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Fanconi anaemia
This condition is characterised by progressive bone marrow failure, various physical anomalies, and a higher risk of developing certain cancers. It affects individuals from birth and requires lifelong monitoring and management.
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Overview
Fanconi anaemia is a rare genetic condition that primarily affects the body's ability to produce healthy blood cells in the bone marrow. It is a type of inherited bone marrow failure syndrome. Individuals with Fanconi anaemia may experience fatigue, frequent infections, and bleeding problems due to insufficient blood cell production. It can also cause various physical differences and an increased risk of specific cancers over time [PMID:31536709].
Although Fanconi anaemia is present from birth, symptoms can vary widely and may not appear until later in childhood or even adulthood. The condition affects approximately 1 in 160,000 individuals worldwide. Comprehensive care and regular monitoring are essential for managing this complex disorder.
Symptoms & clinical features
The symptoms of Fanconi anaemia can be diverse and may include problems related to bone marrow failure, physical abnormalities, and an increased risk of cancer. Bone marrow failure often leads to pancytopaenia, a reduction in all types of blood cells. This can result in anaemia (low red blood cells), causing fatigue and pallor; leucopaenia (low white blood cells), leading to frequent infections; and thrombocytopaenia (low platelets), which causes easy bruising and bleeding [PMID:31536709].
Physical differences can affect various parts of the body. These may include skeletal abnormalities, such as malformed thumbs or forearms, short stature, and hip dislocations. Kidney problems, heart defects, and skin pigmentation changes, like 'café-au-lait' spots, are also commonly observed. Some individuals may experience developmental delay, and eye or ear abnormalities [PMID:31536709].
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Affected organs
Fanconi anaemia primarily affects the bone marrow, the soft tissue inside bones responsible for producing blood cells. Over time, the bone marrow's ability to make healthy red blood cells, white blood cells, and platelets declines, leading to bone marrow failure.
Beyond the bone marrow, the condition can impact various organ systems. Skeletal abnormalities often affect the limbs, particularly the hands and arms. The kidneys, heart, and digestive system may also show structural differences or functional issues. Skin pigmentation changes are common, and some individuals may have involvement of the eyes and ears.
Risks & severity
The severity of Fanconi anaemia varies considerably among affected individuals, even within the same family. Bone marrow failure typically progresses over time, often becoming a significant concern by school age. Many individuals will eventually require a stem cell transplant to treat the bone marrow failure.
Individuals with Fanconi anaemia have a significantly increased lifetime risk of developing certain cancers. These include acute myeloid leukaemia (AML), squamous cell carcinoma of the head and neck, and gynaecological cancers. Regular surveillance is crucial for early detection and management of these potential complications. The onset of symptoms and complications varies widely, making individualised monitoring important.
Genetic causes
Fanconi anaemia is caused by pathogenic variants in genes involved in the Fanconi anaemia (FA) pathway, which is essential for repairing damaged DNA. Two common genes associated with this condition are FANCA and FANCC.
FANCA, located on chromosome 16, provides instructions for a protein critical in maintaining the stability of the genome. This protein helps prevent harmful cross-links between DNA strands during DNA replication. Pathogenic changes in FANCA are a frequent cause of Fanconi anaemia, impairing the cell's ability to repair DNA effectively.
Similarly, FANCC provides instructions for another protein component of the FA pathway. This pathway enables cells to respond to DNA damage, especially when replication stalls due to abnormal cross-links. When the FANCC protein is faulty, the DNA repair pathway does not function correctly, leading to chromosomal instability and the features of Fanconi anaemia.
- FANCA FA complementation group AThe FANCA gene provides instructions for a protein crucial to the Fanconi Anaemia pathway, which is vital for repairing DNA damage and maintaining genomic stability.
- FANCC FA complementation group CFANCC encodes a protein that forms part of the Fanconi anaemia core complex, critical for repairing DNA damage and maintaining genomic stability.
Inheritance pattern
Fanconi anaemia is typically inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic gene variant - one from each parent - to develop the condition.
If both parents are carriers of a pathogenic variant (meaning they each have one altered copy and one normal copy of the gene), they usually do not show symptoms themselves. However, with each pregnancy, there is a 25% chance of their child inheriting two altered copies and developing Fanconi anaemia, a 50% chance of their child being an asymptomatic carrier like them, and a 25% chance of their child inheriting two normal copies of the gene.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
A diagnosis of Fanconi anaemia is often suspected based on characteristic physical differences, a family history of the condition, or signs of bone marrow failure. The first step typically involves a specialised blood test called a chromosomal breakage test [PMID:32130761]. This test assesses how sensitive a person's cells are to certain chemicals that cause DNA damage, which is a hallmark of Fanconi anaemia.
