Introduction

Fanconi anaemia (FA) is a rare, inherited genetic disorder that causes abnormalities in the bone marrow and other parts of the body. These abnormalities result in a susceptibility to blood disorders and certain types of cancers, which often develop at a young age. FA can also commonly cause physical abnormalities, which may result in an abnormal appearance. Treatment varies depending on the clinical signs and may include a bone marrow transplant, androgen therapy, synthetic growth factors, or surgery to help repair physical abnormalities. FA is caused by mutations in specific genes inherited from one’s parents; therefore, it is important to understand how this happens if FA runs in your family.¹

Discovery of fanconi anaemia

To understand what causes FA and how the syndrome develops, it is helpful to understand how it was first discovered and subsequently studied. In 1967, Swiss paediatrician Guido Fanconi described what is now called Fanconi Anaemia in two siblings with similar signs - developmental abnormalities and bone marrow failure. These signs are now recognised as hallmarks of FA. Since then, associations between mutations in genes that control DNA repair mechanisms, cancer development, and haematological disorders have all been identified as characteristics of FA.²  

Genetic basis of fanconi anaemia

Inheritance pattern

FA is the most common form of inherited bone marrow failure syndrome and can be passed from parent to child in various ways. Mutations in the FANCA (Fanconi anaemia, complementation group A) gene cause an accumulation of genetic damage due to an inability to repair DNA correctly. 

Autosomal recessive 

This inheritance pattern means each child has a 25% chance of developing FA (i.e., an affected gene from each parent needs to be passed on to the child). There is also a 25% chance of inheriting neither of the pathogenic variants, meaning the child would be totally unaffected. Additionally, there is a 50% chance the child will inherit one pathogenic variant, making them a heterozygote who would not have autosomal recessive FA. However, they may still have a predisposition to develop certain types of cancers.³ Autosomal recessive is the most common type of inheritance in the majority of FA cases. 

Autosomal dominant

Autosomal dominant inheritance describes a pattern in which only one allele of the affected gene needs to be inherited for the condition to be present. This is the case with a specific type of FA—Fanconi Anaemia type R—which is caused by mutations in the RAD51 gene. RAD51 is a gene involved in DNA repair.³ 

X-linked

For females carrying a copy of the pathogenic variant, there is a 50% of passing it on to their offspring. If the child is male and the affected gene was passed on then he will usually be affected, however, if the child is female, she will usually only be a carrier.³ X-linked inheritance is rare, accounting for approximately 2% of FA cases.⁴

Fanconi anaemia genes

Over 23 Fanconi Anaemia complementation genes (FANC) have been discovered. All 23 are involved in different aspects of DNA repair. Mutations in these genes result in DNA damage that is either repaired incorrectly or not repaired at all, leading to chromosomal damage. Every cell accumulates DNA damage on a daily basis due to a variety of mechanisms including exposure to UV light, radiation, and mistakes during cell replication. This is a normal process, and if healthy, the damage is repaired efficiently through several mechanisms, including the FA pathway. However, in FA patients, this damage accumulates over time, resulting in the clinical signs associated with FA. The most commonly affected genes include biallelic mutations of FANCA, FANCC, and FANCG, which together form part of the FA core complex. In over 80% of FA patients, these three genes drive the condition.⁴ 

What do fanconi anaemia genes do?

The main role of FA genes is to maintain genomic stability and protect cells against the accumulation of DNA damage. They are responsible for facilitating the repair of DNA interstrand cross-links, which are links between the two strands of DNA that prevent separation and hence DNA replication. Certain types of drugs used to treat cancers—including bifunctional alkylating agents (such as cyclophosphamide, chlorambucil, and melphalan), platinum agents (cisplatin, carboplatin, and oxaliplatin) and natural agents like mitomycin C—all induce interstrand cross-links to create genomic instability and promote cell death. Patients with FA are hypersensitive to treatment using DNA cross-linking agents due to an inability to repair the cross-links—this forms the basis for one of the diagnostic tests, the chromosome breakage assay.⁵ 

Fanconi anaemia and bone marrow failure

The risk of developing haematological abnormalities with FA is very high around 90% of patients will have at least one abnormality by the age of 40.³ Bone marrow failure typically occurs before 10 years of age in patients with the most common FA mutations. It is believed that bone marrow failure develops due to the destruction of CD34+ cells. CD34 is a marker of haematopoietic stem cells, which are able to self-renew and facilitate the production of mature blood cells, such as erythrocytes, leucocytes, lymphocytes, and platelets.⁶ Processes that contribute to this selective destruction include abnormalities in DNA repair, replication, and cytokine regulation.⁴ With a lack of CD34+ cells, aplastic anaemia develops and may be treated with a stem cell transplant, which has significantly improved the outlook for many patients with FA.⁷ Progressive bone marrow failure results in pancytopenia, a decrease in all three blood cell lines. The earlier this can be detected, the higher the chances of successful treatment and fewer complications.⁴ 

Fanconi anaemia and cancer predisposition

FA is a complex syndrome that can present differently in individual patients. A mutation in any one of the FA genes causes a genetically distinct subtype, resulting in heterogeneity. A common feature among all patients is an inability to efficiently repair DNA damage. The exact mechanism varies depending on which genes are mutated, but all FA patients are susceptible to genomic instability. This instability places FA patients at a significantly higher risk of developing certain cancers due to the accumulation of mutations, which can lead to uncontrolled cell proliferation, immune evasion, and resistance to programmed cell death. The most common types of cancers include: 

• Acute myeloid leukaemia
• Head and neck squamous cell carcinomas
• Gynaecological squamous cell carcinomas

Heterozygous patients who do not have FA but carry a pathogenic allele are also predisposed to cancer development. Mutations of FA genes within the BRCA pathway can increase the likelihood of developing hereditary breast and ovarian cancer (HBOC). Biallelic mutations in either BRCA gene ultimately lead to FA.

It is also possible to develop cancer due to somatic gene mutations within the FA pathway in patients who do not have FA. These mutations develop over time, are not inherited, and result in sporadic cancer development. They are most commonly seen in cutaneous squamous cell carcinoma, as well as in bladder, breast, and pancreatic cancers. FANCA inactivation has also been identified in cases of acute myeloid leukaemia in non-FA patients.⁸   

Fanconi anaemia and non-haematological manifestations

In addition to the typical progressive bone marrow failure and susceptibility to cancer development, other clinical signs often appear at a young age. Approximately 75% of patients exhibit congenital abnormalities. The severity and type of these abnormalities vary greatly between patients; however, the most common features include:

• Short stature
• Abnormal skin pigmentation
• Limb abnormalities
• Head and facial anomalies 
• Hypogonadism

Some of these manifestations result from abnormal development during gestation, due to genomic instability and the accumulation of mutations.⁴  

Summary 

FA is a very rare, complex inherited syndrome that results in a combination of progressive bone marrow failure, cancer predisposition, and a range of congenital and developmental abnormalities. FA genes are responsible for producing proteins that are involved in numerous DNA repair pathways, including the facilitation of interstrand cross-link repair. When mutations occur in any one of these genes, the body loses the ability to effectively repair DNA. This promotes genomic instability, which is responsible for the clinical signs associated with FA. Further research over the last 20 years has increased our understanding of this heterogeneous disease; however, there are still unknowns regarding the exact pathophysiology and the complex interactions among all the FANC genes in various DNA damage repair pathways. Continued research will hopefully provide more insight into the development of FA, as well as the role FA genes play in the development and/or suppression of cancer, which may provide new targets for cancer therapies.