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Case Presentation: A 37-year-old man presented with breathlessness and wheeze of 3 weeks' duration. There was no chest pain, cough, palpitation, pedal edema, or fever. For the past 12 years, he had been experiencing episodic breathlessness and wheeze, which improved with inhaled salbutamol. He also had symptoms of nasal obstruction, nasal discharge, and sneezing. There was no history of smoking, substance abuse, or the use of any over-the-counter medication. The current episode of bronchial asthma exacerbation was managed with bronchodilators and systemic glucocorticoids. Despite symptomatic relief and clinical improvement, his oxygen saturation remained at 75% to 80%, and he was referred to our facility for further evaluation. [ABSTRACT FROM AUTHOR]

Traumatic Brain Injury (TBI) patients more often than not develop fever within the first few days of their hospitalization. Studies report that causes are variable and according to the pathogenesis, fever may be harmful or protective. The study was conducted to correlate the development of fever with clinical prognosis. Throughout the study spanning 6 months, a total of 98 patients of TBI were included. In the first 48 hours, 54 patients did not develop fever (temperature >37), 20 patients recorded temperatures between 37 and 39; and 24 patients developed high fever (39). On regular temperature monitoring and follow up, it was found that patients developing fever relatively early during hospitalization were more likely to end up with a poor outcome (Glasgow outcome scale 4 to 5). Therefore, fever is independently a predictor of poor prognosis in TBI patients and should be managed diligently in the first few days. [ABSTRACT FROM AUTHOR]

Compound heterozygosity for one of the Hb Lepore mutations and β-thalassemia (β-thal) is a rare cause of non transfusion-dependent thalassemia. We report a 4-year-old boy who presented clinically as homozygous/compound heterozygous β-thal intermedia (β-TI), an impression that was corroborated by the initial hemoglobin (Hb) high performance liquid chromatography (HPLC). However, the correct diagnosis of a rare compound heterozygous Hb Lepore-Hollandia/β-thal was revealed after parental studies and molecular analyses including β-globin gene sequencing. Our patient highlights the importance of a logical stepwise multi modality approach and the vital importance of parental screening and molecular studies in accurate characterization of complex hemoglobinopathies. Correct diagnosis is especially crucial if pre natal detection is anticipated for future pregnancies. Molecular analyses alone may not compensate for the unavailability of parental testing. This is because the molecular results may be misinterpreted, especially if limited tests are conducted. The infrequent prior reports of this combination from distant parts of the Indian subcontinent suggests that the origin of Hb Lepore-Hollandia from sporadic mutations occurs in isolated families. [ABSTRACT FROM AUTHOR]

Introduction: Thalassemias are common monogenic autosomal recessive hemoglobin disorders. The usually asymptomatic heterozygotes (β‐thalassemia traits, βTT) may rarely develop non‐transfusion‐dependent‐thalassemia (NTDT) due to co‐inheritance of supernumerary α‐globin genes. Literature on phenotypic/genotypic features of these rare combinations is limited. Materials and Methods: We studied the demographic, clinical, and laboratory data from 47 persons with co‐inherited βTT + supernumerary α‐globin genes. HBB mutations were tested for by ARMS‐PCR and/or Sanger sequencing, ααα(anti3.7)/ααα(anti4.2) and deletional α‐thalassemia testing by multiplex gap‐PCRs, and Xmn1Gγ genotyping by PCR‐RFLP. Results: The 47 cases comprised 0.08% of 61 010 hemoglobinopathy screenings during the study period. Mean age was 31.9 ± 14.7 years (range 5.5–83 years), with 57.4% males. Thirty (63.8%) had NTDT‐phenotype, 16 (34%) were asymptomatic/minimally symptomatic, and 1 became transfusion‐dependent at the age of 20 years. Anemia/pallor and jaundice were the commonest complaints (76% each); 40% had required blood transfusions. Twenty‐one had splenomegaly, 14 had hepatomegaly. Mean hemoglobin was 9.0 ± 1.9 g/dl (range 4.0–13.0). HbA2 was 5.1 ± 0.7% (3.4%–6.3%) and HbF% 4.2 ± 3.2% (0.5%–18.4%). Forty‐four (93.6%) had αααanti3.7, while 3 (6.4%) had αααanti4.2 triplications. HBB:c.92+5G>C (47%), HBB:c.27_28insG (14.9%), and HBB:c.47G>A (8.5%) were the commonest β‐globin mutations. One case showed HBB:c.‐138C>T (β++), while the rest had β0 or severe‐β+ mutations. Symptomatic cases had significantly lower hemoglobins and higher HbF% than asymptomatic ones. Conclusion: This largest Indian and globally second‐largest study reports the βTT + ααα4.2 state for the first time in such genotypically‐complex Indian cases. Supernumerary α‐genes should be suspected in all βTT with disproportionate clinical symptoms, mild‐to‐moderately elevated HbF, and unexplained anisopoikilocytosis. [ABSTRACT FROM AUTHOR]

