The concurrent occurrence of BCR::ABL1 rearrangement and JAK2 V617F mutation is an exceptionally rare phenomenon, with reported frequencies of 0.2%-2.5% in tested myeloproliferative neoplasm (MPN) cohorts and an estimated overall rate of approximately 0.4% in patients screened for both alterations. These molecular drivers are generally considered mutually exclusive, as BCR::ABL1 defines Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), while JAK2 V617F characterizes Ph-negative MPNs. We report a male patient in his 50s with a previously detected JAK2 V617F mutation, initially managed as essential thrombocythemia, who later presented with leukocytosis, macrocytic anemia, thrombocytopenia, and absolute monocytosis. Bone marrow demonstrated marked myeloid hyperplasia with atypical megakaryocytes, comprising scattered dwarf forms together with larger forms with "cloud-like" nuclei and focal reticulin fibrosis (MF-1). These findings, together with the known JAK2 V617F mutation, prompted targeted molecular investigation. High-sensitivity RT-PCR confirmed an isolated e1a2 (p190) BCR::ABL1 transcript, the minor breakpoint cluster region isoform occurring in only 1%-2% of CML cases, with the complete absence of the p210 isoform, alongside a concurrent JAK2 V617F mutation (allele burden 16%). Standard p210-focused quantitative assays would have produced a false-negative result in this case. The patient received first-line asciminib and was subsequently transitioned to dasatinib, with the BCR::ABL1/ABL1 ratio declining from 88.5% at diagnosis to 0.79% at most recent assessment. This case highlights the critical importance of integrated morphologic, cytogenetic, and molecular evaluation in atypical MPN presentations. The admixed megakaryocytic atypia superimposed on myeloid hyperplasia reflected the coexistence of two drivers. Comprehensive profiling, including high-sensitivity RT-PCR capable of detecting the p190 isoform and concurrent JAK2 testing, is essential for accurate diagnosis, prognostication, and therapy selection in these rare dual-driver cases.

Neurofibromatosis type 1 (NF1) is a multisystem disorder, but its hematological features remain incompletely characterized. We investigated whether erythrocyte-related indices show coordinated alterations in adults with NF1. In this retrospective single-institute study, 225 adults with NF1 were analyzed. Z-scores for erythrocyte-related parameters were calculated relative to a reference population. One-sample tests, correlation analyses, and comparisons across tumor burden (D-class) were performed. A composite score, defined as the mean of parameter-specific Z-scores, was used to assess coordinated changes. Z-scores for red blood cell count, hemoglobin, hematocrit, and mean corpuscular volume were modest but significantly increased, whereas mean corpuscular hemoglobin concentration shifted in the opposite direction. Individual effect sizes were small; however, the composite score showed a moderate effect size (Cohen's d = 0.43), indicating a coherent directional shift. Mean corpuscular volume was inversely correlated with red blood cell count (r = -0.390, P < .001), and a higher tumor burden was associated with lower mean corpuscular hemoglobin concentration. Adult patients with NF1 exhibit subtle but coordinated erythrocyte alterations, suggesting a macrocytic and relatively hypochromic profile, with erythrocyte hemoglobin concentration tending to decrease with increasing tumor burden. These findings may represent a systemic feature of NF1 and warrant further investigation.

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.

VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an adult-onset autoinflammatory disorder caused by somatic UBA1 mutations linking systemic inflammation with haematologic dysfunction. We report a 59-year-old man presenting with fatigue, fevers, and severe macrocytic anaemia (haemoglobin 8.1 g/dL, MCV >120 fL), mild thrombocytopenia, and markedly elevated inflammatory markers. Autoimmune and malignancy workup was negative. Bone marrow biopsy showed hypercellularity with multilineage dysplasia and cytoplasmic vacuolisation, and genetic testing confirmed a somatic UBA1 mutation. High-dose glucocorticoids led to rapid resolution of inflammatory manifestations and normalisation of inflammatory markers; however, cytopenias progressed despite erythropoiesis-stimulating agents and ruxolitinib, with haemoglobin declining to <7 g/dL, resulting in transfusion dependence. The patient is undergoing evaluation for allogeneic haematopoietic stem cell transplantation (HSCT). This case highlights VEXAS syndrome as an aggressive haematoinflammatory disorder with limited responsiveness to conventional and targeted therapies and emphasises early consideration of advanced strategies, including HSCT, in selected patients.

Classic hairy cell leukemia (HCL) is a rare, indolent B-cell lymphoproliferative disorder characterized by bone marrow fibrosis causing pancytopenia, splenomegaly, and a near-universal BRAF V600E mutation. Purine nucleoside analogs (PNAs) are the standard first-line therapy but are contraindicated in patients with significantly advanced chronic kidney disease (CKD) or end-stage renal disease (ESRD) due to renal excretion and risk of prolonged myelosuppression. Data on the use of targeted therapies, such as BRAF inhibitors, in dialysis-dependent HCL patients are lacking.

Telomere biology disorders (TBDs) are inherited conditions that can present in adulthood with pancytopenia and liver disease. We describe a case of a 45-year-old man with a high body mass index (BMI), long-standing macrocytic pancytopenia, and biopsy-proven steatohepatitis who was found to have markedly short telomeres and a heterozygous telomerase reverse transcriptase (TERT)variant. The patient had a clear hematologic response to danazol but developed progressive cirrhosis with portal hypertension, ultimately requiring orthotopic liver transplantation with sleeve gastrectomy; after transplant, liver chemistries normalized, but cytopenias recurred under tacrolimus-based immunosuppression. This case highlights the need to consider TBDs in adults with unexplained macrocytic cytopenias and progressive liver disease, and to recognize that liver transplantation corrects hepatic failure but not the underlying bone marrow disorder.

