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1.
EJHaem ; 3(3): 1013-1017, 2022 Aug.
Article in English | MEDLINE | ID: mdl-36051042

ABSTRACT

Clonal evolution in acute leukemias is one of the most important factors that leads to therapeutic failure and disease relapse. Delay in therapeutic intervention is one of the reasons that leads toward clonal evolution. In this report, we present a case of acute lymphoblastic leukemia in which therapeutic delay resulted in clonal evolution that was detected by conventional karyotyping and was responsible for non-responsiveness of the disease to conventional chemotherapy. A 17-year-old boy presented with generalized body aches, rapidly progressive pallor and lethargy. Bone marrow analysis was consistent with the diagnosis of B-cell ALL. Karyotypic analysis revealed 46, XY male karyotype. The patient left the hospital due to financial reasons and after 40 days came back to the hospital. Repeated bone marrow analysis including cytogenetic studies revealed presence of three different clones of blast cells: one clone showed 46, XY with del(9p) and t (11;14), second clone showed 46, XY with del(7q) and del(9p), and the third clone showed 46, XY normal karyotype. The patient did not respond to chemotherapy and died within 1 week of induction chemotherapy (HyperCVAD-A). Timely diagnosis and institution of chemotherapy in acute leukemias patients is the key to prevent clonal evolution and thus resistance of the disease to therapeutic interventions.

2.
Front Pediatr ; 10: 875877, 2022.
Article in English | MEDLINE | ID: mdl-35685917

ABSTRACT

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a prevalent condition worldwide and is caused by loss-of-function mutations in the G6PD gene. Individuals with deficiency are more susceptible to oxidative stress which leads to the classical, acute hemolytic anemia (favism). However, G6PD deficiency in newborn infants presents with an increased risk of hyperbilirubinemia, that may rapidly escalate to result in bilirubin induced neurologic dysfunction (BIND). Often with no overt signs of hemolysis, G6PD deficiency in the neonatal period appears to be different in the pathophysiology from favism. This review discusses and compares the mechanistic pathways involved in these two clinical presentations of this enzyme disorder. In contrast to the membrane disruption of red blood cells and Heinz bodies formation in favism, G6PD deficiency causing jaundice is perhaps attributed to the disruption of oxidant-antioxidant balance, impaired recycling of peroxiredoxin 2, thus affecting bilirubin clearance. Screening for G6PD deficiency and close monitoring of affected infants are important aspects in neonatal care to prevent kernicterus, a permanent and devastating neurological damage. WHO recommends screening for G6PD activity of all infants in countries with high prevalence of this deficiency. The traditional fluorescent spot test as a screening tool, although low in cost, misses a significant proportion of cases with moderate deficiency or the partially deficient, heterozygote females. Some newer and emerging laboratory tests and diagnostic methods will be discussed while developments in genomics and proteomics contribute to increasing studies that spatially profile genetic mutations within the protein structure that could predict their functional and structural effects. In this review, several known variants of G6PD are highlighted based on the location of the mutation and amino acid replacement. These could provide insights on why some variants may cause a higher degree of phenotypic severity compared to others. Further studies are needed to elucidate the predisposition of some variants toward certain clinical manifestations, particularly neonatal hyperbilirubinemia, and how some variants increase in severity when co-inherited with other blood- or bilirubin-related genetic disorders.

