Bone marrow failure syndromes

Bone marrow failure syndromes

Bone marrow failure syndromes

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Aplastic Anemia - Empty Marrow Misery

  • Pathogenesis: Autoimmune T-cell destruction of multipotent hematopoietic stem cells → pancytopenia with a hypocellular, fatty marrow ("empty marrow").
  • Etiologies: Idiopathic (~70%), drugs (chloramphenicol, carbamazepine, NSAIDs), toxins (benzene), viral (Hepatitis, Parvovirus B19, EBV), radiation.
  • Clinical & Labs: Pancytopenia symptoms (fatigue, infections, bleeding). ↓ Reticulocytes, ↑ EPO. No hepatosplenomegaly.
  • Diagnosis: Gold standard is bone marrow biopsy → hypocellular marrow (<25%) replaced by fat.

Aplastic Anemia Bone Marrow Biopsy: Hypocellularity & Fat

  • Treatment: Supportive care (transfusions). Definitive: Allogeneic HSCT for young (<50 yrs), immunosuppression (ATG, cyclosporine) for older/unfit.

⭐ Up to 50% of aplastic anemia patients may have a co-existing Paroxysmal Nocturnal Hemoglobinuria (PNH) clone, detectable by flow cytometry for CD55/CD59.

PNH - Defective Anchor Drama

  • Acquired somatic mutation in the PIGA gene of a hematopoietic stem cell, leading to an inability to synthesize glycosylphosphatidylinositol (GPI) anchors.
  • Cells lack GPI-anchored proteins like CD55 (Decay Accelerating Factor) & CD59 (MAC Inhibitory Protein), making them susceptible to complement-mediated destruction.
  • Classic Triad: Intravascular hemolysis (dark urine, esp. in AM), pancytopenia, and venous thrombosis (often in atypical sites).
  • Diagnosis: Flow cytometry showing absent CD55/CD59 on RBCs and granulocytes.

⭐ A major cause of mortality in PNH is thrombosis, particularly in unusual locations like hepatic (Budd-Chiari syndrome), portal, or cerebral veins.

  • Treatment: C5 inhibitors (Eculizumab, Ravulizumab).

PNH flow cytometry: CD55/CD59 negative granulocytes

Myelodysplastic Syndromes - Dysfunctional Factory

Clonal hematopoietic stem cell disorders with ineffective hematopoiesis, leading to peripheral cytopenias despite a hypercellular bone marrow. It's a "factory" producing faulty cells.

  • Hallmark: Dysplasia in ≥1 cell line.
    • Myeloid: Pseudo-Pelger-Huët cells (bilobed neutrophils).
    • Erythroid: Ring sideroblasts.
    • Megakaryocytic: Small, separated nuclei (pawn-ball megakaryocytes).
  • Diagnosis: Bone marrow biopsy shows hypercellularity, dysplasia, and < 20% blasts.
  • Risk: Transformation to AML (defined by ≥ 20% blasts).

Pseudo-Pelger-Huët anomaly in myelodysplastic syndrome

5q- Syndrome: A specific MDS subtype, often in older women, with macrocytic anemia, normal/↑ platelets, and a favorable prognosis.

Inherited Syndromes - Faulty Blueprints

  • Fanconi Anemia (FA)

    • Defect in DNA crosslink repair (e.g., BRCA genes).
    • Presents with progressive pancytopenia, macrocytic anemia.
    • Associated with café-au-lait spots, short stature, and thumb/radial defects.
    • ↑ risk of AML, MDS, and solid tumors.

    ⭐ Chromosomal breakage analysis after exposure to DNA cross-linking agents (e.g., diepoxybutane) is diagnostic.

  • Diamond-Blackfan Anemia (DBA)

    • Congenital pure red cell aplasia due to ribosomal protein gene mutations.
    • Presents in infancy with macrocytic anemia, reticulocytopenia.
    • Craniofacial and thumb abnormalities (triphalangeal thumb).
  • Dyskeratosis Congenita (DC)

    • Defective telomere maintenance (TERC, TERT genes).
    • Classic triad: abnormal skin pigmentation, nail dystrophy, oral leukoplakia.
    • 📌 Mnemonic: CAN of worms: Cancer, Aplastic anemia, Nail/skin changes.

Fanconi Anemia: Thumb and Radial Defects

High‑Yield Points - ⚡ Biggest Takeaways

  • Aplastic anemia presents with pancytopenia and a hypocellular bone marrow; key causes include drugs, viruses, and autoimmune damage.
  • Fanconi anemia (AR) combines pancytopenia with café-au-lait spots and thumb/radial defects; diagnosed by chromosomal breakage tests.
  • Diamond-Blackfan anemia is a congenital pure red cell aplasia with macrocytic anemia, low reticulocytes, and physical anomalies.
  • PNH (PIGA mutation) causes hemolysis, thrombosis, and pancytopenia from CD55/CD59 deficiency.
  • Myelodysplastic syndromes (MDS) feature cytopenias despite a hypercellular marrow; carries a high risk of AML transformation.

Practice Questions: Bone marrow failure syndromes

Test your understanding with these related questions

An 11-year-old boy presents to your clinic after 4 months of pain and swelling in his thigh. His mother states that at first she thought his condition was due to roughhousing, but it hasn’t gone away and now she’s concerned. You perform an X-ray that shows an ‘onion skin’ appearance on the diaphysis of the femur. You are concerned about a malignancy, so you perform a PET scan that reveals lung nodules. Which of the following is most associated with this disease?

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Flashcards: Bone marrow failure syndromes

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_____ disorders are neoplastic proliferations of mature cells of myeloid lineage

TAP TO REVEAL ANSWER

_____ disorders are neoplastic proliferations of mature cells of myeloid lineage

Myeloproliferative

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