Congenital dyserythropoietic anemia is a group of hereditary disorders characterized by erythroid hyperplasia and ineffective erythropoiesis, resulting in anemia of varying severity. Congenital dyserythropoietic anemia Type 1 (CDA-1) is classically associated with biallelic mutations in the CDAN1 gene. Here, we report the first case of compound heterozygous CDAN1 mutations p.(D1043V) and p.(S1036F) in clinical practice, presenting in a 24-year-old woman with mild, asymptomatic macrocytic anemia and hyperferritinemia. These variants are currently classified as variants of uncertain significance; however, this report represents the first clinical case of this compound heterozygous CDAN1 variant combination in a patient with a phenotype consistent with CDA-1. As the phenotypic boundaries of CDA-1 continue to expand, clinicians should consider CDA-1 in the differential diagnosis of unexplained macrocytic anemia, even in the absence of severe anemia.

In complex neurodevelopmental disorders such as Lennox-Gastaut syndrome (LGS), treatable metabolic comorbidities may be masked by the severity of the primary phenotype. We report an 8-year-old boy with LGS and bilateral polymicrogyria whose underlying Imerslund-Gräsbeck syndrome was unmasked following a palliative Gamma Knife corpus callosotomy. Although the patient underwent Gamma Knife corpus callosotomy, his seizures remained uncontrolled. Consequently, vagus nerve stimulator implantation was planned; however, severe anemia (hemoglobin: 3.3 g/dL) was detected on admission for the procedure. Initially, the hematologic abnormalities were attributed to polypharmacy, prompting a dose reduction in antiepileptic medications. A concurrent anemia workup revealed vitamin B12 deficiency, and intramuscular B12 replacement therapy was initiated. However, because the macrocytic anemia was unexpectedly severe and other hematopoietic lineages remained unaffected, advanced investigations were performed. Genetic analysis revealed compound heterozygous missense variants in the CUBN gene. Following parenteral vitamin B12 replacement, the patient achieved not only hematologic recovery but also a remarkable reduction in seizure frequency over the subsequent 9 months. This case illustrates diagnostic overshadowing and underscores the necessity of considering comprehensive genetic and metabolic testing in refractory epilepsy, as addressing a metabolic second hit can significantly optimize neurologic outcomes.

Megaloblastic anemia, characterized by macrocytic anemia, is most commonly caused by nutritional vitamin B12 deficiency; however, inherited disorders of cobalamin absorption should be considered in children with adequate dietary intake. One such disorder is Imerslund-Gräsbeck syndrome (IGS), a rare autosomal recessive condition characterized by selective intestinal malabsorption of vitamin B12 due to mutations in the CUBN or AMN genes. We report a 7-year-old boy, born of a third-degree consanguineous marriage, who presented with generalized rash, easy fatigability, and recurrent oral ulceration. Examination revealed pallor and hyperpigmented knuckles without organomegaly. Growth parameters were between the 10th and 25th centiles. Investigations showed severe macrocytic anemia (hemoglobin 2.5 g/dL), leukopenia, thrombocytopenia, markedly reduced vitamin B12 levels (<50 pg./mL), and peripheral smear findings of macrocytosis with hypersegmented neutrophils. In view of adequate nutritional intake, further evaluation for malabsorption was undertaken. There was no clinical evidence of gastrointestinal malabsorption, and anti-intrinsic factor antibody testing was negative. Urinalysis demonstrated mild proteinuria. Genetic analysis identified a homozygous mutation in the AMN gene, confirming the diagnosis of IGS. The child started on parenteral vitamin B12 therapy with plans for lifelong supplementation at intervals guided by clinical response. IGS should be suspected in children with megaloblastic anemia despite adequate dietary intake, particularly in the presence of proteinuria, parental consanguinity, or a poor response to oral supplementation. Early diagnosis and timely initiation of lifelong vitamin B12 therapy are essential to ensure optimal hematological recovery, growth, and neurodevelopmental outcomes.

This article details the diagnosis and treatment of an elderly male patient with VEXAS syndrome who came with fatigue and fever.The patient thereafter developed several clinical manifestations，including macrocytic anemia，tracheal and bronchial wall thickening，polyarthritis，rashes，and elevated levels of inflammatory markers.The final clue for subsequent genetic testing came from the bone marrow smear，which showed vacuolar degeneration in the cytoplasm of immature granulocytes.The UBA1 gene testing showed the mutation c.121A>C （p.Met41Val），which confirmed the diagnosis of VEXAS syndrome.Following glucocorticoid therapy，the patient's clinical conditions were significantly ameliorated.However，the patient's recurrence of fever and anemia months after discontinuing glucocorticoid medication was consistent with the repeated relapses described in VEXAS syndrome.The whole diagnostic process for the patient suggests that in clinical settings，thorough integration of clinical clues is crucial for making an appropriate diagnosis.To accomplish precision therapy，clinicians must retain an open mind and actively participate in multidisciplinary collaboration.