Fanconi anemia

Fanconi anemia

Updated: 7/9/2024

© Jun Wang, MD, PhD

 

General features

  • Most common form of inherited aplastic anemia
  • Autosomal recessive
  • Approximately 25% of aplastic anemia
  • Associated with cytopenias, predisposition to malignancy, and congenital and developmental abnormalities

Major causes

  • Mutations in one of over 22 genes, FANCA to FANCW
  • Most commonly mutated genes: FANCA, FANCC, and FANDG

Key pathogenesis

  • Biallelic mutations of FANCA, FANCC, and FANCG most common
  • Heterozygous FA mutations considered asymptomatic carriers, except

o   FANCB (X-linked recessive)

o   FANCR (autosomal dominant)

o   FANCS and FANCD1 (AKA BRCA1 and BRCA2, respectively)

  • Defects in DNA interstrand crosslink repair
  • Cells highly vulnerable to endogenous injuries, such as ROS
  • Anemia associated with selective destruction of CD34+ stem cells

Key clinical findings

  • Early onset with concurrent birth defects
  • Cytopenia/bone marrow failure

o   Macrocytic anemia

o   Thrombocytopenia: bleeding

o   Neutropenia infections

o   Pancytopenia

Key Laboratory findings

  • Blood: Cytopenia including macrocytic anemia, thrombocytopenia, leukopenia or pancytopenia
  • Bone marrow

o   Hypocellular

o   Loss of myeloid and erythroid precursors

o   Loss of megakaryocytes

o   Relative lymphocytosis

o   Severe cases with fatty changes

o   Features of MDS or leukemia

Diagnosis

  • Based on findings of chromosome breaks, or FA mutations
  • Indications for screening

o   Persistent moderate to severe cytopenias: >2 weeks of moderate or severe cytopenias in ≥2 lineages with severely hypocellular bone marrow, without any known cause

o   Characteristic physical findings: ≥3 of the following: vertebral anomalies, anal atresia, congenital heart disease, tracheoesophageal fistula, esophageal atresia, renal anomalies, limb anomalies, and hydrocephalus) or multiple malformations, such as short stature, cafĂ©-au-lait spots, thumb/radial ray abnormalities, or hypospadias that are strongly associated with FA

o   Relative with FA patients

o   Unexplained cytopenias associated with characteristic congenital abnormalities

o   Individuals ≤40 years with MDS, AML, or certain cytogenetic abnormalities

o   Squamous cell cancer (SCC) of the head, neck, or anorectal region with no known attributable exposure

o   Patients who had severe toxicity with chemotherapy or radiation therapy 

Management

  • Supportive: transfusion
  • Hematopoietic stem cell transplantation
  • MDS or leukemia may be treated or prevented by hematopoietic stem cell transplantation
  • Androgens if stem cell transplantation not an option
  • Treatments of concurrent defects or disorders

Prognosis

  • Death due to bleeding or infection
  • Incidence of solid tumor rising due to improvement of survival

 

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