ratio is suggestive of thalassaemia trait than of IDA. However, more studies are required to establish the role of M/H ratio as a screening tool for thalassaemia discrimination in hypochromic anaemia.

  9. Saad Eldeen Bakheet O, Yusof N, Raja Zahratul A, Ithnin A, Abdul Aziz S, Alias H
    Indian J Hematol Blood Transfus, 2016 Jun;32(Suppl 1):262-6.
    PMID: 27408409 DOI: 10.1007/s12288-015-0582-6
    Secondary sea-blue histiocytosis occurs more frequently than the primary form and occurs consequent to a wide range of metabolic and haematologic disorders including thalassaemia. We report an 18-year-old Chinese boy with transfusion-dependent HbE-beta thalassaemia who complained of pain and swelling at the left iliac crest region for 2 months duration. Physical examination revealed pallor with hepatosplenomegaly. Local examination revealed a huge swelling 12 cm × 12 cm in diameter, firm in consistency and tender. Histopathological examination of the mass revealed an osteosarcoma. His bone marrow aspirate showed numerous sea-blue histiocytes, the cytoplasm of which was closely packed with fine granules that stained blue with May-Grunwald-Giemsa. The nuclei were centrally located in some cells and displaced towards the periphery in other cells. There was no malignant cell infiltration in the marrow. The case is reported due to the co-incidental dual pathology in our patient (HbE-beta thalassaemia and osteosarcoma) and the unusual bone marrow finding of numerous sea-blue histiocytes.
  10. Alauddin H, Langa M, Mohd Yusoff M, Raja Sabudin RZA, Ithnin A, Abdul Razak NF, et al.
    Malays J Pathol, 2017 Apr;39(1):17-23.
    PMID: 28413201 MyJurnal
    INTRODUCTION: Haemoglobin Bart's (Hb Bart's) level is associated with α-thalassaemia traits in neonates, enabling early diagnosis of α-thalassaemia. The study aimed to detect and quantify the Hb Bart's using Cord Blood (CB) and CE Neonat Fast Hb (NF) progammes on fresh and dried blood spot (DBS) specimen respectively by capillary electrophoresis (CE).

    METHODS: Capillarys Hemoglobin (E) Kit (for CB) and Capillarys Neonat Hb Kit (for NF) were used to detect and quantify Hb Bart's by CE in fresh cord blood and dried blood spot (DBS) specimens respectively. High performance liquid chromatography (HPLC) using the β-Thal Short Programme was also performed concurrently with CE analysis. Confirmation was obtained by multiplex ARMS Gap PCR.

    RESULTS: This study was performed on 600 neonates. 32/600 (5.3%) samples showed presence of Hb Bart's peak using the NF programme while 33/600 (5.5%) were positive with CB programme and HPLC methods. The range of Hb Bart's using NF programme and CB programme were (0.5-4.1%) and (0.5-7.1%), respectively. Molecular analysis confirmed all positive samples possessed α-thalassaemia genetic mutations, with 23/33 cases being αα/--SEA, four -α3.7/-α3.7, two αα/-α3.7 and three αα/ααCS. Fifty Hb Bart's negative samples were randomly tested for α-genotypes, three were also found to be positive for α-globin gene mutations. Thus, resulting in sensitivity of 91.7% and 88.9% and specificity of 100% for the Capillarys Cord Blood programme and Capillarys Neonat Fast programme respectively.

    CONCLUSION: Both CE programmes using fresh or dried cord blood were useful as a screening tool for α-thalassaemia in newborns. All methods show the same specificity (100%) with variable, but acceptable sensitivities in the detection of Hb Bart.
  11. Mansor NA, Yusof N, Tang YL, Ithnin A, Azma RZ, Tumian NR, et al.
    Malays J Pathol, 2018 Aug;40(2):191-197.
    PMID: 30173238 MyJurnal
    INTRODUCTION: Essential thrombocythaemia (ET) is a chronic myeloproliferative neoplasm (MPN) characterised by persistent thombocytosis. It is an indolent disorder but transformation to myelofibrosis (MF), acute myeloid leukaemia (AML) or myelodyplastic syndrome (MDS) has been reported.

