Introduction

Definition of fanconi anaemia (FA)

Fanconi anaemia is a rare disease in 1 to 5 million people.¹ Fanconi anaemia is a hereditary disease (it is a disease caused due to a mutation of genes inherited from one or both parents). It is also a recessive disease ( which means that for a person to have this disease, they should receive a non-working copy of the gene from both parents).

Fanconi anaemia is known to be associated with bone marrow failure. It can be associated with other disorders like myelodysplasia (MDS) ( it is a very rare type of blood cancer), acute non-lymphocytic anaemia (it is a type of blood disease that can be caused by bone marrow failure) and other tumours.¹

Fanconi anaemia is characterised by developing pancytopenia (significantly low numbers of blood cells).² A person suffering from Fanconi anaemia can also suffer from skeletal disorders or any disorder affecting major organs. This varies according to the patient.²

Fanconi anaemia: a brief overview

Clinical features and symptoms

Some symptoms are very common with Fanconi anaemia, like retardation of the growth and small size of the head, some spots on the skin with the colour cafe au lait and radial ray abnormalities (an abnormality where there is a defect in the radius bone in the arm).

Not all patients suffer from major congenital malformations. Only two-thirds of patients have major congenital malformations.² Patients with radial ray abnormality usually have it on one side, but it can be on both sides even if the patient has it on both sides, it is asymmetric.

Patients who have Fanconi anaemia and suffer minor congenital malformations usually have some changes in their height, weight, growth, and also the size of the head.

The common symptoms that almost all patients have are the cafe au lait spots and the small head size. Fanconi anaemia can affect the hearing ability of the person who has it by affecting the ear's structure, leading to hearing loss. Fanconi anaemia affects the ear structure as follows: either the ear is positioned in an abnormal position, the ears are significantly prominent, or there is an absent pinna( the large cartilaginous part of the ear).

A person with Fanconi anaemia will have growth-related problems, such as short stature. This is due to Fanconi anaemia and hormonal deficiencies like a decreased function in the pituitary gland (the master gland influences other glands in the body and is found in the brain), decreased function of the gonads (glands that produce the reproduction hormones), a growth hormone deficiency, insulin deficiency and dysfunction of the thyroid gland.

Fanconi anaemia also causes infertility as it affects the gonads. It was found that pregnant women with Fanconi anaemia go through premature pregnancy while men with Fanconi anaemia are infertile².

Diagnosis of fanconi anaemia

Besides the clinical diagnosis based on the signs and symptoms, some lab tests can confirm the diagnosis. The patient suspected to have Fanconi anaemia will be given a peripheral blood sample to be tested to see whether it crosslinks with agents like DEB and mitomycin C (MMC). The use of these agents has proven to be sensitive, reproducible and specific.²

Bone marrow failure: definition and mechanisms

Normal bone marrow function and hematopoiesis

Bone marrow is the main site for blood cell maturation and development.

It is located in axial and long bones within their central cavities. It's made of hematopoietic tissues (blood cells forming tissues) and fat cells surrounded by some blood vessels. Bone marrow makes up 5% of the human body weight.³

Hematopoiesis is the production of blood cells in the bone marrow. Bone marrow is the primary hematopoietic organ. It is responsible for the production, differentiation and maturation of the red blood cells, white blood cells, and platelets. It plays an important role in immunity.³

Definition of bone marrow failure

A person is said to have bone marrow failure when they have a condition called pancytopenia, which means a very low number of blood cells. As the bone marrow’s main function is to produce blood cells, pancytopenia is considered an indicator of bone marrow failure.⁴

Common causes of bone marrow failure

Several diseases, syndromes, or conditions cause bone marrow failure or are associated with it like:

