Fanconi Anemia

What goes wrong in Fanconi anemia

More than 20 genes (FANCA through FANCW and others) work together in the "Fanconi anemia pathway" to repair DNA crosslinks, a type of damage where the two DNA strands get stuck together. When this pathway fails, chromosomes break easily. Blood stem cells are particularly sensitive and die off over time, and cells that survive are prone to becoming cancerous.

Inheritance

Most FA is autosomal recessive: a child inherits one faulty copy from each parent. When both parents are carriers, each pregnancy has a 1 in 4 chance of FA. FANCA is the most commonly affected gene. One form (FANCB) is X-linked and affects boys, and one rare form (RAD51) is dominant. Carrier frequency is higher in Ashkenazi Jewish, South African Afrikaner and some Roma and other communities.

Fanconi anemia is different from Fanconi syndrome, a kidney tubule disorder with a similar name.

Signs and symptoms

Physical differences at birth

About 60 to 75 percent of people with FA have at least one physical difference:

• thumb abnormalities: missing, extra, small or misplaced thumbs; underdeveloped radius bone in the forearm
• short stature and low birth weight
• café-au-lait spots or areas of lighter or darker skin
• small head and eyes
• kidney malformations
• heart defects
• hearing loss and ear abnormalities
• genital and fertility problems
• gastrointestinal anomalies such as esophageal or duodenal atresia; some children fit the VACTERL association pattern

About a quarter to a third have no obvious physical signs, so FA can be missed until blood counts fall.

Bone marrow failure

Usually appears between ages 5 and 10, sometimes earlier or in adulthood. Most people with FA develop it by middle age. Symptoms:

• tiredness, paleness and breathlessness from anemia
• bruising, nosebleeds and tiny red spots from low platelets
• frequent infections from low white cells

See aplastic anemia and bone marrow failure.

Cancer predisposition

• Myelodysplastic syndrome and acute myeloid leukemia: risk hundreds of times higher than average, mostly in childhood and young adulthood.
• Squamous cell carcinoma of the mouth, tongue, throat, esophagus, vulva and anus, often in the 20s and 30s and at much higher rates than in the general population.
• Liver tumors, particularly with androgen treatment.

Endocrine problems

Short stature, low thyroid function, glucose intolerance, low bone density and early menopause are common.

Diagnosis

1. Chromosome breakage test: blood cells are exposed to DNA-crosslinking chemicals (diepoxybutane or mitomycin C). Excess chromosome breakage confirms FA. It is the key screening test.
2. Genetic testing identifies the specific gene variants and allows carrier and prenatal testing for the family.
3. Baseline evaluation: blood counts, bone marrow examination, kidney ultrasound, heart echo, hearing test, endocrine tests and hand X-rays.

FA should be considered in any child or young adult with unexplained marrow failure, MDS or leukemia, and in people who have severe reactions to chemotherapy or radiation, or early squamous cell cancers. Testing for FA is essential before a transplant, because standard doses of chemotherapy and radiation are dangerous in FA.

Treatment

Bone marrow failure

• Hematopoietic stem cell transplant is the only treatment that restores normal blood production. It uses reduced-intensity conditioning (fludarabine-based, low or no radiation) adapted for FA's sensitivity. Results are best with a matched sibling donor who does not have FA, and before leukemia develops.
• Androgens such as oxymetholone or danazol can raise blood counts for some years in people who are not transplanted; they require liver monitoring.
• Supportive care: transfusions, growth factors, infection treatment and iron chelation.
• Gene therapy is being studied in clinical trials.

Cancer surveillance and prevention

Transplant does not remove the risk of solid cancers and may increase it. Recommended measures include:

• mouth, throat and ENT examinations every 6 to 12 months from childhood, often with a specialist
• gynecologic exams and HPV vaccination
• avoiding smoking, alcohol and other carcinogens
• excellent dental care
• prompt biopsy of persistent mouth lesions
• yearly bone marrow and blood count monitoring before transplant

Cancer treatment in FA must be adapted because standard chemotherapy and radiation cause severe toxicity.

Other care

Hand surgery for thumb and forearm differences, kidney and heart care, hearing aids, endocrine treatment and fertility counseling.

Outlook

Survival has improved dramatically with better transplants and surveillance. Many people with FA now live into adulthood, with median survival into the 30s or beyond, but solid cancers remain a major risk. Care at an experienced FA center with a multidisciplinary team gives the best outcomes.

Frequently asked questions

What is Fanconi anemia?

Fanconi anemia is a rare inherited disorder in which cells cannot repair a certain type of DNA damage. It causes bone marrow failure, often in childhood, a very high risk of leukemia and head and neck cancers, and physical differences such as thumb abnormalities and short stature.

How is Fanconi anemia inherited?

Most cases are autosomal recessive, meaning both parents are carriers and each child has a 1 in 4 chance of being affected. A rare form is X-linked and affects boys. Genetic testing allows carrier testing of relatives and prenatal or preimplantation testing.

How is Fanconi anemia diagnosed?

The main test is a chromosome breakage test, in which blood cells are exposed to chemicals that damage DNA. Cells from people with Fanconi anemia show much more chromosome breakage than normal. Genetic testing then identifies the gene involved.

What is the life expectancy with Fanconi anemia?

It has improved greatly with modern stem cell transplants and cancer surveillance. Many people now live into their 30s, 40s and beyond. Outcomes depend on timing of transplant, response to treatment and early detection of cancers.

Is Fanconi anemia the same as Fanconi syndrome?

No. Fanconi anemia is an inherited bone marrow and DNA repair disorder. Fanconi syndrome is a kidney condition in which the kidney tubules fail to reabsorb substances such as glucose, phosphate and amino acids. They share only the name of the doctor who described them.