Severe Macrocytic Anemia Associated With a Novel ALAS2 Mutation: A Case Report and Literature Review

X-linked sideroblastic anemia (XLSA), caused by pathogenic variants in ALAS2, typically presents as microcytic anemia in males. However, heterozygous females occasionally exhibit an atypical macrocytic phenotype, often leading to diagnostic ambiguity and confusion with nutritional anemias or myelodysplastic syndromes. This study aims to characterize a novel ALAS2 variant and explore the possible mechanisms underlying macrocytosis in a female patient. We analyzed a 15-year-old female with an 8-year history of refractory macrocytic anemia. Diagnostic evaluations included hematological profiling, iron metabolism studies, and bone marrow examination. Whole-exome sequencing (WES) was employed to identify genetic variants, followed by Sanger validation. Protein structural modeling was performed using AlphaFold 3. The patient presented with severe macrocytic anemia, iron overload, and borderline folate status despite supplementation. WES identified a novel frameshift variant in ALAS2, c.1277dupT (p.M426Ifs*66), which supported the diagnosis of atypical XLSA. Structural modeling suggested that this variant alters the C-terminal region and may affect the conformation of the catalytic site, including the spatial configuration around Lys391, potentially impairing enzymatic function. Additional variants in DHX34, FANCI, and BRIP1 were also identified, although their potential contributions to the phenotype remain uncertain because functional evidence is lacking. In conclusion, we identified a novel, predicted loss-of-function variant in ALAS2 associated with early-onset macrocytic XLSA. Macrocytosis in this case may reflect a proposed "high-turnover" failure involving intramedullary attrition of mutant clones and stress-induced premature maturation of wild-type clones; however, this mechanism remains speculative. Secondary nutrient depletion and additional genetic variants may also contribute, although their roles require further validation. This case underscores the value of genomic sequencing in resolving atypical, refractory anemias in female patients and preventing long-term misdiagnosis.