Spectrum of Adrenal Dysfunction in Hemoglobin E/Beta Thalassemia.

BACKGROUND: Adrenal insufficiency (AI) in hemoglobin E (HbE)/beta thalassemia, including evaluation of mineralocorticoid axis, had not been studied. AIMS AND OBJECTIVES: In this study, we attempted to evaluate the prevalence of AI in HbE/beta thalassemia and wanted to determine if the prevalence of AI varied according to severity of HbE/beta thalassemia and transfusion requirements. METHODS: In this observational, cross-sectional study, 104 patients with HbE/beta thalassemia were evaluated. Among them, 57 and 47 were transfusion dependent and non-transfusion dependent. According to Mahidol criteria, patients were classified into mild (n = 39), moderate (n = 39), and severe (n = 26) disease. Early morning (8 Am) serum cortisol, plasma ACTH, and plasma aldosterone, renin were measured. Patients with baseline cortisol of 5 to 18 µg/dL underwent both 1 µg and 250 µg short Synacthen test. According to these results, patients were classified as having either normal, subclinical, or overt (primary/secondary) adrenal dysfunction. RESULTS: Adrenal insufficiency was found in 41% (n = 43). Among them 83.7% (n = 34) had primary AI and 16.3% (n = 9) had secondary AI. Thirty-three patients (31%) with normal or elevated ACTH and with low or normal aldosterone with high renin were diagnosed as having subclinical AI. There was no difference in prevalence of AI between transfusion dependent and non-transfusion dependent (P = .56) nor was there was any difference in prevalence of AI according to disease severity (P = .52). CONCLUSION: Adrenal insufficiency is common in HbE/beta thalassemia and is independent of transfusion dependency and disease severity.

Thalidomide-Induced Primary Amenorrhea in a Patient With HbE/Beta-Thalassemia.

An 18-year-old girl was evaluated for primary amenorrhea. She was diagnosed with hemoglobin E (HbE)/beta-thalassemia during childhood and needed blood transfusions every month to maintain adequate hemoglobin levels. She was started on thalidomide to reduce her transfusion requirements at 12 years of age and became transfusion independent after 6 months. She had normal stature and Tanner stage 4 sexual maturation, but she failed to attain menarche. Investigations revealed that she had elevated serum gonadotropin levels, indicating primary ovarian dysfunction. Her karyotype was 46,XX. Ultrasonographic examination demonstrated the absence of follicles in both ovaries. There was no evidence of abnormalities of the urogenital tract. Thalidomide was stopped, and she attained menarche spontaneously 3 months thereafter. Subsequently, her menstrual cycles were regular. Repeat ultrasound scans demonstrated the presence of ovarian follicles as well as an increase in ovarian volume. Mechanistic links between ovarian dysfunction and thalidomide remain to be found. One possibility is impaired blood flow and follicular development.

Key Determinants of Phenotypic Heterogeneity of Hb E/ß Thalassemia: A Comparative Study from Eastern India.

HbE Beta thalassemia is phenotypically very diverse disease. We aim to study role of various genetic factors in determining severity of this disease. 243 diagnosed cases of HbE Beta thalassemia were included in this study. Patients were divided in two arms-transfusion dependent and non-transfusion dependent arms. Various factors (percentage of haemoglobin F, hemoglobin E, type of Beta mutation, Xmn1 polymorphism, alpha deletion, HPFH mutation) were evaluated in these patients. Xmn1 polymorphism (homozygous and heterozygous), presence of HPFH mutation and alpha deletion were more prevalent in NTDT arm versus TDT arm (p value < 0.001). Higher prevelance of severe beta mutation IVS 1-5 (G → C) mutation {64(61.54%) vs 38(27.34); p value < 0.001} was found in TDT arm when above factors were excluded from analysis. Higher mean haemoglobin F and mean Hemoglobin E percentage was associated with NTDT arm (p value < 0.001). Various factors (hemoglobin F and E percentage, Xmn1 polymorphism, HPFH mutation, alpha deletion and IVS 1-5 Beta mutation) were identified to affect severity of this cohort.

Genetic polymorphisms of HbE/beta thalassemia related to clinical presentation: implications for clinical diversity.

HbE/Beta thalassemia (HbE/ß-thalassemia) is one of the common genetic disorders in South East Asia. It is heterogeneous in its clinical presentation and molecular defects. There are genetic modifiers which have been reported to influence the disease severity of this disorder. The aim of this study was to determine the genetic polymorphisms which were responsible for the disease clinical diversity. A case-control study was conducted among Malay transfusion-dependent HbE/ß-thalassemia patients. Patients who were confirmed HbE/ß-thalassemia were recruited and genotyping study was performed on these subjects. Ninety-eight patients were selected and divided into moderate and severe groups based on clinical parameters using Sripichai scoring system (based on hemoglobin level, spleen size, growth development, the age of first transfusion and age of disease presentation). Forty-three (44.9%) and 55 (56.1%) patients were found to have moderate and severe clinical presentation, respectively. Genotyping analysis was performed using Affymetrix 6.0 microarray platform. The SNPs were filtered using PLINK and Manhattan plot by R software. From the GWAS results, 20 most significant SNPs were selected based on disease severity when compared between moderate and severe groups. The significant SNPs found in this study were mostly related to thalassemia complications such as rs7372408, associated with KCNMB2-AS1 and SNPs associated with disease severity. These findings could be used as genetic predictors in managing patients with HbE/ß-thalassemia and served as platform for future study.

Association of alpha hemoglobin-stabilizing protein (AHSP) gene mutation and disease severity among HbE-beta thalassemia patients.

In this study, we aimed to investigate the pattern and association of genetic mutations occurring within the alpha hemoglobin-stabilizing protein (AHSP) gene among HbE beta thalassemia patients with varying phenotypic expressions. Fifty-four diagnosed cases of HbE beta thalassemia (transfusion dependent and independent) were included in the study. Among them, 38 patients with similar genotypes (IVS 1-5, alpha gene deletion and triplication, Xmn polymorphism) were selected for further analysis. AHSP gene sequencing was done for these 38 samples to study associated mutations in AHSP gene. HbE beta thalassemia patients with similar genotypes but different phenotypic expressions were found to have mutations in the AHSP gene. There were five mutations found most prevalent among the samples analyzed for AHSP gene sequencing. Among these, two mutations were from intron 1 region of AHSP and three mutations were found in exon 3. The most prevalent mutation was found at the Oct binding site at intron 1 of AHSP. The mutations in exon 3 were more prevalent among the TDT groups. A mutation in exon 3 changing the amino acid (33rd) from serine to phenylalanine was found to be associated with only TDT group. This study documents that among the HbE beta thalassemia patients with varying severity, an exon mutation in AHSP is significantly prevalent only among the TDT group. Further understanding of the mechanism will shed light upon the impact of AHSP in modifying the disease severity in thalassemia.

Thalassemias in South Asia: clinical lessons learnt from Bangladesh.

Thalassemias are emerging as a global public health concern. Due to remarkable success in the reduction of childhood mortality by controlling infectious diseases in developing countries, thalassemias are likely to be a major public health concern in the coming decades in South Asia. Despite the fact that Bangladesh lies in the world's thalassemia belt, the information on different aspects (epidemiology, clinical course, mortality, complications and treatment outcomes) of thalassemias is lacking. In this comprehensive review, the aim is to to depict the epidemiological aspects of thalassemias, mutation profile and current treatment and management practices in the country by sharing the experience of dealing with 1178 cases over 2009-2014 time periods in a specialized thalassemia treatment centre. We have also discussed the preventative strategies of thalassemias from the context of Bangladesh which could be effective for other developing countries.