Fanconi anaemia (FA) is a rare, inherited condition that affects the bone marrow and internal organs of the body, as well as causing physical abnormalities. FA is not to be confused with  Fanconi Syndrome, which is a rare kidney disease.

This condition is caused by a mutation in any of the 23 FA pathway genes (FANC prefix), with 80-90% of cases caused by mutations in the FANCA, FANCC, and FANCG genes.¹ Due to an impaired FA pathway, DNA damage cannot be properly repaired, which can lead to excessive cell growth, contributing to a higher risk of cancer. It can also lead to excessive cell death, resulting in bone marrow failure.

What is FA?

FA is a rare disease that occurs in about 1 in 160,000 births. The condition typically manifests when a person inherits a mutated FA allele from each parent (autosomal recessive inheritance). About 2% of cases occur due to X-linked inheritance, as the FANCB gene lies on the X chromosome. Therefore, people assigned male at birth (AMAB) have a slightly higher risk of inheriting the disease, as they only have one X chromosome. If two people carrying a mutated FA allele have a child, there is a 25% chance that their child will inherit the condition.

Illustration of a chromosome pair. We inherit one allele from each parent, and together these make up a gene. Made by Dania Salim with BioRender.

This disease mainly impacts the bone marrow, the tissue found in the centre of our bones, responsible for producing blood cells and platelets. 9 in 10 FA patients present with bone marrow failure, which means their bone marrow produces little, if any, of these cells. 3 in 4 children born with FA will also have physical abnormalities, impacting their physical appearance, as well as the functioning of their internal organs.

If you are suffering from FA, support is available to you at Fanconi Hope UK.

Symptoms

Here are some symptoms that people with this condition may experience: 

• Anaemia
  • Constantly feeling tired
  • Headaches
  • Breathlessness
  • Increased heart rate
  • Pale skin
  • Dizziness or feeling faint
• Bone marrow failure syndrome
  • Excessive bleeding, usually from the gums and the nose
  • A decreased white blood cell count, which increases the risk of contracting bacterial and fungal infections
• Physical abnormalities
  • People with FA are usually shorter than average
  • Having an extra thumb, or missing a thumb
  • Scoliosis
  • A small head, which may be a sign of microcephaly
  • A large head, which is a sign of hydrocephalus
  • Difficulty with hearing due to small ears
  • Café-au-lait spots, which are light-brown coloured patches on the skin

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Images showing café-au-lait spots. Left image by Denise Nepraunig on Wikimedia Commons. Right image by Klaus D. Peter, Wiehl Germany on Wikimedia Commons.

Complications

FA can develop into:

• Aplastic anaemia
• Myelodysplastic syndrome (MDS), which is a form of pre-leukemia

10-30% of FA patients develop cancers such as leukaemia, and breast and ovarian cancer. These occur at much younger ages in the FA population compared to those without the disease.

FA and DNA repair

Every day, about 10,000 random mutations occur in our genome² due to natural processes, such as exposure to the sun and other carcinogens. Thanks to our body’s built-in DNA repair mechanisms, less than 1% of these mutations are permanent. ² The FA pathway is mainly involved in the repair of interstrand crosslinks. This takes place when DNA is being copied before the cell divides. The cell’s original DNA, known as the parent DNA, is copied to produce a new daughter DNA molecule.^3,4

DNA strands are made up of nucleotides, consisting of a phosphate group, sugar, and the DNA base. Typically, two DNA strands are joined together by the bases, forming weak hydrogen bonds between the strands. In the case of interstrand crosslinks, the two DNA strands become covalently linked. This acts as a glue, making it difficult for the DNA to unwind and replicate before cell division.

Image of a DNA nucleotide. Adapted from Dr TOsborne on Wikimedia Commons.

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Schematic showing typical DNA and DNA with interstrand crosslink. Made by Dania Salim with BioRender.

The FA pathway is typically split into three parts:¹

1. Proteins join to form the FA core complex at the crosslink.
2. The FA core complex adds a small protein called ubiquitin to FANCD2 and FANCI. This is considered the activation step. Once the proteins join together, they move to the site of DNA damage.
3. The ID complex can then activate different repair pathways and functions.