    CASE REPORT: We described a patient with ET whose disease evolved into MDS with fibrosis and complex karyotype after 15 years of stable disease. She was asymptomatic and was on hydroxyurea (HU) treatment until recently when she presented with worsening anaemia. Physical examination showed mild splenomegaly. Full blood picture showed leukoerythroblastic picture with presence of 3% circulating blasts and background of dysplastic features such as hypogranular cytoplasm and nuclear hyposegmentation of neutrophils. The bone marrow aspiration was haemodiluted but revealed presence of 6% blast cells, trilineage dysplasia and predominant erythroid precursors (60%). Trephine biopsy showed no excess of blast cells and normal quantity of erythroid precursors, but there was increased in fibrosis (WHO grade 2) and presence of dysmegakaryopoeisis such as nuclear hypolobation, multinucleation and micromegakaryocytes. Cytogenetic study showed complex karyotype; monosomy of chromosome 2, chromosome 5, chromosome 18 and presence of a marker chromosome (42~44, XX,-2,-5,-18,+mar). Fluorescence in situ hybridisation (FISH) showed 5q deletion (CSF1R and EGR1).

    CONCLUSION: The findings were consistent with transformation of ET to MDS with fibrosis and complex karyotype. ET progression to MDS is considered rare. The presence of complex karyotype and fibrosis in MDS are associated with unfavourable outcome.

  12. Zailani MAH, Raja Sabudin RZA, Ithnin A, Alauddin H, Sulaiman SA, Ismail E, et al.
    Front Genet, 2023;14:1098828.
    PMID: 37388931 DOI: 10.3389/fgene.2023.1098828
    Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked hereditary disorder and a global public health concern that is most prevalent in malaria-endemic regions including Asia, Africa, and the Mediterranean. G6PD-deficient individuals are at high risk of developing acute hemolytic anemia following treatment with antimalarial drugs including Primaquine and Tafenoquine. However, the currently available tests for G6PD screening are complex and often have been misclassifying cases, particularly for females with intermediate G6PD activity. The latest innovation of quantitative point-of-care (POC) tests for G6PD deficiency provides an opportunity to improve population screening and prevent hemolytic disorders when treating malaria. Aim(s): To assess the evidence on the type and performance of quantitative point-of-care (POC) tests for effective G6PD screening and hence, radical elimination of Plasmodium malaria infections. Methods: Relevant studies published in English language confined from two databases, Scopus and ScienceDirect were searched from November 2016 onwards. The search was conducted using keywords including "glucosephosphate dehydrogenase" or "G6PD", "point-of-care", "screening" or "prevalence", "biosensor" and "quantitative". The review was reported following the PRISMA guidelines. Results: Initial search results yielded 120 publications. After thorough screening and examination, a total of 7 studies met the inclusion criteria, and data were extracted in this review. Two types of quantitative POC tests were evaluated, namely, the CareStartTM Biosensor kit and the STANDARD G6PD kit. Both tests showed promising performance with high sensitivity and specificity ranging mostly from 72% to 100% and 92%-100%, respectively. The positive and negative predictive values (PPV and NPV) ranged from 35% to 72% and 89%-100%, with accuracy ranging from 86% to 98%. Conclusion: In areas with a high prevalence of G6PD deficiency that overlap with malaria endemicity, availability and validation of the diagnostic performance of quantitative POC tests are of absolute importance. Carestart™ biosensor and STANDARD G6PD kits showed high reliability and performed well in comparison to the spectrophotometric reference standard.
  13. Alauddin H, Jaapar NA, Azma RZ, Ithnin A, Razak NF, Loh CK, et al.
    Hemoglobin, 2014;38(4):277-81.
    PMID: 24829075 DOI: 10.3109/03630269.2014.916720
    Hb Adana [HBA2: c179G>A (or HBA1); p.Gly60Asp] is a rare hemoglobin (Hb) variant due to a mutation at codon 59 of the α2- or α1-globin gene resulting in a glycine to aspartic acid substitution. Two siblings with a unique coinheritance of Hb Adana and Hb Constant Spring (Hb CS, α142, Term→Gln, TAA>CAA; HBA2: c.427 T>C) (α(codon 59)α/α(CS)α), were compared phenotypically with another two siblings carrying the Hb Adana mutation and a 3.7 kb deletion (α(codon 59)α/-α(3.7)). Although they all had α-thalassemia intermedia (α-TI), the former were clinically more severe than the latter. The first pair of siblings presented at a much younger age than the second pair and showed lower Hb levels and significant extramedullay hemopoiesis. Another case of a hydropic fetus as a result of Hb H/Hb Adana is also described. Their clinical phenotypes and hematological parameters are all presented for comparison.
  14. Azma RZ, Othman A, Azman N, Alauddin H, Ithnin A, Yusof N, et al.
    Malays J Pathol, 2012 Jun;34(1):57-62.
    PMID: 22870600
    Haemoglobin Constant Spring (Hb CS) mutation and single gene deletions are common underlying genetic abnormalities for alpha thalassaemias. Co-inheritance of deletional and non-deletional alpha (alpha) thalassaemias may result in various thalassaemia syndromes. Concomitant co-inheritance with beta (beta) and delta (delta) gene abnormalities would result in improved clinical phenotype. We report here a 33-year-old male patient who was admitted with dengue haemorrhagic fever, with a background history of Grave's disease, incidentally noted to have mild hypochromic microcytic red cell indices. Physical examination revealed no thalassaemic features or hepatosplenomegaly. His full blood picture showed hypochromic microcytic red cells with normal haemoglobin (Hb) level. Quantitation of Hb using high performance liquid chromatography (HPLC) and capillary electrophoresis (CE) revealed raised Hb F, normal Hb A2 and Hb A levels. There was also small peak of Hb CS noted in CE. H inclusions was negative. Kleihauer test was positive with heterocellular distribution of Hb F among the red cells. DNA analysis for alpha globin gene mutations showed a single -alpha(-3.7) deletion and Hb CS mutation. These findings were suggestive of compound heterozygosity of Hb CS and a single -alpha(-3.7) deletion with a concomitant heterozygous deltabeta thalassaemia. Co-inheritance of Hb CS and a single -alpha(-3.7) deletion is expected to result at the very least in a clinical phenotype similar to that of two alpha genes deletion. However we demonstrate here a phenotypic modification of alpha thalassemia presumptively as a result of co-inheritance with deltabeta chain abnormality as suggested by the high Hb F level.
  15. Tan TL, Ahmad NS, Nasuruddin DN, Ithnin A, Tajul Arifin K, Zaini IZ, et al.
    PLoS One, 2016;11(3):e0152065.
    PMID: 27003588 DOI: 10.1371/journal.pone.0152065
    INTRODUCTION: Early diagnosis of sepsis and bacterial infection is imperative as treatment relies on early antibiotic administration. There is a need to develop new biomarkers to detect patients with sepsis and bacterial infection as early as possible, thereby enabling prompt antibiotic treatment and improving the survival rate.

