Fanconi Anemia (FA) is a rare inherited bone marrow failure syndrome characterized by progressive pancytopenia, congenital anomalies, and cancer predisposition. It is most commonly inherited in an autosomal recessive pattern, although X-linked forms exist.

The underlying defect involves impaired DNA interstrand cross-link repair, leading to chromosomal instability, cellular apoptosis, and hematopoietic stem cell depletion.

FA is associated with:

• Bone marrow failure

• Congenital malformations

• Increased risk of acute myeloid leukemia (AML)

• Increased risk of solid tumors (especially head, neck, and gynecologic cancers)

Without treatment, severe aplastic anemia carries a poor prognosis.

Genetics and Pathophysiology

• Caused by mutations in ≥22 FANC genes (FANCA–FANCW)

• Most common mutations: FANCA, FANCC, FANCG

• Defective DNA repair → chromosomal breakage

• Hypocellular bone marrow → progressive pancytopenia

Risk Factors

• Consanguinity

• Positive family history

• Sibling with bone marrow failure

• Known carrier parents

Clinical Presentation

Symptoms typically appear between ages 4–10 years.

A. Hematologic Manifestations

• Fatigue

• Pallor

• Dyspnea on exertion

• Recurrent infections (neutropenia)

• Bleeding tendencies (thrombocytopenia)

B. Congenital Abnormalities

• Short stature

• Radial ray defects (absent/dysplastic thumbs or radii)

• Microcephaly

• Café-au-lait spots

• Abnormal skin pigmentation

• Hypogonadism

• Renal anomalies

• Hearing impairment

C. Long-Term Complications

• Severe aplastic anemia

• Myelodysplastic syndrome (MDS)

• Acute myeloid leukemia (AML)

• Solid tumors (head & neck, esophageal, gynecologic)

Diagnostic Criteria

Diagnosis is based on:

1. Clinical suspicion (congenital anomalies + cytopenia)

2. Laboratory evidence of bone marrow failure

3. Confirmatory chromosomal breakage testing

Investigations

A. Laboratory Tests

• Complete blood count (pancytopenia)

• Reticulocyte count (low)

• Bone marrow biopsy (hypocellular marrow)

B. Diagnostic Confirmation

• Chromosomal breakage test using diepoxybutane (DEB) or mitomycin C

• Genetic testing for FANC gene mutations

C. Additional Workup

• Renal ultrasound

• Audiology assessment

• Endocrine evaluation

• Cancer surveillance screening

Management

Management requires multidisciplinary care and referral to a tertiary hematology center.

A. Supportive (Non-Pharmacological) Management

• Irradiated, leukodepleted red blood cell transfusion when Hb <7 g/dL

• Single-donor platelet transfusion if bleeding

• Broad-spectrum antibiotics for infections

• Neutropenic precautions (mask use, isolation if necessary)

• Avoid radiation and DNA-damaging agents

B. Definitive Treatment

1. Hematopoietic Stem Cell Transplantation (HSCT)

• Only curative therapy for bone marrow failure

• Recommended for severe disease

• Best outcomes in patients <45 years

• Prefer HLA-matched sibling donor

C. Pharmacological Therapy

1. Immunosuppressive Therapy (if HSCT unavailable)

• Anti-thymocyte globulin (ATG)

  • 40 mg/kg/day IV for 4 daysOR

  • 10–20 mg/kg/day IV for 8–14 days

• Cyclosporine

  • 3–7 mg/kg/day for 4–6 months

• Methylprednisolone

  • 5–10 mg/kg/day for 3–14 days

2. Androgen Therapy

• Danazol 5 mg/kg/day for up to 6 months

• May improve blood counts temporarily

3. Other Options (Selected Cases)

• Cyclophosphamide 45 mg/kg/day for 4 days

• Growth factors (G-CSF in severe neutropenia)

Complications

• Severe aplastic anemia

• Leukemia (AML)

• Myelodysplastic syndrome

• Solid tumors

• Endocrine disorders

• Infertility

Prognosis

• Median survival without treatment is limited

• HSCT significantly improves survival

• Lifelong cancer surveillance required

Prevention & Counseling

• Genetic counseling for affected families

• Carrier testing

• Prenatal diagnosis (chorionic villus sampling)

• Avoid exposure to DNA-damaging agents

• Regular cancer screening

Referral

All suspected or confirmed cases must be referred to a tertiary hospital with:

• Hematology services

• Genetic testing

• Stem cell transplantation capability