Compound Heterozygous Hemoglobin E-Beta (HbE-β)-Thalassemia Presenting With Chipmunk or Rodent Facies, and a Severe Thalassemia Major Phenotype

Hemoglobin E-beta (HbE-β)-thalassemia is a common compound hemoglobinopathy in South and Southeast Asia and is marked by considerable clinical heterogeneity, ranging from mild anemia to a severe, transfusion-dependent condition resembling β-thalassemia major (β-TM). The severity of disease is largely determined by the nature of the associated β-thalassemia mutation, modifiers of fetal hemoglobin, and access to early diagnosis and regular treatment. Severe skeletal deformities are now uncommon in the era of structured transfusion programs, but continue to be encountered in regions with delayed diagnosis and inadequate care. We report a 20-year-old female from Northeast India who presented with progressive facial disfigurement, dental malocclusion, growth failure, and delayed puberty. She had a history of long-standing anemia treated intermittently with blood transfusions and no prior iron chelation. Clinical examination revealed classical craniofacial abnormalities, including frontal bossing, prominent malar eminences, and marked maxillary hypertrophy, producing the characteristic chipmunk or rodent facies. Radiological evaluation of the skull demonstrated widening of the diploë with a hair-on-end appearance, consistent with chronic marrow hyperplasia and extramedullary hematopoiesis. Molecular analysis confirmed compound heterozygosity for HbE (HBB:c.79G>A) and a severe β-thalassemia splice-site mutation, IVS-I-5 (G>C) (HBB:c.92+5G>C). Despite the HbE-β-thalassemia genotype, the patient exhibited a phenotype indistinguishable from classical β-TM, including severe anemia, stunted growth, primary amenorrhea, and advanced skeletal deformity. This case highlights the severe end of the HbE-β-thalassemia spectrum and underscores that compound heterozygous states may present with a β-TM-like phenotype. Early diagnosis, regular transfusion-chelation therapy, and genotype-phenotype-guided management are essential to prevent irreversible skeletal and endocrine complications.