    METHODS: Fifty-one adult patients with suspected bacterial sepsis on admission to the Emergency Department (ED) of a teaching hospital were included into the study. All relevant cultures and serology tests were performed. Serum levels for Group II Secretory Phospholipase A2 (sPLA2-IIA) and CD64 were subsequently analyzed.

    RESULTS AND DISCUSSION: Sepsis was confirmed in 42 patients from a total of 51 recruited subjects. Twenty-one patients had culture-confirmed bacterial infections. Both biomarkers were shown to be good in distinguishing sepsis from non-sepsis groups. CD64 and sPLA2-IIA also demonstrated a strong correlation with early sepsis diagnosis in adults. The area under the curve (AUC) of both Receiver Operating Characteristic curves showed that sPLA2-IIA was better than CD64 (AUC = 0.93, 95% confidence interval (CI) = 0.83-0.97 and AUC = 0.88, 95% CI = 0.82-0.99, respectively). The optimum cutoff value was 2.13μg/l for sPLA2-IIA (sensitivity = 91%, specificity = 78%) and 45 antigen bound cell (abc) for CD64 (sensitivity = 81%, specificity = 89%). In diagnosing bacterial infections, sPLA2-IIA showed superiority over CD64 (AUC = 0.97, 95% CI = 0.85-0.96, and AUC = 0.95, 95% CI = 0.93-1.00, respectively). The optimum cutoff value for bacterial infection was 5.63μg/l for sPLA2-IIA (sensitivity = 94%, specificity = 94%) and 46abc for CD64 (sensitivity = 94%, specificity = 83%).

    CONCLUSIONS: sPLA2-IIA showed superior performance in sepsis and bacterial infection diagnosis compared to CD64. sPLA2-IIA appears to be an excellent biomarker for sepsis screening and for diagnosing bacterial infections, whereas CD64 could be used for screening bacterial infections. Both biomarkers either alone or in combination with other markers may assist in decision making for early antimicrobial administration. We recommend incorporating sPLA2-IIA and CD64 into the diagnostic algorithm of sepsis in ED.

