Bone Marrow Failure Syndromes

BMF Basics - Marrow Meltdown Intro

Bone Marrow Failure (BMF) is a "marrow meltdown": pancytopenia (↓RBCs, ↓WBCs, ↓Platelets) with a hypocellular bone marrow. Hematopoietic stem cells (HSCs) fail to produce mature blood cells.

• Core Problem: Deficient hematopoiesis.
• Mechanisms:
  • Intrinsic HSC defects (genetic mutations)
  • Extrinsic insults (drugs, toxins, viruses, immune destruction)
  • Defective marrow microenvironment (stromal dysfunction)
• Types:
  • Inherited: Fanconi Anemia, Dyskeratosis Congenita, Shwachman-Diamond Syndrome.
  • Acquired: Aplastic Anemia (idiopathic, secondary), Paroxysmal Nocturnal Hemoglobinuria (PNH), Myelodysplastic Syndromes (MDS).
• Key Presentation: Symptoms of cytopenias - fatigue (anemia), recurrent infections (neutropenia), bleeding/petechiae (thrombocytopenia).

⭐ Bone marrow biopsy showing hypocellularity (e.g., <25% cellularity for age, or <50% cellularity with <30% hematopoietic cells) is crucial for BMF diagnosis, distinguishing it from other causes of pancytopenia like hypersplenism or infiltrative disorders where marrow is often hypercellular or normocellular but ineffective (e.g., MDS).

Fanconi & DBA - Genetic Gloomies

Fanconi Anemia (FA)

• Inheritance: Autosomal Recessive (AR); Patho: Defective DNA repair.
• Onset: Age 5-10 yrs with progressive pancytopenia.
• Anomalies (~75%): Skeletal (thumb/radial defects, short stature), skin (café-au-lait, pigmentary changes), renal.
• Diagnosis: ↑ AFP, ↑ HbF. Chromosomal breakage test (DEB/MMC) is diagnostic.
• Malignancy risk: ↑ AML, MDS, solid tumors (e.g., SCC).
• Management: HSCT (curative), androgens, G-CSF. 📌 FANconi: Failure (pancytopenia), Anomalies, Neoplasia.

Diamond-Blackfan Anemia (DBA)

• Inheritance: Autosomal Dominant (AD, RPS19 gene); Patho: Ribosomopathy.
• Onset: Infancy (<1 yr) with Pure Red Cell Aplasia (PRCA); macrocytic anemia.
• Anomalies (~50%): Craniofacial (Cathie facies), triphalangeal thumbs, cardiac defects.
• Diagnosis: ↑ MCV, reticulocytopenia, normal WBC/platelets, ↑ HbF. BM: Erythroid hypoplasia.

  ⭐ Elevated erythrocyte adenosine deaminase (eADA) activity is a key diagnostic marker.

• Management: Corticosteroids (1st line), transfusions, HSCT.

​

SDS, DC & Acquired AA - More Marrow Mayhem

• Shwachman-Diamond Syndrome (SDS)

  • Exocrine pancreatic insufficiency (steatorrhea, FTT)
  • Neutropenia (often cyclical), skeletal abnormalities (metaphyseal chondrodysplasia, short stature)
  • SBDS gene mutation; ↑ Risk of MDS/AML

• Dyskeratosis Congenita (DC)

  • Classic triad: Reticular skin hyperpigmentation, nail dystrophy, oral leukoplakia
  • Defective telomere maintenance (e.g., DKC1, TERC, TERT genes)
  • BMF, MDS/AML, solid tumors (SCC), pulmonary fibrosis

• Acquired Aplastic Anemia (AA)

  • Pancytopenia + hypocellular bone marrow (<25% cellularity, or <50% if <30% hematopoietic cells)
  • Etiology: Idiopathic (~70%, immune-mediated), drugs (chloramphenicol), toxins (benzene), viruses (hepatitis)
  • Severe AA (SAA): BM criteria + ≥2 of:
    • ANC < 0.5 x 10⁹/L
    • Platelets < 20 x 10⁹/L
    • Reticulocytes < 1%
  • Very Severe AA (VSAA): SAA criteria + ANC < 0.2 x 10⁹/L
  • Treatment: Immunosuppression (IST: ATG + cyclosporine), HSCT

⭐ PNH clones in many AA patients predict IST response.

BMF Workup & Fixes - Lab Sleuths & Cures

• Diagnosis:
  • CBC (pancytopenia), ↓reticulocytes, peripheral smear.
  • Bone Marrow Aspiration & Biopsy: Key! Shows hypocellularity (<25%), dysplasia; cytogenetics (e.g., monosomy 7); rules out infiltration.
• Etiology Tests:
  • Fanconi: DEB/MMC stress test.
  • PNH: Flow cytometry (CD55/CD59).
  • Dyskeratosis Congenita: Telomere length.
• Management:
  • Supportive: Irradiated transfusions, antibiotics, iron chelation.
  • Definitive:
    • Acquired AA: IST (ATG+Cyclosporine) or HSCT (1st line for severe/young with donor).
    • Inherited BMF: HSCT is curative.
    • Refractory AA: Eltrombopag.

⭐ Severe AA: Marrow <25% cells (or <50% if <30% hematopoietic) AND ≥2 of: ANC <0.5x10⁹/L, Plt <20x10⁹/L, Retics <1% (corrected).

High‑Yield Points - ⚡ Biggest Takeaways

• Fanconi Anemia: AR, DNA repair defect; pancytopenia, café-au-lait spots, thumb/radial defects; ↑ AML/MDS risk.
• Diamond-Blackfan Anemia: AD (mostly), ribosomal protein defect; pure red cell aplasia, craniofacial/thumb defects.
• Shwachman-Diamond Syndrome: AR, SBDS gene; neutropenia, pancreatic insufficiency, skeletal issues; ↑ MDS/AML risk.
• Dyskeratosis Congenita: Telomere defect; triad: skin pigmentation, nail dystrophy, oral leukoplakia; pancytopenia.
• Severe Congenital Neutropenia: ELANE gene common; severe neutropenia (<200/µL), infections; ↑ MDS/AML risk.