3.
J Med Case Rep ; 12(1): 276, 2018 Sep 17.
Article in English | MEDLINE | ID: mdl-30223886

ABSTRACT

BACKGROUND: Acquired thrombotic thrombocytopenia purpura is very rarely encountered in children. It is often misdiagnosed initially when the condition is not inherited. CASE PRESENTATION: We describe a 3-year-old Malay boy who presented with simple febrile seizure and had no neurological deficit, however, he was found to have microangiopathic hemolytic anemia, thrombocytopenia, and elevated serum lactate dehydrogenase. An ADAMTS13 assay results showed zero activities (0%), and markedly high level of ADAMTS13 inhibitor (93.15 U/mL) confirming the diagnosis of secondary thrombotic thrombocytopenia purpura. He received fresh frozen plasma infusions for 3 days and subsequently his platelet levels normalized. Serial ADAMTS13 assay results showed improvement. He was also given a short course of prednisolone after which the ADAMTS13 activity normalized (> 114%) at the end of prednisolone course. CONCLUSIONS: At presentation, acquired thrombotic thrombocytopenia purpura in a very young child is commonly misdiagnosed as other conditions like idiopathic thrombocytopenic purpura, Evans syndrome, atypical hemolytic-uremic syndrome, or malignancy. ADAMTS13 assay should be performed early when thrombotic thrombocytopenia purpura is suspected as this condition is associated with dire consequences.


Subject(s)
ADAMTS13 Protein/deficiency , Purpura, Thrombotic Thrombocytopenic/diagnosis , Purpura, Thrombotic Thrombocytopenic/genetics , Child, Preschool , Humans , Male , Purpura, Thrombotic Thrombocytopenic/therapy
4.
Hemoglobin ; 42(4): 247-251, 2018 Jul.
Article in English | MEDLINE | ID: mdl-30623696

ABSTRACT

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.


Subject(s)
Hemoglobin A2/genetics , Hemoglobins, Abnormal/genetics , alpha-Thalassemia/genetics , Child , Diagnosis, Differential , Erythrocyte Indices , Heterozygote , Humans , Male , RNA Splice Sites , alpha-Globins/genetics
5.
Diagn Pathol ; 11(1): 89, 2016 Sep 15.
Article in English | MEDLINE | ID: mdl-27632978

ABSTRACT

BACKGROUND: The World Health Organization (WHO) classification system defines recurrent chromosomal translocations as the sole diagnostic and prognostic criteria for acute leukemia (AL). These fusion transcripts are pivotal in the pathogenesis of AL. Clinical laboratories universally employ conventional karyotype/FISH to detect these chromosomal translocations, which is complex, labour intensive and lacks multiplexing capacity. Hence, it is imperative to explore and evaluate some newer automated, cost-efficient multiplexed technologies to accommodate the expanding genetic landscape in AL. METHODS: "nCounter® Leukemia fusion gene expression assay" by NanoString was employed to detect various fusion transcripts in a large set samples (n = 94) utilizing RNA from formalin fixed paraffin embedded (FFPE) diagnostic bone marrow biopsy specimens. This series included AL patients with various recurrent translocations (n = 49), normal karyotype (n = 19), or complex karyotype (n = 21), as well as normal bone marrow samples (n = 5). Fusion gene expression data were compared with results obtained by conventional karyotype and FISH technology to determine sensitivity/specificity, as well as positive /negative predictive values. RESULTS: Junction probes for PML/RARA; RUNX1-RUNX1T1; BCR/ABL1 showed 100 % sensitivity/specificity. A high degree of correlation was noted for MLL/AF4 (85 sensitivity/100 specificity) and TCF3-PBX1 (75 % sensitivity/100 % specificity) probes. CBFB-MYH11 fusion probes showed moderate sensitivity (57 %) but high specificity (100 %). ETV6/RUNX1 displayed discordance between fusion transcript assay and FISH results as well as rare non-specific binding in AL samples with normal or complex cytogenetics. CONCLUSIONS: Our study presents preliminary data with high correlation between fusion transcript detection by a throughput automated multiplexed platform, compared to conventional karyotype/FISH technique for detection of chromosomal translocations in AL patients. Our preliminary observations, mandates further vast validation studies to explore automated molecular platforms in diagnostic pathology.


Subject(s)
Biomarkers, Tumor/genetics , Gene Fusion , In Situ Hybridization, Fluorescence , Leukemia, Myeloid, Acute/genetics , Multiplex Polymerase Chain Reaction , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , RNA, Messenger/genetics , Translocation, Genetic , Adolescent , Adult , Aged , Aged, 80 and over , Automation, Laboratory , Biopsy , Bone Marrow Examination , Child , Child, Preschool , Female , High-Throughput Nucleotide Sequencing , Humans , Karyotyping , Leukemia, Myeloid, Acute/diagnosis , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Predictive Value of Tests , Reproducibility of Results , Young Adult
6.
EXCLI J ; 15: 155-62, 2016.
Article in English | MEDLINE | ID: mdl-27103895

ABSTRACT

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.

