Fanconi anaemia: an inherited DNA repair disorder

When low blood counts run in the family

When a child or young adult develops low blood counts, one of the first questions is whether the cause is acquired later in life or present from birth. Fanconi anaemia is an inherited answer to that question. It is a genetic condition that is there from conception, and the marrow failure is only one part of it. Fanconi anemia, the US spelling, describes the same condition.

This page explains what goes wrong inside the cells, how the condition is passed down, which physical features may or may not be present, and why cancer checks continue for life. It also covers how the diagnosis is confirmed and why it changes transplant planning. For the wider picture of inherited and acquired causes, see acquired versus inherited bone marrow failure. Other inherited marrow failure syndromes, such as dyskeratosis congenita, have different underlying causes.

A repair problem inside every cell

Fanconi anaemia is caused by changes, called variants, in more than 20 genes. The proteins made from these genes work together in the Fanconi anaemia pathway, a repair system that switches on when damage blocks the copying of DNA. MedlinePlus Genetics explains that the pathway repairs these breaks so the cell can keep dividing. When it does not work properly, damage builds up over time.

Most cases, between 80 and 90 percent according to the same source, involve changes in FANCA, FANCC or FANCG. The cells most affected are the ones that divide quickly, such as the stem cells in the marrow and the cells of a developing fetus. That explains both the falling blood counts and the physical differences that can appear from birth. The exact number of genes is still being revised, so your team may quote a slightly different figure.

How it is passed down

In most families the condition follows an autosomal recessive pattern. A child is affected when they inherit a changed copy of the gene from each parent. The parents are usually carriers, each with one changed copy and no symptoms of their own.

When both parents are carriers, each pregnancy has a 1 in 4 chance of an affected child, a 1 in 2 chance of a child who is a carrier, and a 1 in 4 chance of a child who is neither, according to the NHS Genomics Education Programme. Some carrier relatives face a different question. Variants in certain genes, including BRCA2 and PALB2, are linked to a higher cancer risk even when only one copy is changed, so referral to clinical genetics is worth considering.

A small minority of families follow other patterns. The NHS notes that FANCB, which underlies less than 1 percent of cases, is inherited in an X-linked pattern.

Physical features that may or may not be present

Physical differences are common, but they are not universal. GeneReviews, the clinical reference hosted on the NCBI Bookshelf, lists a group of features seen in roughly three in four affected people. These include:

• short stature, before or after birth
• thumb or forearm differences
• light patches or café-au-lait spots on the skin
• a smaller than usual head
• kidney or urinary tract differences
• eye, hearing or heart differences

Some children look typical at birth, and some people show no obvious signs until adulthood. In those cases the blood count is often the first clue. Easy bruising, nosebleeds, frequent infections or unusual tiredness can prompt testing. The Fanconi Cancer Foundation notes that diagnosis usually comes before the age of 12, though not always.

Marrow failure and the timing of change

Progressive bone marrow failure is among the most common and serious complications. GeneReviews describes it as a gradual drop in red cells, white cells and platelets, usually beginning in the first decade of life.

Supportive care is a large part of the plan at this stage. Blood transfusions help with symptoms. Oral androgens such as oxymetholone or danazol may give a temporary lift to red cell and platelet counts in around half of people, and a growth factor can raise white cell counts in some. GeneReviews stresses that all of these therapies carry potential significant toxicity, so decisions are made case by case with the specialist team.

Cancer risk and why checks continue

The cancer risk is the feature that most changes long-term care. GeneReviews reports that myelodysplastic syndrome or acute myeloid leukaemia develops in about 35 percent of people with Fanconi anaemia by age 40. Head and neck, skin and genitourinary cancers are also more common. MedlinePlus gives a 10 to 30 percent likelihood of developing one of the cancers linked to the condition.

The Fanconi Cancer Foundation describes head and neck cancer as among the most frequently diagnosed solid tumours, and says cancer has become the main cause of death in adulthood for people with the condition. It recommends regular mouth and throat check-ups and avoiding smoking, alcohol and second-hand smoke, because there is currently no curative treatment for these cancers.

Which checks apply, and how often, is a question for your haematology team and the specialist centre that follows you. A child may also need physiotherapy, hearing or growth support alongside the blood team.

How the diagnosis is confirmed

The key laboratory test is the chromosome breakage test. Blood cells are grown in the laboratory and exposed to chemicals called diepoxybutane (DEB) or mitomycin C (MMC). In cells from someone with Fanconi anaemia, chromosomes break far more readily than normal, and GeneReviews treats this response as the defining finding. For how the wider investigation is organised, see diagnosing bone marrow failure.

Genetic testing then looks for the specific variant responsible. The NHS notes that some tests read the DNA sequence while others look for breakage itself, and that the two approaches can help each other. A breakage result can help clarify a variant whose significance is uncertain.

Testing does not stop with the affected child. GeneReviews recommends breakage or molecular testing of all siblings, so that early diagnosis and monitoring can happen in time.

Why it changes the transplant plan

A stem cell transplant is the only curative treatment for the blood problems of Fanconi anaemia, according to GeneReviews. It does not remove the rest of the condition, including the raised risk of some cancers, which may even rise after transplant.

Before transplant, the detail that matters most is sensitivity to treatment. Because cells struggle to repair DNA damage, standard chemotherapy and radiation can cause unusually severe toxicity. GeneReviews notes that data on reduced doses and schedules are limited, and that severe or fatal reactions have been reported. Transplant teams therefore plan the preparative regimen around this, and some regimens remove radiation entirely.

Donor choice matters too. A brother or sister can be considered as a donor, but only after testing shows they are not affected. The Fanconi Cancer Foundation reports that matched sibling transplant success has risen to close to 100 percent at some specialist centres.

Specialist care and where to find support

Where possible, people with Fanconi anaemia are best cared for at comprehensive clinics that specialise in the condition. The Fanconi Cancer Foundation recommends these teams, which bring together haematology, endocrinology, orthopaedics, gynaecology, dermatology, nutrition and hearing care, because the condition touches many systems.

Support is available beyond the clinic. The Genetic and Rare Diseases Information Center offers free, plain-language information and can connect people with specialists and patient organisations. Patient groups can also put families in touch with other families living with the condition.

Early testing keeps the most options open

A diagnosis of Fanconi anaemia opens a long relationship with specialist teams, and the sooner that relationship starts, the more choices a family keeps. Testing siblings, arranging cancer checks and choosing a centre with real experience all shape what comes next. Bring these questions to your haematology team.