  16. Haidary AM, Azma RZ, Ithnin A, Alauddin H, Tumian NR, Tamil AM, et al.
    Malays J Pathol, 2019 Aug;41(2):149-160.
    PMID: 31427550
    INTRODUCTION: BCR-ABL fusion gene, the oncogenic driver of CML, results from a translocation between short arms of chromosome 9 and 22. Monitoring of CML patients during treatment is essential, not only for tailoring the treatment but also to detect early relapse to enable timely intervention. Commonly used methods for detection of residual disease are conventional karyotyping, FISH and molecular methods. In this study, we compared FISH with QRT-PCR for detection of residual disease in CML.

    MATERIALS AND METHODS: CML patients on tyrosine kinase inhibitor (TKI) therapy and on regular follow up at University Kebangsaan Malaysia Medical Center (UKMMC) were selected. A comparative study was conducted between FISH and QRT-PCR for BCR-ABL transcripts at diagnosis and during follow-up.

    RESULTS: There was good correlation between FISH and QRT-PCR for BCR-ABL. At 6th month of follow-up post diagnosis, FISH had a sensitivity of 83.3% and specificity of 65.2% (k >0.339, p<0.033). At 12th month, the sensitivity of FISH was 83% and the specificity was 59.1% (k >0.286, p <0.065). Similarly, at the 24th month, FISH had a sensitivity of 100% and specificity of 68.8% (k >0.642, p<0.000).

    DISCUSSION: Early achievement of major molecular response (MMR) and complete cytogenetic remission (CCyR) were reliable predictors of long-term maintenance of molecular remission.