7.
Malays J Pathol ; 36(1): 27-32, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24763232

ABSTRACT

Alpha (Α) thalassaemia is the most common inherited disorder in Malaysia. The clinical severity is dependant on the number of Α genes involved. Full blood count (FBC) and haemoglobin (Hb) analysis using either gel electrophoresis, high performance liquid chromatography (HPLC) or capillary zone electrophoresis (CE) are unable to detect definitively alpha thalassaemia carriers. Definitive diagnosis of Α-thalassaemias requires molecular analysis and methods of detecting both common deletional and non-deletional molecular abnormailities are easily performed in any laboratory involved in molecular diagnostics. We carried out a retrospective analysis of 1623 cases referred to our laboratory in Universiti Kebangsaan Malaysia Medical Centre (UKMMC) for the diagnosis of Α-thalassaemia during the period October 2001 to December 2012. We examined the frequency of different types of alpha gene abnormalities and their haematologic features. Molecular diagnosis was made using a combination of multiplex polymerase reaction (PCR) and real time PCR to detect deletional and non-deletional alpha genes relevant to southeast Asian population. Genetic analysis confirmed the diagnosis of Α-thalassaemias in 736 cases. Majority of the cases were Chinese (53.1%) followed by Malays (44.2%), and Indians (2.7%). The most common gene abnormality was ΑΑ/--(SEA) (64.0%) followed by ΑΑ/-Α(3.7) (19.8%), -Α(3.7) /--(SEA) (6.9%), ΑΑ/ΑΑCS (3.0%), --(SEA)/--(SEA) (1.2%), -Α(3.7)/-Α(3.7) (1.1%), ΑΑ/-Α(4.2) (0.7%), -Α(4.2)/--(SEA (0.7%), -Α(3.7)/-Α(4.2) (0.5%), ΑΑ(CS)/-- SEA) (0.4%), ΑΑ(CS)/ΑΑ(Cd59) (0.4%), ΑΑ(CS)/ΑΑ(CS) (0.4%), -Α(3.7)/ΑΑ(Cd59) (0.3%), ΑΑ/ΑΑ(Cd59) (0.1%), ΑΑ(Cd59)/ ΑΑ(IVS I-1) (0.1%), -Α(3.7)/ΑΑ(CS) (0.1%) and --(SEA) /ΑΑ(Cd59) (0.1%). This data indicates that the molecular abnormalities of Α-thalassaemia in the Malaysian population is heterogenous. Although Α-gene deletion is the most common cause, non-deletional Α-gene abnormalities are not uncommon and at least 3 different mutations exist. Establishment of rapid and easy molecular techniques is important for definitive diagnosis of alpha thalassaemia, an important prerequisite for genetic counselling to prevent its deleterious complications.


Subject(s)
Asian People/genetics , Asian People/statistics & numerical data , Hemoglobin A/genetics , Hemoglobins, Abnormal/genetics , alpha-Thalassemia/ethnology , alpha-Thalassemia/genetics , Female , Gene Deletion , Genetic Heterogeneity , Heterozygote , Humans , Incidence , Malaysia/epidemiology , Male , alpha-Thalassemia/diagnosis
8.
Malays J Pathol ; 34(1): 57-62, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22870600

ABSTRACT

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.


Subject(s)
Gene Deletion , Hemoglobins, Abnormal/metabolism , alpha-Globins/genetics , beta-Thalassemia/diagnosis , delta-Thalassemia/diagnosis , Adult , Chromatography, High Pressure Liquid , Electrophoresis, Capillary/methods , Family Health , Female , Genotype , Hemoglobins, Abnormal/chemistry , Heterozygote , Humans , Male , Siblings , Young Adult , beta-Thalassemia/blood , beta-Thalassemia/genetics , delta-Thalassemia/blood , delta-Thalassemia/genetics
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