Resistance to thyroid hormone alpha (RTHα) is a rare, inherited disorder of thyroid hormone action caused by pathogenic variants in the thyroid hormone receptor alpha gene. Unlike resistance to thyroid hormone beta, RTHα typically presents with near-normal thyroid function tests and a non-elevated thyroid-stimulating hormone (TSH), contributing to substantial underdiagnosis. The biochemical hallmark is a low or low-normal free thyroxine (FT4) level with a disproportionately high free triiodothyronine (FT3) level, yielding a reduced FT4:FT3 ratio and often a low or low-normal reverse T3. Clinical features reflect the tissue distribution of TRα1 and include growth retardation, delayed skeletal maturation, constipation, normocytic anemia, neurodevelopmental delay, dyspraxia, and macrocephaly. These closely mimic primary hypothyroidism but occur without TSH elevation. Most pathogenic THRA variants are heterozygous and act through a dominant-negative mechanism, whereby mutant receptors interfere with co-expressed wild-type TRα activity. Frameshift and nonsense variants generally produce more severe phenotypes than missense variants, though considerable variability exists even among individuals carrying identical mutations. Levothyroxine remains the only therapeutic intervention reported, with evidence suggesting that earlier treatment initiation is associated with better neurodevelopmental and growth outcomes, while established skeletal abnormalities show limited reversibility. Standard newborn screening programs typically fail to detect RTHα, contributing to diagnostic delay. This narrative review consolidates current knowledge on the genetic basis, molecular pathophysiology, clinical spectrum, differential diagnosis, and treatment outcomes of RTHα. Its aim is to enhance clinician recognition and guide future research, including expanded screening strategies and genotype-informed treatments.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic fibroinflammatory condition with highly variable pulmonary manifestations that frequently overlaps clinically, radiologically, and metabolically with primary malignancy, granulomatous disease, and vasculitis. Tissue diagnosis with immunohistochemical quantification of IgG4-positive plasma cells remains the diagnostic cornerstone. A 50-year-old male ex-smoker presented with a two-month history of progressive cough, dyspnoea, chest pain, and 8 kg of unintentional weight loss. Examination revealed digital clubbing and bilateral crepitations. Laboratory investigations showed mild normocytic anaemia, leukocytosis with neutrophilic predominance, and a markedly elevated erythrocyte sedimentation rate of 109 mm/h. Serum IgG4 was elevated at 2.23 g/L (reference range <1.35 g/L). Total IgG and comprehensive autoimmune and infectious serology were unremarkable. Positron Emission Tomography-Computed Tomography (PET-CT) demonstrated multiple bilateral pulmonary nodules (some cavitating) with an exceptionally high maximal standardised uptake value (SUVmax 20.1) and mediastinal lymphadenopathy, prompting strong initial suspicion of primary pulmonary malignancy. CT-guided lung biopsy revealed dense storiform fibrosis, a lymphoplasmacytic infiltrate rich in eosinophils, and features of fibroinflammatory change; however, immunohistochemistry did not demonstrate an increased number of IgG4-positive plasma cells, and formal histopathological criteria for IgG4-related disease were not fulfilled. In the context of compatible clinical, radiological, and serological findings, a diagnosis of probable IgG4-related lung disease was considered. Oral prednisolone at 0.6 mg/kg/day produced substantial clinical and radiological improvement, with near-complete resolution of opacities and reduction in nodule size by six months. This case illustrates the diagnostic pitfalls of IgG4-related lung disease, which can produce exceptionally high 18F-fluorodeoxyglucose (FDG) avidity on PET-CT, cavitating nodules, and constitutional features indistinguishable from malignancy. Histopathological evaluation with formal IgG4 cell quantification and ratio calculation is essential for accurate diagnosis; however, cases with supportive clinicoradiological features but non-diagnostic immunostaining may still pose significant diagnostic challenges. Early corticosteroid treatment yields excellent outcomes and prevents unnecessary oncological intervention.

