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.

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.

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.

Megaloblastic anemia may present with biochemical features suggestive of hemolysis, creating diagnostic uncertainty. We describe two middle-aged women who presented with severe symptomatic macrocytic anemia, markedly elevated lactate dehydrogenase (LDH), undetectable haptoglobin, and low reticulocyte counts. Further investigation confirmed a combined vitamin B12 and folate deficiency. No definitive underlying cause was identified, although long-term proton pump inhibitor (PPI) use was considered a potential contributing factor to vitamin B12 deficiency. Both patients were treated with vitamin replacement therapy and discontinuation of PPI therapy, resulting in rapid clinical and hematological improvement. These cases highlight that combined vitamin B12 and folate deficiency may mimic hemolytic anemia and that the combination of elevated LDH, low haptoglobin, and a low reticulocyte count should raise suspicion of ineffective erythropoiesis rather than true hemolysis.

Pernicious anemia (PA) is an autoimmune-mediated vitamin B12 deficiency that classically presents with macrocytic anemia and neurologic dysfunction. The case described highlights a rare variant of PA that paralleled concerns for microangiopathic hemolytic anemia (MAHA) like thrombotic thrombocytopenic purpura (TTP). A 40-year-old African American female with limited past medical history presented with progressive fatigue, lower-extremity weakness, gait instability, and ataxia, accompanied by chronic gastrointestinal symptoms, weight loss, and menorrhagia. Initial evaluation revealed profound macrocytosis, pancytopenia, laboratory evidence of hemolysis, including an elevated lactate dehydrogenase (LDH) and undetectable haptoglobin level without evidence of acute kidney injury (AKI), and neurologic deficits concerning for subacute combined degeneration. This case was complicated by right lower lobe pneumonia, urinary tract infection, and a left Bartholin cyst. Further testing demonstrated elevated methylmalonic acid and homocysteine levels, positive intrinsic factor (IF) antibodies, and only mildly reduced ADAMTS13 activity, which confirmed the diagnosis of PA. The patient was treated with parenteral vitamin B12, folate, and supportive care, resulting in gradual recovery. Although inpatient rehabilitation was recommended, the patient declined and was instead discharged home with arrangements for outpatient follow-up and lifelong intramuscular vitamin B12 replacement therapy. This case underscores the importance of recognizing that, in rare cases, PA can present as a mimicker of thrombotic microangiopathies such as TTP, as early identification can prevent unnecessary therapeutic intervention, reduce morbidity, and facilitate timely, disease-specific therapy.

Transcobalamin deficiency is an autosomal recessive disease caused by pathogenic variants in the TCN2 gene. It is a multisystem disorder, with haematological manifestations such as megaloblastic anaemia and pancytopenia. Neurological manifestations include ataxia, hypotonia and neuropathy. Gastrointestinal and immunological clinical presentations include diarrhoea, cytomegalovirus (CMV) colitis, failure to thrive and recurrent infections.We report a female toddler who initially presented at early infancy with severe failure to thrive, diarrhoea, CMV colitis and pancytopenia and was initially diagnosed with childhood myelodysplastic syndrome based on bone marrow examination and a strong family history in her cousins. Whole exome sequencing revealed a homozygous pathogenic variant, c.927_930del (p.(Cys309Trpfs*50)), in the TCN2, consistent with a diagnosis of autosomal recessive transcobalamin deficiency. Treatment with parenteral hydroxocobalamin resulted in dramatic improvement in her symptoms and resolved the myelodysplastic changes.

Osmotic demyelination syndrome (ODS) is a rare neurological disorder typically associated with rapid correction of hyponatremia, whereas alcohol-related peripheral neuropathy (ALN) is a common complication of chronic alcohol use. The coexistence of ODS and ALN is uncommon and may obscure timely diagnosis. We report the case of a 51-year-old man with a long-standing history of alcohol dependence who presented to the emergency department with vomiting and diarrhea persisting for six days. Laboratory tests revealed hyponatremia, macrocytic anemia, thrombocytopenia, and electrolyte imbalances. Neurological examination demonstrated distal paresthesia, diminished reflexes in the lower extremities, and positive Babinski and Chaddock signs. MRI revealed a hyperintense trident-shaped lesion in the pons consistent with ODS. These findings suggested the concomitant presence of ALN and ODS. The patient was treated conservatively with vitamin supplementation, careful correction of electrolytes, and gradual nutritional rehabilitation. Sodium levels normalized without the need for rapid correction, and the patient's symptoms improved, leading to discharge on the eighth hospital day. This case underscores two essential points: ODS was identified before any documented rapid in-hospital correction of hyponatraemia, and alcohol-dependent patients may present with overlapping features of ALN and ODS. Recognition of pyramidal signs is critical for differentiating central from peripheral neurological complications in this population. Clinicians should maintain a high index of suspicion for concomitant ODS in alcohol-dependent patients with neuropathy, particularly when pyramidal signs are present.