Fanconi Anemia Workup

The diagnosis of Fanconi anemia is not made using routine laboratory tests; it must be considered and tested for using chromosome breakage in blood or fibroblasts, or germline mutation analysis. Siblings who do not apparently have Fanconi anemia need to be screened for occult Fanconi anemia.

Prenatal Fanconi anemia diagnosis can be accomplished by demonstration of chromosome breaks in cells obtained in utero from chorionic villus biopsy, amniocentesis, or cord blood (by cordocentesis) or by identification of Fanconi anemia gene mutations in DNA extracted from fetal cells.

Preimplantation genetic diagnosis can be established using molecular methods, resulting in implantation of an embryo without Fanconi anemia mutations and, if so desired, who is human leukocyte antigen (HLA)–matched with an affected child with Fanconi anemia. Cord blood from the delivery can be used for hematopoietic stem cell transplantation, resulting in the cure of the sibling's aplastic anemia or leukemia.

CBC count

In Fanconi anemia, the complete blood count (CBC) may reveal trilineage pancytopenia or may only show RBCs that are macrocytic for age. Thrombocytopenia or leukopenia may precede full-blown aplasia.

Chromosome breakage test

Chromosome breakage is usually examined in short-term cultures of peripheral blood T-cell mitogen–stimulated lymphocytes in the presence of DNA cross-linkers, such as DEB or MMC. These agents lead to increased numbers of breaks, gaps, rearrangements, and quadriradii in Fanconi anemia homozygote cells.

Some patients may have hematopoietic somatic mosaicism, with correction of the Fanconi anemia defect in the blood. In these cases, skin fibroblasts may be needed for the chromosome breakage test.

Flow cytometry

Flow cytometry of Fanconi anemia cells cultured with nitrogen mustard and other clastogens demonstrates an arrest in G2/M.

Fetal hemoglobin study

Fetal hemoglobin (HbF) may be increased for age as a manifestation of stress erythropoiesis.

Adenosine deaminase study

Red cell adenosine deaminase (ADA) is increased in approximately 85% of patients with Diamond-Blackfan anemia (DBA) but appears to be normal in Fanconi anemia.

Serum erythropoietin study

Serum erythropoietin (Ep) levels are markedly increased and higher than expected for the degree of anemia, similar to that observed in DBA. However, levels may be low in patients with impaired renal function.

Skeletal survey

Perform a skeletal survey to identify all developmental defects involving bone. Keep in mind that radiation doses should be limited in patients with Fanconi anemia.

Ultrasonography

Perform initial abdomen ultrasonography to document the size and location of the kidneys, and perform follow-up ultrasonography annually to monitor for liver tumors or peliosis hepatis.

Perform cardiac ultrasonography to evaluate for congenital anomalies.

MRI

Central nervous system (CNS) magnetic resonance imaging (MRI) is indicated to identify any structural defects, such as absence of the corpus callosum, small pituitary, or cerebellar hypoplasia.

Gene analysis

Mutations in specific Fanconi anemia genes can often be identified.

These tests are generally performed only in research laboratories, with the exception of the relatively common Fanconi anemia mutation found in Ashkenazi Jews (IVS4 +4 A to T).

Fanconi anemia lymphocytes are treated with vectors containing normal clones of the known Fanconi anemia genes; correction of chromosome breakage or of impaired growth by a specific vector indicates that the cells have a mutation in that gene. The specific mutation can then be determined by various molecular diagnostic approaches.

Bone marrow aspiration and biopsy

Bone marrow aspiration and biopsy may reveal hypocellularity, loss of myeloid and erythroid precursors and megakaryocytes (with relative lymphocytosis), or full-blown aplasia with a fatty marrow. Signs of myelodysplastic syndrome include dyserythropoiesis (multinuclearity, ringed sideroblasts), dysmyelopoiesis (hyposegmentation, hypogranularity, hypergranularity), and hypolobulated or hyperlobulated megakaryocytes. Presence of a cytogenetic clone in a high and increasing proportion over time may suggest an evolution to leukemia, but this is currently unproven.