Research suggests that the FA pathway is involved in coordinating nucleotide excision repair (NER), translesion synthesis (TLS) and homologous recombination (HR). Although the exact mechanisms remain unknown, the following process has been suggested^3,4

1. NER cuts DNA on both sides of the crosslink to ‘unhook’ it
2. TLS fills the gaps on the strand that has been cut
3. HR or NER can repair the break on the second strand
4. HR can repair the daughter strand

NER

In NER, a nuclease (DNA-cutting enzyme) unhooks the crosslink from one strand, leaving it hanging on the other strand. It’s unclear whether the FA pathway regulates this process or is directly involved in it. However, the FA protein FANCP can bind nucleases and allow them to work efficiently. It has also been suggested that the removal of the cross-link by nucleases can help activate the FA pathway. ⁵

TLS

Now that one strand has been cut, the gaps need to be filled in by TLS. Since there’s a loose nucleotide attached to the unhooked crosslink, the cell will create a cut in this second strand. It has been suggested that the FA core complex is needed to activate TLS.³ A study has also found that TLS and FA gene expression impact one another, and cells lacking FANCC or TLS genes both showed signs of FA.⁶

HR

Once the parent DNA has been repaired, DNA exchange can occur, allowing the missing bases to be filled in on the daughter DNA strand. Mutations in the FA pathway have been shown to impact HR activity.⁶ Similar to NER, FANCP can help the nucleases involved in this process.¹ FANCD1 can also interact with HR protein Rad51, helping it to locate the DNA damage site.⁷ 

Diagram illustrating possible interstrand link repair model. Made by Dania Salim with BioRender.

The majority of FA patients have a mutation in an FA core complex gene, so these repair mechanisms cannot be performed. Given this, it is not surprising that the most striking genetic feature of this disease is the increased number of interstrand crosslinks. As a result, cells can grow uncontrollably, leading to cancer; excessive cell death can also occur, resulting in bone marrow failure.³

Diagnosis

This condition is usually diagnosed during childhood, although some people don’t show symptoms until they reach early adulthood. 3 in 10 adults with FA are diagnosed with the condition while undergoing treatment for a form of cancer. The gold-standard treatment for this condition is a chromosomal breakage test. This involves taking a sample of blood and skin cells and applying diepoxybutane (DEB) and mitomycin C (MMC), which form crosslinks in the DNA. Since FA cells already have impaired DNA repair, a higher number of unrepaired crosslinks in the chromosomes compared to typical cells indicates FA. A genetic screening test to detect mutations in FA genes may follow to confirm the diagnosis. ³

Treatment

The only treatment that can cure FA is haematopoietic stem cell transplantation (HSC),⁸ although other treatments can improve symptoms and help prevent cancer:

• Bone marrow transplant: this is a form of HSC, although this can also be done using cord blood or blood throughout the body. The success rate for bone marrow transplants between an FA patient and an unrelated donor has increased from 0% to almost 90% since 1989
• Androgen therapy: this helps the body make red blood cells, and is useful for those with leukaemia or those who don’t respond well to HSC. Oxymetholone, danazol, and oxandrolone are often used for this treatment
• Surgery: this can be used to treat physical abnormalities
• Synthetic growth factors: these help the bone marrow make more blood cells
• Gene therapy: this involves replacing a mutated gene with its unmutated form. This can be delivered using an inactive virus (which cannot cause disease), or by editing a patient’s genes using CRISPR/Cas9. This treatment is still being studied as the long-term efficacy and impacts remain unclear.⁸ Patients receiving this treatment also remain susceptible to cancers.¹

If you’re being treated for cancer and have FA, it's important that your medical team is aware of your condition. Chemotherapy and radiotherapy involve creating crosslinks to kill tumour cells, but this can have serious effects on patients with FA.³

Summary

FA is a rare genetic disorder affecting the bone marrow and internal organs, causing physical abnormalities. It occurs due to mutations in any of the 23 FA pathway genes, with most cases being linked to FANCA, FANCC, and FANCG mutations. FA impacts DNA repair, particularly for interstrand crosslinks, leading to a higher risk of cancer and stunted cell growth. Symptoms include anaemia, bone marrow failure, and various physical abnormalities like short stature, and extra or missing thumbs. Diagnosis typically involves chromosomal breakage tests and genetic screening. Treatments range from HSC to androgen therapy and gene therapy. Managing FA requires specialised care, especially during cancer treatment, due to the sensitivity of FA cells to DNA-damaging therapies.