If the chromosomal breakage test suggests Fanconi anaemia, genetic testing is then performed to identify the specific pathogenic variants in genes like FANCA or FANCC. This confirms the diagnosis and can help determine the specific type of Fanconi anaemia. Referrals for genetic testing in the UK for suspected bone marrow failure syndromes, including Fanconi anaemia, would typically fall under an NHS Genomic Medicine Service (GMS) pathway, with relevant R-codes for inherited bone marrow failure. Paediatricians or haematologists would usually refer patients to clinical genetics services for assessment and testing.
Management & lifestyle
Managing Fanconi anaemia involves a multidisciplinary approach focused on monitoring disease progression, preventing complications, and treating symptoms. Regular blood tests are essential to track blood cell counts and bone marrow function. Surveillance for specific cancers, such as oral cancer, is also an important part of ongoing care.
Treatment for bone marrow failure can include regular blood transfusions, stimulant medications to boost blood cell production, and in severe cases, a haematopoietic stem cell transplant. This transplant involves replacing the faulty bone marrow with healthy stem cells from a donor. Genetic counsellors can provide vital support and information to individuals and families regarding inheritance patterns, genetic testing, and family planning options.
UK care pathway
In the UK, individuals suspected of having Fanconi anaemia would generally be referred to specialist services through the NHS Genomic Medicine Service. Clinical geneticists and genetic counsellors play a key role in confirming a diagnosis and providing information and support. Genetic testing for inherited bone marrow failure syndromes, including Fanconi anaemia, is accessible via specific R-codes through the GMS testing directory. Care typically involves close collaboration between haematology, genetics, and other specialist teams.
Frequently asked questions
Is Fanconi anaemia always serious?
Fanconi anaemia is considered a serious condition because it affects the bone marrow and increases cancer risk. However, the severity can vary widely between individuals. Some people have milder symptoms, while others experience more significant health problems requiring intensive treatment.
Can Fanconi anaemia be cured?
Currently, the only potential curative treatment for the bone marrow failure aspect of Fanconi anaemia is a haematopoietic stem cell transplant. This procedure replaces the faulty bone marrow with healthy stem cells. However, it does not prevent the increased risk of certain cancers.
What is life like for someone with Fanconi anaemia?
Life with Fanconi anaemia involves ongoing medical care, including regular check-ups and monitoring for bone marrow function and cancer. Many individuals lead fulfilling lives, but they may need to manage symptoms like fatigue, infections, or bleeding and undergo specific treatments as required.
How does Fanconi anaemia affect future children?
Since Fanconi anaemia is typically inherited in an autosomal recessive pattern, if both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit the condition. Genetic counselling can provide detailed information about reproductive options and risks.
What kind of doctors treat Fanconi anaemia?
Management of Fanconi anaemia usually involves a team of specialists. This often includes haematologists (blood specialists), clinical geneticists, genetic counsellors, and other specialists as needed, such as oncologists for cancer surveillance or orthopaedic surgeons for skeletal issues.
References
- Taylor AM. Chromosome instability syndromes. Best practice & research. Clinical haematology. 2001. PMID: 11640873
- Tischkowitz MD, Hodgson SV. Fanconi anaemia. Journal of medical genetics. 2003. PMID: 12525534
- Maric M, Segura-Bayona S, Kuthethur R. EXO1 as a therapeutic target for Fanconi Anaemia, ZRSR2 and BRCA1-A complex deficient cancers. Nature communications. 2025. PMID: 41006228
- Webster ALH, Sanders MA, Patel K. Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer. Nature. 2022. PMID: 36450981
- Woodward ER, Meyer S. Fanconi Anaemia, Childhood Cancer and the BRCA Genes. Genes. 2021. PMID: 34680915
- Nalepa G, Clapp DW. Fanconi anaemia and cancer: an intricate relationship. Nature reviews. Cancer. 2018. PMID: 29376519
- Crawford D, Dearmun A. Fanconi anaemia. Nursing children and young people. 2017. PMID: 28162059
- Daza-Martin M, Starowicz K, Jamshad M. Isomerization of BRCA1-BARD1 promotes replication fork protection. Nature. 2019. PMID: 31270457