Cation exchange high performance liquid chromatography (HPLC) is commonly utilized as the first method of screening for thalassemias and hemoglobinopathies worldwide. This method of diagnosis requires knowledge of the clinical background and complete blood counts as well as skill and experience in interpreting the sometimes complex results produced. An asymptomatic 27-year-old pregnant North Indian woman was found to have a highly unusual chromatographic pattern with multiple unexpected peaks during routine antenatal screening. Most concerning was a C-window peak as Hb C ( HBB: c.19G>A) is rare in ethnic Asian Indian populations. Cellulose acetate electrophoresis at alkaline pH (8.6) and parental screening were performed. These revealed the correct diagnosis to be a double heterozygosity for Hb Q-India ( HBA1: c.193G>C) (an uncommon asymptomatic α-globin chain variant) plus Hb D-Punjab ( HBB: c.364G>C) (a β-globin chain variant that is common in this region and is asymptomatic in the heterozygous state). The unexpected C-window peak was the hybrid of the abnormal α-Q-India and β-D-Punjab globin chains. Another small peak was explained as a variant Hb A2 formed by the combination of α-Q-India and δ-globin chains. Hematopathologists should be cognizant of the complex pattern resulting from coinheritance of both α- and β-globin structural variants. Second-line testing and parental testing are invaluable in resolving unknown peaks, especially if rare or unexpected variants are being considered. Although both Hb Q-India and Hb D-Punjab are relatively common in northwestern India, to the best of our knowledge, only two recent reports describe a total of three cases of such diagnostically puzzling coinheritance. [ABSTRACT FROM AUTHOR]

The article focuses on the first reported case of GATA1-related X-linked thrombocytopenia with co-inherited β-thalassemia trait (XLTT) in a 16-year-old boy. Topics include the role of GATA1 mutations in various hematopoietic disorders, the specific mutation (p.Arg216Gln) affecting GATA1 in this case, and the complexity of the phenotype resulting from the co-inheritance of XLTT and β-thalassemia.

Among these, low oxygen-affinity Hb variants are a peculiar subset, displaying autosomal dominant inheritance of normocytic anemia, cyanosis, and usually inapparent hypoxemia detected by a low SpO2 on pulse oximetry. However, other abnormal Hb variants like Hb Beth Israel, Hb Kansas, and Hb Saint Mande also lead to cyanosis without overt methemoglobinemia [[2]]. We report here a family with Hb Beth Israel, a rare Hb variant with very low oxygen affinity. [Extracted from the article]

A 60-year-old male with myelodysplastic syndrome with excess blasts-1 had unexplained microcytic hypochromic anemia. The cause of his anemia was revealed on supravital staining, hemoglobin studies and next-generation sequencing to be a novel hemizygous potentially pathogenic missense/splice site variant NM_000489.5:c.6848A>C, (p.Lys2283Thr) in exon 31 of the ATRX gene. [ABSTRACT FROM AUTHOR]

