What are the clinical presentation and management of Fanconi anemia?

Fanconi Anemia: Clinical Presentation and Management

Fanconi anemia is a rare autosomal recessive syndrome characterized by chromosomal instability, bone marrow failure, congenital anomalies, and high predisposition to various cancers, particularly leukemia and head and neck squamous cell carcinomas. 1

Clinical Presentation

Patients with Fanconi anemia typically present with:

Physical Manifestations

• Congenital anomalies (present in most but not all patients):
  • Short stature
  • Abnormal thumbs (hypoplastic or absent)
  • Café au lait spots
  • Other skeletal abnormalities
  • Microcephaly
  • Developmental delays 1

Hematologic Manifestations

• Bone marrow failure (typically presenting in childhood)
  • Progressive cytopenias (anemia, thrombocytopenia, neutropenia)
  • Macrocytosis often precedes other cytopenias
  • Aplastic anemia 1, 2

Laboratory Findings

• Chromosomal breakage test: Hypersensitivity to DNA cross-linking agents (e.g., mitomycin C) - diagnostic hallmark
• Elevated fetal hemoglobin
• Macrocytosis
• Pancytopenia 1, 3

Cancer Predisposition

Fanconi anemia patients have markedly increased cancer risks:

• Hematologic malignancies:

  • Acute myeloid leukemia (AML) - most common, accounting for >80% of leukemias
  • Myelodysplastic syndrome (MDS)
  • Risk varies by genetic subtype (FANCD1/BRCA2 has 80% cumulative leukemia risk by age 10) 1, 2

• Solid tumors:

  • Head and neck squamous cell carcinomas (600-fold increased risk)
  • Cancers of vulva, cervix, esophagus, liver, and brain 1, 2, 4

Genetic Basis

• Caused by biallelic mutations in at least 22 genes (FANCA through FANCX) involved in DNA damage repair
• Most common subtype is FANCA (60-65% of cases)
• FANCD1/BRCA2 subtype has the most severe phenotype with earliest cancer onset
• All Fanconi anemia proteins cooperate with BRCA1/BRCA2 in the "Fanconi anemia-BRCA pathway" for DNA repair 1, 5

Management

Diagnosis

• Chromosomal breakage test using peripheral blood lymphocytes exposed to DNA cross-linking agents
• Genetic testing: Multiplex ligation-dependent probe amplification (MLPA) and PCR-based Sanger sequencing or next-generation sequencing to identify specific mutations 3

Surveillance and Monitoring

• Regular hematologic monitoring with complete blood counts
• Annual bone marrow evaluation to detect early signs of MDS or leukemia
• Proactive monitoring for clonal evolution 1

Treatment Options

• Hematopoietic stem cell transplantation (HSCT):

  • Curative for bone marrow failure, MDS, and leukemia
  • Consideration of preemptive transplant in some cases
  • Requires modified conditioning regimens due to DNA repair defects 1, 2

• Supportive care:

  • Androgen therapy may be tried for bone marrow failure
  • Transfusion support
  • Infection prevention 6

Cancer Surveillance

• Regular screening for solid tumors, particularly head and neck cancers
• Gynecologic cancer screening for female patients
• Early intervention for suspicious lesions 1, 4

Special Considerations

• Hypersensitivity to chemotherapy: Patients show extreme sensitivity to DNA cross-linking agents like mitomycin C, requiring dose modifications 1

• Post-transplant risks: Even after successful HSCT, patients remain at high risk for solid tumors, particularly oral cavity cancers 4

• Genetic counseling: Essential for families, allowing for:

  • Carrier testing
  • Prenatal diagnosis
  • Preimplantation genetic diagnosis 3

Prognosis

Without treatment, progressive bone marrow failure typically leads to death in childhood or early adulthood. With modern management including HSCT, many patients survive into adulthood but require lifelong surveillance for secondary malignancies 7, 2.

The severity of the disease varies significantly based on the specific genetic mutation, with FANCD1/BRCA2 having the most severe phenotype and earliest cancer onset 5.