  17. Wan Mohd Zohdi WA, Ismail AZ, Yusof N, Ithnin A, Shuib S, Masir N, et al.
    Clin Pathol, 2022 01 09;15:2632010X211070774.
    PMID: 35036912 DOI: 10.1177/2632010X211070774
    Diffuse large B-cell lymphoma (DLBCL) is a type of non-Hodgkin Lymphoma commonly presenting as a solid tumor either by nodal or extra-nodal manifestations. Here we describe two atypical presentations of lymphoma, finally resulting in the diagnosis of DLBCL. Case 1: A 53-year-old man with a previous history of nasopharyngeal carcinoma presented with a two-week history of B-symptoms and hyperleukocytosis. Peripheral blood film showed 78% abnormal mononuclear cells. Immunohistochemical stain showing Ki-67 of 90%, negative c-myc, BCL2 and BCL6, and negative c-MYC with fluorescence in-situ hybridization studies on the trephine biopsy, concluded the diagnosis of CD5+ DLBCL of ABC subtype. He received intravenous cyclophosphamide and oral prednisolone for cytoreduction, followed by 6 cycles of chemo-immunotherapy. However, he succumbed due to severe sepsis after the completion of therapy. Case 2: A 56-year-old lady who was initially investigated for pyrexia of unknown origin was noted to have hemophagocytosis upon bone marrow aspirate examination. The bone marrow trephine biopsy revealed some atypical clusters of B-cells positive for CD20 which was inconclusive. PET-CT scan noted an enlarged hypermetabolic spleen without lymphadenopathy. Splenic biopsy with immunohistochemical studies revealed DLBCL of ABC subtype. The diagnosis was consistent with primary splenic DLBCL. She became unwell post splenic biopsy and was admitted to the intensive care unit where she passed away 2 weeks later from Candida and Sternotrophomonas septicemia. These cases highlight the atypical presentations of a common subtype of NHL in our center. Arriving at the definitive diagnosis can be difficult especially when patients are acutely ill, hampering the necessary invasive procedures for diagnosis. The outcomes of both cases are briefly discussed hoping to spread awareness among clinicians on the rare and acutely critical presentations of DLBCL.
  18. Alauddin H, Mohamad Nasir S, Ahadon M, Raja Sabudin RZ, Ithnin A, Hussin NH, et al.
    Malays J Pathol, 2015 Dec;37(3):287-92.
    PMID: 26712677
    Haemoglobin (Hb) Lepore is a variant Hb consisting of two α-globin and two δβ-globin chains. In a heterozygote, it is associated with clinical findings of thalassaemia minor, but interactions with other haemoglobinopathies can lead to various clinical phenotypes and pose diagnostic challenges. We reported a pair of siblings from a Malay family, who presented with pallor and hepatosplenomegaly at the ages of 21 months and 14 months old. The red cell indices and peripheral blood smears of both patients showed features of thalassaemia intermedia. Other laboratory investigations of the patients showed conflicting results. However, laboratory investigation results of the parents had led to a presumptive diagnosis of compound heterozygote Hb Lepore/β-thalassaemia and co-inheritance α+-thalassaemia (-α3.7). Hb Lepore has rarely been detected in Southeast Asian countries, particularly in Malaysia. These two cases highlight the importance of family studies for accurate diagnosis, hence appropriate clinical management and genetic counseling.
  19. Alauddin H, Kamarudin K, Loong TY, Azma RZ, Ithnin A, Jalil N, et al.
    Hemoglobin, 2018 Jul;42(4):247-251.
    PMID: 30623696 DOI: 10.1080/03630269.2018.1528985
    Nondeletional α-globin mutations are known to cause more serious clinical effects than deletional ones. A rare IVS-I-1 (G>A) (HBA2: c.95+1G>A) donor splice site mutation interferes with normal splicing of pre mRNA and results in activation of a cryptic splice site as well as a frameshift mutation. Hb Adana [HBA2: c.179G>A (or HBA1)] is a highly unstable variant hemoglobin (Hb) resulting from a mutation at codon 59 on the HBA2 or HBA1 gene, recognized to cause severe α-thalassemia (α-thal) syndromes. We report a unique case of compound heterozygosity for these two mutations in a 9-year-old boy who presented with a Hb level of 5.3 g/dL and hepatomegaly at the age of 15 months. He required regular blood transfusions in view of a Hb level of <7.0 g/dL and failure to thrive. He had thalassemic red cell indices and peripheral blood film. The Hb electrophoresis only showed a raised Hb F level (3.3%) and a pre run peak but the Hb H inclusion test was negative. His father had thalassemic red cell indices but a normal Hb level. His mother had almost normal Hb levels and red cell indices. Hb Adana involving the HBA2 gene was detected by mutiplex amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in the proband and his father. DNA sequencing of the HBA2 gene confirmed the IVS-I-1 mutation in the proband and his mother. This case highlighted the unique interaction of the IVS-I-1 mutation with Hb Adana in a young Malay boy presenting with transfusion-dependent α-thal.
  20. Razak SAA, Murad NAA, Masra F, Chong DLS, Abdullah N, Jalil N, et al.
    Curr Mol Med, 2018;18(5):295-305.
    PMID: 30289070 DOI: 10.2174/1566524018666181004121604
    BACKGROUND: The phenotypic severity of β-thalassemia is highly modulated by three genetic modifiers: β-globin (HBB) mutations, co-inheritance of α-thalassemia and polymorphisms in the genes associated with fetal haemoglobin (HbF) production. This study was aimed to evaluate the effect of HbF related polymorphisms mainly in the HBB cluster, BCL11A (B-cell CLL/lymphoma 11A) and HBS1L-MYB (HBS1-like translational GTPase-MYB protooncogene, transcription factor) with regards to clinical severity.

    METHODS: A total of 149 patients were included in the study. HBA and HBB mutations were characterised using multiplex PCR, Sanger sequencing and multiplex ligationdependent probe amplification. In addition, 35 HbF polymorphisms were genotyped using mass spectrometry and PCR-restriction fragment length polymorphism (PCRRFLP). The genotype-phenotype association was analysed using SPSS version 22.

    RESULTS: Twenty-one HBB mutations were identified in the study population. Patients with HBB mutations had heterogeneous phenotypic severity due to the presence of other secondary modifiers. Co-inheritance of α-thalassemia (n = 12) alleviated disease severity of β-thalassemia. In addition, three polymorphisms (HBS1LMYB, rs4895441 [P = 0.008, odds ratio (OR) = 0.38 (0.18, 0.78)], rs9376092 [P = 0.030, OR = 0.36 (0.14, 0.90)]; and olfactory receptor [OR51B2] rs6578605 [P = 0.018, OR = 0.52 (0.31, 0.89)]) were associated with phenotypic severity. Secondary analysis of the association between single-nucleotide polymorphisms with HbF levels revealed three nominally significant SNPs: rs6934903, rs9376095 and rs9494149 in HBS1L-MYB.

    CONCLUSION: This study revealed 3 types of HbF polymorphisms that play an important role in ameliorating disease severity of β-thalassemia patients which may be useful as a predictive marker in clinical management.

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