Fanconi anemia

Fanconi anemia is an inherited disorder of DNA repair. It is named after the anemia, but that is only part of it — it affects bones, kidneys, growth, hormones and hearing, and it is a cancer-predisposition syndrome rather than only a blood disease.

The specific fault is in clearing a kind of DNA damage called an interstrand crosslink: a chemical bridge that glues the two strands of the DNA ladder together and stops a cell copying its own genetic code. Cells that cannot clear those bridges accumulate breakage, and then die or turn abnormal.

The repair crew involved is a chain of at least 21 genes. FANCA accounts for roughly 60% to 70% of cases. Some of the genes in this pathway are ones people know by other names — BRCA1, BRCA2, PALB2 — which is why a child’s diagnosis often triggers cancer-risk counselling for relatives on both sides.

The classic test is a chromosome breakage test. White blood cells are exposed to a DNA-damaging chemical and then examined; cells from someone with Fanconi anemia show excess breakage and chromosomes fused into cross- or star-shaped forms. A negative blood test does not always settle it — in 15% to 20% of people a blood stem cell has spontaneously corrected itself and repopulated the blood, so the test is repeated on cells grown from a small skin sample.

It is genetic and present from conception. Nothing a parent did or was exposed to causes it.

Most forms are autosomal recessive: the child inherits one non-working copy of the same gene from each parent. The parents are carriers and are healthy. For two carrier parents, each pregnancy carries a 25% chance the child is affected, a 50% chance of a carrier, and a 25% chance of neither.

Two exceptions matter for families. One gene, FANCB, is X-linked, so it affects boys and is inherited through the mother. Another, RAD51, is dominant and in every reported case so far has arisen new in that child rather than being inherited.

Carrying one faulty copy does not put a parent at risk of Fanconi anemia. But because some of these genes are BRCA1, BRCA2, PALB2 and their relatives, carrying one copy can raise that person’s own risk of breast and other cancers — which is why the diagnosis reaches outward through a family.

The marrow progressively fails to make enough blood cells. Most people show at least mild failure within the first decade, and the usual order is low platelets or low white cells first, with anemia arriving later. More than nine in ten have unusually large red blood cells from infancy.

Over time, the risk is not only that the marrow empties but that it turns abnormal — into a myelodysplastic neoplasm, or into acute myeloid leukemia. Serial marrow tests watch for groups of cells acquiring the same chromosome change, because that can appear before the blood counts move.

The most common solid tumour is squamous cell carcinoma of the head and neck, and the Fanconi Cancer Foundation guidelines describe it as the main cause of death in adulthood. It appears at roughly 20 to 50 years of age rather than 60 to 70, most often in the mouth, usually at an advanced stage — and often without the tobacco and alcohol exposure that drives it in other people.

Physical differences present from birth are common: short stature in around 43%, differences in the thumb and the thumb-side forearm bones in around 40%, café-au-lait skin patches in 37%, kidney differences in 27%, a small head in 27%. Hypothyroidism, impaired glucose handling, hearing loss and reduced fertility are also more common.

There is no treatment that repairs the DNA-repair defect throughout the body. Everything below manages consequences.

Androgens — male hormones such as oxymetholone or danazol — can temporarily raise red cell and platelet counts in around half of people. They are not curative and do not prevent progression to leukemia, and only 10% to 20% on continuous low-dose treatment are long-term responders. The costs are real: masculinising changes, effects on growth, and liver toxicity requiring liver tests every three to six months and scans every six to twelve.

A transplant using another person’s blood-forming cells can cure the blood problems — the marrow failure, and MDS or leukemia if they develop. It does not correct the rest of Fanconi anemia and it does not remove the solid-tumour risk.

And here is the central safety point of the whole page. Conditioning — the treatment given before a transplant to clear the person’s own marrow — works by damaging DNA. These are cells that cannot repair DNA damage. Standard doses are toxic. Reduced-intensity conditioning is recommended, and regimens that avoid radiation altogether are used, which became possible largely because fludarabine reduced graft failure enough to allow radiation to be dropped.

A related warning is easy to miss: chemotherapy given before a donor has been secured can cause severe, prolonged or even irreversible marrow suppression in Fanconi anemia. Guidance is that it should not be started until a potential donor has been identified where that is possible.

Care belongs at a centre that specialises in this condition. Gene therapy — correcting a person’s own stem cells — is experimental and not standard care.

Diagnosis often starts with something small — an unusual thumb, a child not growing, a platelet count that will not resolve. Then it lands on the whole family at once. Parents learn they are carriers, siblings are tested, and relatives on both sides may be offered cancer-risk counselling because of the BRCA-family genes in this pathway.

Siblings are tested with the chromosome breakage test even when they are completely well. Families are being asked to test a healthy-looking child — for that child’s own sake, and because they may be considered as a donor.

Then years of watching. Blood counts every few months, marrow biopsies, chromosome studies — monitoring a decline that is expected but whose timing nobody can give. Families describe it as living with “when” rather than “if”.

Androgens buy time for some children at the cost of visible masculinising changes and regular liver monitoring, which is a hard trade for a school-age child.

And curing the blood disease is not the end of medical life. Head and neck examinations every six months from around age ten, for life. Gynaecological and skin surveillance too. For a survivor in their twenties that is a permanent schedule, and it is the main protection they have.

A transplant from a matched donor is the one treatment that can cure the blood problems — the marrow failure, and MDS or leukemia if they develop. So a donor is the route to that treatment.

But sibling matching here is filtered twice, and the second filter is the one people do not expect. A brother or sister must be HLA-matched AND shown not to have Fanconi anemia themselves. The guidelines are explicit that every biological sibling should have a chromosome breakage test, and that this matters particularly when a family member is being considered as a donor.

The reason is mechanical rather than precautionary. Because severity varies so much even within one family, an affected sibling can have normal blood counts, no visible physical difference and no symptoms yet. Transplanting their marrow would transplant the same failing disease.

Both filters remove candidates. That is precisely why unrelated volunteer donors matter in this condition — for many families, the sibling who matches on tissue type turns out not to be usable, and there is nobody else at home.

Timing matters too. Referral before MDS or leukemia develops is one of the reasons survival has improved, and chemotherapy is best not started until a donor has been identified.