Fanconi anemia (FA)

Doctors often think of Fanconi anemia when a child's blood counts fall, usually low platelets or white cells first. Large red blood cells and a raised fetal hemoglobin level are common too. About 3 in 4 people have physical differences, such as short height, thumb or arm differences, or patches of darker or lighter skin. Some are found only later, because of a head and neck cancer at a young age or an unexpectedly severe reaction to cancer treatment.

The main test is a chromosome breakage test. A blood sample is treated in the lab with chemicals called DEB (diepoxybutane) or MMC (mitomycin C), and the cells are checked for broken chromosomes. Care guidelines say only experienced, accredited labs should do this test. About 15 to 20% of people with Fanconi anemia have a mix of cells (mosaicism), so a blood test can look normal. If doubt remains, a small skin sample is tested. A gene panel then looks for the exact cause among more than 20 known genes.

The median age at diagnosis is about 7, but people with no obvious physical differences may not be diagnosed until adulthood. After diagnosis, care teams usually do a marrow test with chromosome studies (cytogenetics and FISH). They HLA-type the patient, brothers and sisters, and parents, and every brother and sister is tested for Fanconi anemia. When the family's gene change is known, testing is possible before birth. A newborn can also be tested using cord blood.

Care combines blood and marrow monitoring, cancer surveillance and treatment of organ-specific problems. Transfusions, infection treatment and sometimes androgen therapy can support blood production, but do not repair the underlying genetic defect.

Allogeneic transplantation is considered for significant marrow failure or concerning myelodysplastic or leukemic changes. Conditioning must be adapted because Fanconi cells are unusually sensitive to DNA-damaging treatment. The transplant team balances disease control, graft failure and treatment toxicity.

Successful transplantation can restore blood production. Congenital differences, endocrine problems and solid-tumor susceptibility still require care. Cancer surveillance continues after transplant.

When a transplant from a donor is planned, the team usually tests brothers and sisters first. Each full sibling has about a one in four chance of being a full match.

Most patients do not have a matched relative. In the words of NMDP, the U.S. registry, “75% of patients don’t have a fully matched donor in their own family.” The team then searches registries of volunteer donors around the world and banks of donated cord blood. In some transplants, a half-matched parent, child or sibling can also be the donor.

Matching depends on inherited tissue markers called HLA, so a patient is most likely to match someone who shares their ancestry. Every person who joins makes the search a little more likely to succeed, especially for patients from groups that are underrepresented on registries.

In the Italian Fanconi Anemia Registry, about 9 in 10 people had developed a blood problem by age 20, often starting in childhood. What shapes the outlook most is whether marrow failure, MDS or AML, or a solid cancer develops, and when. The gene matters too. Children with the BRCA2 (FANCD1) form have a very high risk of leukemia and other cancers in early childhood. The FANCC and FANCG forms tend to cause marrow failure earlier and more often.

A donor transplant is the only cure for the blood problems. Results are best when the transplant happens before MDS or leukemia and before many transfusions, at a center experienced with Fanconi anemia. These centers use gentler, lower-dose treatment before transplant, usually built around a medicine called fludarabine. Survival is much lower when the transplant is for MDS or AML than for marrow failure alone.

The higher cancer risk remains after transplant, especially for head, neck and gynecologic cancers. Past chronic graft-versus-host disease adds to that risk, so cancer screening continues for life. Decades ago, children with Fanconi anemia rarely reached adulthood. Today a growing number of adults live with it, and cancer is now the main cause of death in adults. Group numbers come from specific registries and eras, and they cannot predict how any one person will do.