What is Fanconi anaemia?

Fanconi anaemia (FA) is a rare genetic disorder that is considered the most common cause of inherited bone marrow failure. The bone marrow is found within the central part of bones and plays an essential role in replenishing blood cell populations. Bone marrow is vital to keep you healthy from delivering oxygen to vital organs in your body, fighting off harmful infections to clotting blood after being wounded. A defect of the bone marrow can therefore have significant health consequences. Furthermore, Fanconi anaemia is associated with physical abnormalities, one of which is renal and urological malformations. This article will delve into Fanconi anaemia and associated renal and urological issues.^1,2

What causes Fanconi anaemia?

Fanconi anaemia disease is caused by a mutation in the FA pathway, which is involved in DNA repair. Approximately 90% of the mutations occur in the FANCA, FANCG and FANCC genes. These mutations inhibit the cells’ ability to repair the damage that occurs to the DNA, leading to the subsequent bone marrow failure, physical dysfunctions and predisposition for cancer.

This mutation is passed down in an autosomal recessive fashion, meaning that both parents must be carriers for the disease to manifest. The documented carrier frequency is 1 in 300, with the disease frequently observed in individuals of Ashkenazi Jewish heritage, black South Africans, and the Roma communities in Spain.^2,3

What are the symptoms associated with Fanconi anaemia?

In addition to bone marrow failure, Fanconi anaemia is associated with a variety of congenital and developmental issues, and a distinct predisposition for cancers, especially acute myelogenous leukemia (AML).

Abnormalities of the kidneys and urinary tract have been seen in 30% of cases, where case studies have shown individuals with Fanconi anaemia tend to have frequent urinary tract infections (UTIs) in early childhood due to their abnormal kidney anatomy.

These symptoms can usually be identified at birth or in early childhood. However, in cases with minimal symptoms, diagnosis may be delayed, only occurring after the bone marrow failure has worsened.^2,4,5,6

Symptoms of bone marrow failure

• Fatigue
• Nosebleeds
• Bruising easily
• Frequent infections
• Blood in stool and urine

Physical symptoms of Fanconi anaemia

• Short stature
• Microcephaly
• Abnormal skin pigmentation (café au lait spots)
• Skeletal malformations (no thumb or radius bone)
• Thumb and arm abnormalities
• Small, crossed or widely spaced eyes
• Microphthalmia
• Aberrant urinary and kidney formations

Less common symptoms

• Genital malformation
• Gastrointestinal malformation
• Cardiac malformation in tissue separating the heart
• Central nervous system (CNS) dysfunctions
• Hearing loss

Renal dysfunction in Fanconi anaemia

Renal and urological issues are often associated with a more serious form of Fanconi anaemia, accompanied by heightened haematological complications. Several types of kidney abnormalities have been identified in individuals with Fanconi anaemia, which consist of:^3,4,7

• Dysplastic kidneys
• Pelvic kidneys
• Malrotated kidneys
• Fused ectopia
• Horseshoe kidney
• Multicystic kidney
• Duplex collecting systems
• Chronic atrophic pyelonephritis
• Ectopic kidneys

Urological dysfunction in Fanconi anaemia

Abnormalities of the kidneys can lead to frequent UTIs which can damage the kidneys and lead to chronic pyelonephritis. Urological issues include:^3,7

• Vesicoureteral reflux (VUR)
• Posterior urethral valves (PUV)
• Neurogenic bladder
• Urethral stenosis
• Hydroureter

Difference between Fanconi anaemia and Fanconi syndrome

Fanconi anaemia and Fanconi syndrome are two separate and distinct conditions. Fanconi syndrome is described as a rare kidney disorder which impairs the proximal tube’s ability to absorb electrolytes. Unlike Fanconi anaemia, it can be both inherited and also induced by certain drugs, such as aristolochic acid which can result in renal failure.^8,9

Diagnosis of Fanconi anaemia

Diagnosing Fanconi anaemia is challenging due to its extreme range in clinical presentation and disease severity. Diagnosis of the disease typically will require a variety of specialist opinions.

Individuals with this disease can commonly be diagnosed through blood tests for having low levels of red blood cells, white blood cells and platelets. Physical anomalies can be identified through a variety of imaging including ultrasound and X-ray.

Diagnosis is usually acquired through a combination of clinical presentation, patient history and additional tests like the chromosome breakage test which assesses the DNA repair ability of cells. The chromosome breakage test can even be performed before a baby is born to diagnose Fanconi anaemia.^2,6

Current treatments for Fanconi anaemia

Stem cell transplantation

At present, hematopoietic stem cell transplantation is the sole curative treatment available for Fanconi anaemia, achieved by substituting defective blood cells with healthy ones. Efforts have been made to enhance this transplantation process using cytoreductive regimens like fludarabine and T-cell-depleted grafts, which have demonstrated an increase in survival rates from 50% to 70%. One study has even found a survival rate of 100% after one year of transplant which declines to 84% after 10 years.^6,10

Nonetheless, there are potential long-term complications associated with this transplant, including the risk of organ failure like acute kidney injury, which has been observed at an occurrence rate of 18.7% post-transplantation, however, renal function can show recovery six months following the procedure. Furthermore, therapies such as high-dose myeloablative treatment may be harmful to the kidneys and adversely affect the renal system.^1,11

Surgery

In certain situations, surgical intervention is necessary to resolve physical abnormalities, such as issues with the heart and skeletal system. One such procedure, known as a sting operation, can be utilised to remedy vesicoureteral reflux (VUR) in the kidneys by injecting a bulking agent into the ureteral opening to stop backflow. In some cases, it may be necessary to remove the kidney and perform a transplant.^2,7

Avoidance of chemicals

Some chemicals like tobacco and formaldehyde will need to be avoided to prevent further DNA damage.²

Genetic counseling

Families should assess who are carriers of the disease to understand the likelihood of producing a child with the same defect. Genetic counselling can even assess a certain mutation to determine if an individual is predisposed to specific tumours, which could allow for the development of a treatment plan.^2,5

Summary

Fanconi anaemia (FA) is a rare genetic disorder that is a leading cause of inherited bone marrow failure. Bone marrow is crucial for producing blood cells, which are essential for delivering oxygen, fighting infections, and clotting blood. A defect in bone marrow can have serious health effects, and FA is often linked to physical abnormalities, including kidney and urinary tract issues. FA is caused by mutations in the FA pathway, primarily affecting the FANCA, FANCG, and FANCC genes. These mutations impair the cells' ability to repair DNA, leading to bone marrow failure and an increased risk of cancer. The disorder is inherited in an autosomal recessive manner. It is more common in certain populations, including Ashkenazi Jews, black South Africans, and the Roma in Spain.

Symptoms of FA include bone marrow failure, which can lead to fatigue, frequent infections, bruising, and blood in urine or stool. Physical symptoms may include short stature, abnormal skin pigmentation, and various skeletal malformations. Diagnosing FA can be challenging due to its wide range of symptoms and severity. Blood tests, imaging, and chromosome breakage tests are commonly used to confirm the diagnosis. Currently, the main treatment is hematopoietic stem cell transplantation, which can improve survival rates but may also cause long-term complications. Surgical interventions may be necessary for certain physical abnormalities, and avoiding harmful chemicals is advised. Genetic counselling is recommended for families to understand carrier status and associated risks.