Background High performance liquid chromatography in a newborn girl with congenital cyanosis and a unilateral cleft palate revealed a variant hemoglobin with retention time of 4.8 min, similar to hemoglobin Q-India. Since hemoglobin Q-India did not explain the cyanosis, further investigations were initiated. Methods Sequencing of α-globin genes revealed hemoglobin M-Iwate ([α87 (F8) His→Tyr]) that was confirmed on restriction enzyme analysis. Results Hemoglobin M-Iwate is a rare methemoglobinemic variant formed due to a point mutation in the α-globin gene. Primarily reported from the Iwate prefecture of Japan, there have been occasional case reports from other regions as well. Inherited methemoglobinemia finds only rare mention in Indian literature while hemoglobin M-Iwate has not been reported from India. Conclusions This case illustrates the step-wise logical diagnostic approaches necessary to elucidate the cause of methemoglobinemia in an otherwise healthy child with cyanosis. [ABSTRACT FROM AUTHOR]

Hyperbilirubinemia and pigment gallstones are frequent complications in transfusion-dependent β-thalassemia (TDβT) patients. Bilirubin production and clearance are determined by genetic as well as environmental variables like ineffective erythropoiesis, hemolysis, infection-induced hepatic injury, and drug- or iron-related toxicities. We studied the frequency of the Gilbert syndrome (GS), a common hereditary cause of hyperbilirubinemia in 102 TDβT patients aged 13–43 years (median 26 years). Total and unconjugated hyperbilirubinemia were frequent (81.4% and 84.3% patients respectively). Twenty (19.6%) patients showed total bilirubin > 3.0 mg/dL; 53 (51.9%) had an elevation of either alanine or aspartate aminotransferase, or alkaline phosphatase liver enzymes. Nineteen (18.6% of the 92 tested) were positive for hepatitis B or C, or HIV. The mean total and unconjugated bilirubin levels and AST, ALT, and ALP levels in patients positive for hepatitis B or C were not significantly different from negative cases. Eighteen patients (17.7%) had GS: homozygous (TA)7/7 UGT1A1 promoter motif (the *28/*28 genotype), 48 (47.1%) were heterozygous (TA)6/7. Total + unconjugated bilirubin rose significantly with the (TA)7 allele dose. Fourteen (13.7%) patients had gallstones. There was no significant difference in total/unconjugated bilirubin in patients with/without gallstones and no significant differences in frequencies of gallstones within the three UGT1A1 genotypes. This largest study in Indian TDβT patients suggests that GS should be excluded in TDβT cases where jaundice remains unexplained after treatable causes like infections, chelator toxicity, or transfusion-related hemolysis are excluded. GS was not associated with gallstones, possibly due to a lower incidence of cholelithiasis overall, a younger age cohort, or other environmental factors. [ABSTRACT FROM AUTHOR]

Hyperunstable hemoglobins (Hbs) are challenging to diagnose and may be missed on conventional hemolytic anemia work-up. Here, we report the case of a 2-year-old Indian boy with infancy-onset severe hemolytic anemia. Its etiology was revealed by targeted next-generation sequencing (NGS) to be the rare Hb Mizuho (HBB: c.206T>C). This variant had been missed on the initial routine laboratory investigations (heat and isopropanol tests for unstable Hbs) owing to its hyperunstable nature. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the spectrum of genetic defects in Indian patients with unexplained erythrocytosis. Methods: Fifteen families (18 patients) with unexplained erythrocytosis were enrolled after excluding polycythemia vera and secondary erythrocytosis. Focused Sanger sequencing from genomic DNA was performed for EPOR (exon 8), VHL (exons 2‐3), EGLN1 (exons 2‐5), EPAS1 (exon 12), and all exons of HBB, HBA1, and HBA2 genes. Results: Eleven of the 18 patients (including two pairs of brothers) had Chuvash polycythemia, that is, homozygosity for VHL:c.598C > T (p.Arg200Trp). Three patients (two of whom were brothers) had HBB mutations associated with increased oxygen‐affinity hemoglobin—one had a heterozygous Hb McKees Rocks HBB:c.438T > A (p.Tyr146*), and two brothers showed heterozygous Hb Rainier HBB:c.437A > G (p.Tyr146Cys). No pathogenic variants were found in the remaining four cases. Conclusion: A gene‐by‐gene Sanger sequencing approach could determine a genetic basis for erythrocytosis in 11 of the 15 (73%) Indian families, with homozygous VHL:c.598C > T (p.Arg200Trp) being the commonest pathogenic variant. This first study from the Indian subcontinent provides a rationale for analyzing this variant in patients with suspected congenital erythrocytosis from this region. Rare first occurrences of Hb McKees Rocks and Hb Rainier in Indians are also being reported. [ABSTRACT FROM AUTHOR]