Gastric involvement with Histoplasma capsulatum infection is rare but can mimic peptic ulcers or cancer, delaying diagnosis. A 71-year-old man presented with oral ulcer, abdominal pain, and weight loss. The patient had history of tonsillar histoplasmosis treated 8 years before the current presentation with confirmed resolution. The patient had no history of malignancy, autoimmune diseases, or recent travel. Initial laboratory evaluation revealed normocytic anemia. Imaging did not show acute abnormalities that would account for his symptoms. Esophagogastroduodenoscopy revealed multiple gastric ulcers. Biopsies showed chronic gastritis with ulceration and fungal yeasts consistent with H. capsulatum. Similarly, the oral ulcer showed non-necrotizing granulomas with fungal forms. Itraconazole was initiated and follow-up esophagogastroduodenoscopy showed healing ulcers.

Hereditary elliptocytosis (HE) is a red blood cell (RBC) membrane disorder resulting from a mutation in RBC membrane proteins that predispose the cell to hemolysis. Clinical presentation can range from patients being asymptomatic to hemolysis with splenomegaly and anemia. In this report, we present the case of a 40-year-old female with a history of intermittent normocytic normochromic anemia and chronic left upper abdominal pain with mild splenomegaly. During workup for splenomegaly, she was found to have elliptocytes on her blood smear, leading to a clinical diagnosis of HE. For individuals diagnosed with asymptomatic HE, the management focus should be on counseling about the condition, including education on the complications associated with HE.

Thymic epithelial tumors (TETs) represent the most common primary neoplasms of the anterior mediastinum, yet thymic carcinoma (TC) stands out as an exceptionally rare and biologically aggressive subtype. Unlike thymomas, TCs exhibit marked cytologic atypia, early invasive potential, and a high predisposition for extrathoracic metastasis. We report the case of a 59-year-old male who presented with a seven-month history of progressive, refractory lumbar pain and functional limitation. Initial clinical and laboratory evaluation revealed normocytic anemia, leukocytosis, elevated inflammatory markers, and increased lactate dehydrogenase and beta-2 microglobulin levels. These findings, combined with systemic bone marrow infiltration observed on spinal magnetic resonance imaging, initially suggested a lymphoproliferative disorder. A subsequent thoracic computed tomography scan identified an anterior mediastinal mass with lymphadenopathy. A bone marrow biopsy evidenced infiltration by a poorly differentiated malignant neoplasm, and an immunohistochemical profile of the mediastinal mass confirmed the diagnosis of stage IVb TC, showing positivity for pan-cytokeratin, tumor protein p63, cluster of differentiation 5 (CD5), epithelial membrane antigen (EMA), and cluster of differentiation 117 (CD117), with a Ki-67 proliferation index of 20%, while remaining negative for hematolymphoid, neuroendocrine, and lung-specific markers. The patient was managed through a multidisciplinary approach with systemic palliative chemotherapy. This case highlights a critical diagnostic challenge where TC mimicked a hematological malignancy. The systemic dissemination of TC, particularly the diffuse bone marrow infiltration, is a rare clinical phenotype that obscures the primary mediastinal origin. Our report emphasizes the necessity of including TC in the differential diagnosis of patients presenting with refractory bone pain and systemic hematological abnormalities, even in the absence of respiratory symptoms. Early diagnostic recognition through strategic immunohistochemical profiling is imperative to avoid clinical bias, prevent the initiation of inappropriate therapies, and facilitate a prompt, evidence-based management strategy for patients with advanced, non-resectable disease.

