What are the clinical features of Fanconi anemia?

Clinical Features of Fanconi Anemia

Fanconi anemia presents with a triad of DNA damage repair defects, progressive bone marrow failure, and cancer predisposition, though clinical manifestations are highly variable with 25-40% of patients having no physical anomalies at all. 1

Congenital Anomalies (Present in 60-75% of Patients)

The physical abnormalities are heterogeneous and multisystemic: 1

• Skeletal abnormalities: Short stature, abnormal thumbs or radii, skeletal malformations of the upper limbs 1
• Skin manifestations: Café au lait spots, abnormal skin pigmentation 1
• Renal anomalies: Genitourinary malformations 1
• Cardiac malformations 1
• Ophthalmic manifestations 1
• Gonadal anomalies 1
• Endocrine disorders: Growth hormone deficiency, hypothyroidism, diabetes 1

Critical caveat: Up to one-third of patients have no physical anomalies and are only diagnosed when presenting with cytopenias, making FA a diagnostic challenge. 1

Hematologic Manifestations

Bone marrow failure (BMF) is the dominant clinical feature, developing in more than 95% of patients: 1

• Timing: BMF presents in childhood in most patients, with approximately 40% developing severe BMF by age 20 years and 50% by age 50 years 1
• Risk by age 50: 70% develop severe BMF 1
• Presentation: Progressive cytopenias that may precede any physical findings 1

Important clinical pearl: The absence of BMF does not exclude the diagnosis of FA, and malignancy can precede the diagnosis of BMF. 1

Malignancy Risk

Patients face dramatically elevated cancer risks across multiple organ systems: 1

Hematologic Malignancies

• Acute myeloid leukemia (AML): Most common hematologic malignancy, accounting for more than 80% of leukemias 1
• Cumulative incidence by age 50: Approximately 50% for MDS, 10% for leukemia 1
• Pediatric cancer: 11% of patients develop cancer at pediatric age 1

Solid Tumors

• Head and neck squamous cell carcinoma (HNSCC): Most common solid tumor with a relative risk of approximately 600 compared to the general population, usually presenting in adulthood 1
• Cumulative incidence by age 50: 20-30% for solid tumors 1
• Post-transplant risk: Risk of developing solid tumors is higher in patients who receive hematopoietic cell transplantation 1

Genotype-Specific Phenotypes

Patients with biallelic mutations in FANCD1/BRCA2 have the most severe phenotype: 1

• Severe congenital anomalies 1
• Cumulative incidence of leukemia: 80% by 10 years of age 1
• Cumulative incidence of any malignancy: More than 90% by 7 years of age 1
• High risk of brain tumors (medulloblastoma and others), particularly before age 6 years 1
• Wilms tumor risk 1

FANCN/PALB2 mutations are also associated with high risk of brain tumors before age 6 years and Wilms tumor. 1

FANCS/BRCA1 mutations show high risk of pediatric tumors from very early age, with 4 of 10 patients developing tumors under age 6 years including brain tumors, neuroblastoma, and leukemia. 1

Diagnostic Considerations

Phenotypic heterogeneity is the hallmark: Clinical manifestations vary widely from patient to patient, likely due to modifier genes, environment, and chance effects. 2 The diagnosis requires high clinical suspicion, particularly in patients presenting with isolated cytopenias without obvious congenital anomalies. 1