Interpretation of variant hemoglobins (Hbs) can pose challenges. We describe a puzzling case with multiple variant Hb peaks that was solved by family studies. A 32-year-old female with anemia and jaundice underwent cation exchange high performance liquid chromatography (HPLC), which revealed near-absence of Hb A along with variant peaks in the D- and C-windows (78.9 and 13.3%, respectively) and normal range of Hb F. As the HPLC did not fit any known pattern, family screening was performed. Her mother was heterozygous for Hb D-Punjab (HBB: c.364G>C) and Hb Q-India (HBA1: c.193G>C) with the hybrid αQ-India/βD-Punjab eluting in the C-window on HPLC. Her sister had β-thalassemia (β-thal) trait, while her brother was heterozygous for Hb Q-India. In view of the family study results, the index case was interpreted as a double heterozygote for Hb D-Punjab and β-thal with coinherited Hb Q-India. The Hb Q-India peak [retention time (RT) 4.7 min.] was absent on her HPLC as there were no normal β-globin chains available to bind with the αQ-India chains. To the best of our knowledge, such an HPLC pattern with a missing Q-India peak, despite having inherited the αQ-India variant, has not been previously reported. This case illustrates the importance of family screening as an inexpensive and rapid method to resolve difficult and unusual HPLC patterns. [ABSTRACT FROM AUTHOR]

Background: Raised hemoglobin-A2(HbA2) is the diagnostic hallmark of beta-thalassemia trait (βTT). Diagnostic difficulties may arise in HIV-positive patients on antiretroviral therapy (ART). We compared the effect of various antiretroviral drugs on HbA2levels. We attempted to determine which drugs elevate HbA2levels causing a false-positive diagnosis of βTT and correlate the findings with red cell indices.Methods: A retrospective analysis of the records of an antenatal thalassemia screening program was carried out for 78 HIV-positive adults (70 antenatal women and 8 husbands) to study the effect of antiretroviral drugs on HbA2levels. Three had βTT; 20 treatment-naïve subjects constituted controls. The effects of zidovudine (36 cases), stavudine (7 cases), and tenofovir (12 cases) were evaluated. High-performance liquid chromatography was done for HbA2levels. Values of 3.5–3.9% were borderline and ≥ 4% with hypochromic microcytosis was considered to be βTT.Results: Twenty individuals not on ART had normal HbA2%. Three patients had βTT and showed hypochromic microcytosis despite being on zidovudine. Fourteen of 55 patients on treatment (25.5%) had borderline HbA2values (mean 3.7%): 11 were on a zidovudine-based regimen and 3 on a stavudine-based regimen. One patient on zidovudine had 4.1% HbA2with normal Hb and severe macrocytosis (MCV 128.5 fl), leading to a false suspicion of βTT. All patients on tenofovir had normal HbA2. Hematological parameters, including mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), and HbA2levels were increased due to antiretroviral drugs zidovudine and stavudine.Conclusion: Treatment-naïve subjects and those on tenofovir showed no effect on HbA2levels compared with zidovudine and stavudine. A proportion of patients on zidovudine or stavudine had borderline elevated HbA2levels, which could lead to a false impression of βTT. [ABSTRACT FROM AUTHOR]

The article presents a study on globin gene structure Hemoglobin (Hb) Q-India, for knowing its hematological and Capillary electrophoresis-High-performance liquid chromatography (CE-HPLC) features. Topics include cases confirmed by alkaline potential of hydrogen (pH) agarose gel electrophoresis, blood counts in HbQ showed lower mean corpuscular volume and mean corpuscular hemoglobin, and increasing cases of Q-India traits with microcytosis among boys in India.

The article discusses the findings of a study which investigated the application of cation-exchange (CE)-high performance liquid chromatography (HPLC) in the quantification of hemoglobins and its variants. Topics covered include the unpredictable discrepancies of cellulose acetate electrophoresis (CAE) densitometric hemoglobin fraction levels and the disadvantages of using quantitative screening technique in clinical practice.