Cold agglutinin disease (CAD) is an uncommon, complement-mediated autoimmune hemolytic anemia that predominantly affects older adults. We report a 93-year-old woman with ischemic heart disease, persistent atrial fibrillation treated with rivaroxaban, major valvular disease, and limited mobility who presented with progressive leg edema, dyspnea, chest pain, fatigue, and profound normocytic anemia. Her hemoglobin was 5.1 g/dL, compared with 9.7 g/dL approximately four months earlier. The initial evaluation focused on possible occult bleeding and cardiac decompensation. By the second day of the acute-care episode, the finalized blood-group confirmation result returned from the regional blood center reportedly noted cold-reactive antibodies, providing an early clue to cold-antibody-mediated hemolysis and redirecting the diagnostic work-up. No overt bleeding was identified, although gastrointestinal assessment remained incomplete. Subsequent hemolysis testing showed a lactate dehydrogenase level of 401 U/L, reticulocytes of 4.78%, and a positive direct antiglobulin test with C3d reactivity. Serum immunofixation identified an immunoglobulin M kappa monoclonal protein. Directed questioning then elicited long-standing cold intolerance, severe pain after cold food or beverages, and cold-triggered limb pain. Because the cold agglutinin titer and thermal amplitude were unavailable, the findings were considered strongly supportive of probable CAD associated with an immunoglobulin M-related clonal process rather than proof of a fully characterized hematologic disorder. Evaluation for an underlying cause was limited by the absence of on-site hematology services, and lymphoma or another marrow-based neoplasm could not be excluded. One packed red-cell unit was completed in the emergency department; a second was stopped when dyspnea developed against a background of marked edema and cardiac disease, and two further units were later given under diuretic cover. With transfusion support, diuresis, cold avoidance, and other supportive care, hemoglobin increased to 9.3 g/dL and cardiopulmonary symptoms improved. By discharge, she was alert and oriented to self and her surroundings and could ambulate with assistance or a walker. At approximately 12 weeks after discharge, she remained clinically stable. After discussion of the expected benefits and burdens, the patient, supported by her family, chose not to pursue invasive hematologic evaluation because its results were unlikely to alter the planned conservative management. This case emphasizes directed inquiry about temperature-related symptoms and careful calibration of diagnostic certainty when formal CAD testing is incomplete.

Congenital dyserythropoietic anemias (CDAs) include a heterogeneous group of conditions characterized by insufficient erythropoiesis giving rise to monolinear cytopenia. Based on the morphological features of erythroblasts, three major subtypes have been established: CDA Type I, CDA Type II, and CDA Type III. CDA Type II is the most common type of CDAs, and this disease is characterized by a normocytic anemia with a normal or slightly increased reticulocyte count. The bone marrow is hypercellular with erythroid hyperplasia and binucleated erythroblasts with two nuclei at the same maturation stage. The inheritance is autosomal recessive, and the disease is caused by biallelic mutations in the SEC28B gene. More than 100 pathogenetic variants have been identified. Here, we report on three patients from Somalia with CDA Type II caused by a new SEC23B sequence variant. They came to attention and were diagnosed in early adulthood. Cases 1 and 2 had mild anemia with signs of hemolysis, and Case 3 had mild anemia with reticulocytosis. The eosin-5-maleimide binding test showed reduced binding in all three patients. Molecular genetics disclosed homozygosity for the sequence variant NM_006363.6:c.1580T > C p.(Leu527Ser) in the SEC23B gene. A bone marrow aspirate was performed from Case 2, and the smear disclosed morphological abnormalities typical for CDA Type II.

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) is an inflammatory syndrome of older adults that has been increasingly associated with underlying malignancy. A 67-year-old woman presented with abrupt-onset symmetrical polyarthritis and marked bilateral pitting oedema. Laboratory investigations showed elevated inflammatory markers and normocytic anaemia, with negative rheumatoid serology. She achieved complete remission with low-dose corticosteroids. Months after steroid withdrawal, inflammatory arthritis recurred alongside worsening anaemia (haemoglobin 7.6 g/dL), leukopenia (white blood cell count 2.5 × 10[9]/L; absolute neutrophil count 0.38 × 10[9]/L), platelet count of 150 × 10[9]/L, and circulating blast cells. Bone marrow biopsy confirmed acute myeloid leukaemia (AML) with 33%-40% blasts. Molecular analysis identified IDH1 and KMT2A mutations. Treatment with azacitidine-venetoclax resulted in complete remission of both haematological disease and rheumatologic manifestations without corticosteroids. RS3PE may represent an early paraneoplastic manifestation of AML. Recurrence of symptoms after steroid withdrawal should prompt evaluation for malignancy. Molecular characterisation may provide additional insight into disease mechanisms and treatment response.