1. Anaemia
2. Neutropenia (decrease in the number of neutrophils, which is a type of white blood cell)
3. Thrombocytopenia (decrease in the number of platelets)
4. Pancytopenia
5. Red cell aplasia (absence of the red blood precursor cells that later mature into red blood cells)
6. Sideroblastic anaemia (a type of anaemia that results from a disorder in using iron in the process of production of red blood cells)
7. congenital dyserythropoietic anaemia ( a blood disorder) 
8. Haemolytic anaemia (a type of anaemia where red blood cells are destroyed at a rate faster than they are made )
9. Paroxysmal nocturnal haemoglobinuria (a blood disorder characterised by sudden night brown/black/pink urine)
10.  Iron deficiency anaemia 
11. Megaloblastic anaemia (a disorder where the precursor cells of red blood cells are large in size)
12.  Shwachman–Diamond syndrome (SDS)
13.  Fanconi anemia 
14.  Dyskeratosis congenital (it is a bone marrow failure syndrome characterised by skin and nail abnormalities)
15.  Aplastic anaemia ( a bone marrow failure disorder)
16.  Human immunodeficiency virus (HIV) infection.
17.  Myelodysplastic syndromes 

Why do patients with fanconi anaemia develop bone marrow failure?

DNA repair defects in FA due to genetic mutations 

The FA genes are responsible for DNA repair. During our lifetime, DNA sometimes gets subjected to damage, and the FA genes play an important role in repairing the DNA.  When a child is born with a defect in the FA genes, the damage in the DNA doesn't get properly repaired, which in turn affects other organs, including Bone Marrow.⁵

Impact on hematopoietic stem cells

Most patients with Fanconi anaemia develop Bone marrow failure. At birth, the blood count of the red blood cells, white blood cells, and platelets is normal. When the child reaches the age of seven, the blood count starts to decrease. The child suffers from thrombocytopenia leukopenia (decrease in white blood cell count) and then eventually develops pancytopenia.

This series of events means that a child born with Fanconi anaemia has a defect in the stem cells responsible for the production and maturation of the blood cells.

Studies proved that this defect begins while the patient is still an embryo and then starts to develop till it reaches a bone marrow failure stage.⁵

Management and treatment strategies

Hematopoietic stem cell transplantation (HSCT)

Indications and eligibility criteria

One of the treatments recommended for patients with Bone marrow failure is the transplantation of stem cells. Patients with severe pancytopenia with a neutrophil count of 1,000/L, haemoglobin 8 g/dL, or platelet count of 40 – 50,000/L require stem cell transplantation.

Donor selection

A suitable donor is healthy and has (HLA) antigen. The perfect donor is a sibling with the criteria mentioned.

Androgens 

Patients whose stem cell transplantation is not suitable for them can have an alternative treatment, which is androgens. Androgens can help patients with severe pancytopenia. It is usually recommended for patients who are at a very high risk of bleeding and infection and depend on blood transfusion to raise their platelets and white blood cell count. However, with androgens administration, the liver functions and adenomas' development should be monitored.

Gene therapy 

Some studies and clinical trials are still being conducted regarding gene therapy and gene transfer. It is suggested that one correct blood cell-producing stem cell is sufficient as it will be replicated to help patients of Fanconi anaemia who suffer from bone marrow failure increase their blood count and have normal blood cells.

Prognosis and long-term outcomes

Survival rates and quality of life

Survival rates can differ from one patient to another, but the average survival of the Fanconi anaemic patients is about 30 years. The presence of bone marrow failure greatly impacts the quality of life.

Long-term complications and monitoring

Secondary malignancies

Patients with Fanconi anaemia and Bone marrow failure are at a very high risk of developing malignancies and tumours and should be monitored and checked regularly.

Organ dysfunction

The FA genes affect other organs, so other organs can be affected when there is a defect in one or more of the FA genes.

Summary 

Fanconi anaemia is a rare disease that the patient is born with. It is also a recessive disease. It is caused by a defect in the FA genes and is associated with some abnormalities, including skeletal abnormalities and skin pigmentations. Fanconi anaemia is also associated with Bone marrow failure. Bone marrow failure causes many diseases and can be associated with blood malignancies due to its failure to produce normal blood cells and a normal blood cell count.