Fanconi Anemia (FA)
Category: Inherited bone marrow failure syndrome (IBMFS)
Inheritance: Autosomal recessive (rarely X-linked)
Gene defects: >22 genes identified (FANCA, FANCC, FANCG most common) → defective DNA interstrand crosslink repair.
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| fanconi anemia notes |
1. Pathophysiology
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Defect in DNA repair (Fanconi/BRCA pathway) → chromosomal breakage and hypersensitivity to DNA cross-linking agents (e.g., mitomycin C, diepoxybutane).
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Progressive bone marrow failure (due to stem cell depletion) and genomic instability → predisposition to malignancies.
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Multisystem developmental abnormalities due to impaired cell proliferation during embryogenesis.
2. Epidemiology
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Incidence: ~1 in 100,000–250,000 live births.
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Carrier frequency: ~1 in 200.
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Median age of diagnosis: 7–9 years.
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~90% develop marrow failure by age 40.
3. Clinical Features
A. Hematologic
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Pancytopenia (usually first manifests with thrombocytopenia or macrocytic anemia).
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Progressive bone marrow hypoplasia.
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Increased fetal hemoglobin (HbF).
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Myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) risk ↑ markedly.
B. Physical anomalies (present in ~75%)
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Growth: Short stature, low birth weight.
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Skeletal: Radial ray defects—absent/hypoplastic thumb, radius anomalies.
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Skin: Café-au-lait spots, hypopigmentation, hyperpigmentation.
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Head/Face: Microcephaly, triangular face, microphthalmia.
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Genitourinary: Renal agenesis, horseshoe kidney, hypoplastic gonads, undescended testes, infertility.
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Cardiac: Structural heart defects.
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ENT: Hearing loss.
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GI: Duodenal atresia, anal anomalies (occasionally).
C. Endocrine/Metabolic
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Hypothyroidism, glucose intolerance, gonadal failure, low IGF-1.
D. Malignancy risk
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AML, MDS, and solid tumors (esp. head & neck SCC, gynecologic SCC, liver tumors) due to chromosomal instability.
4. Investigations
| Test | Finding/Use |
|---|---|
| CBC | Pancytopenia, macrocytosis, increased HbF |
| Bone marrow biopsy | Hypocellular marrow with fatty replacement |
| Chromosomal breakage test | Diagnostic — increased breaks after exposure to diepoxybutane (DEB) or mitomycin C |
| Molecular genetic testing | Confirms FANCA–FANC gene mutations |
| Flow cytometry for CD34 | Decreased hematopoietic stem cells |
| Ultrasound abdomen | Renal anomalies |
| Endocrine profile | Hypothyroidism, gonadal failure screening |
5. Differential Diagnosis
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Acquired aplastic anemia
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Dyskeratosis congenita
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Shwachman-Diamond syndrome
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Diamond–Blackfan anemia
6. Management
Supportive
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Regular CBC monitoring.
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Transfusion support (RBCs, platelets) — minimize iron overload.
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Iron chelation therapy if ferritin ↑.
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Androgens (e.g., oxymetholone, danazol) → stimulate erythropoiesis (transient benefit).
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G-CSF for neutropenia (short-term).
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Avoid DNA-damaging agents (chemotherapy, radiation).
Curative
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Allogeneic hematopoietic stem cell transplantation (HSCT) — only curative therapy for marrow failure.
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Ideal: HLA-matched sibling donor.
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Conditioning regimens: low-intensity to minimize toxicity (avoid alkylators, irradiation).
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Malignancy surveillance
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Annual oral, gynecologic, and dermatologic exams.
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CBC every 3–6 months.
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Avoid smoking, alcohol, and UV exposure.
Endocrine and developmental care
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Hormonal replacement as indicated (thyroid, sex steroids, GH).
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Orthopedic/surgical correction for congenital anomalies.
7. Prognosis
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Median survival (without HSCT): ~20–30 years.
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With HSCT: markedly improved, though risk of secondary malignancy persists.
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Lifelong surveillance for cancer and organ dysfunction required.
8. Key Points for Exams
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Classic triad: Bone marrow failure + congenital anomalies + cancer predisposition.
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Diagnostic hallmark: Chromosomal breakage test positive with DEB/Mitomycin C.
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Curative therapy: HSCT.
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Common mutation: FANCA.
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AML/MDS risk: markedly increased.
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Androgens improve counts transiently but cause virilization/hepatotoxicity.
