Introduction

Fanconi anaemia is a rare genetic disorder characterized by a chromosomal abnormality, gradual bone marrow failure leading to decreased blood count, birth defects, physical abnormalities, and an increased risk of malignancy (cancer).¹ It is caused by mutations in one or multiple genes, leading to defects in the DNA sequence due to improper copying and repairing ability of the genetic information in the DNA.² Fanconi anaemia is a extremely rare type of anaemia seen in 1 child out of 136,000 newborns, with a range of 4-7 cases for every million births.³

It is the most common cause of the inherited bone marrow failure syndrome that leads to haematological defects. While certain medications and supportive measures can help control and manage the disease, bone marrow transplantation is the primary treatment for curing and replacing the defective hematopoietic system. Since it's a complex and risky procedure, it's crucial to have a thorough understanding of the pre-transplantation, transplantation, and post-transplantation processes to improve outcomes and enhance the quality of life for patients with Fanconi anaemia.

Fanconi Anaemia: An Overview

Genetic basis

Fanconi anaemia can be inherited in three different patterns: autosomal recessive, autosomal dominant, or X-linked. This occurs during DNA crosslinking, leading to mutations in various genes. Most cases of Fanconi anaemia occur in an autosomal recessive pattern, with a 25-50% chance of individuals inheriting the disease.⁴

The human body consists of a repair pathway known as the FA/BRCA pathway, this pathway is essential for detecting DNA damage, repairing it, and regulating the cell cycle. The Fanconi anaemia pathway involves 22 genes⁵ that encode various proteins responsible for repair and regulation. The most prominent genes in this pathway are FANCG, FANCA, FANCD2, and FANCC. Mutations or changes in these genes are primarily responsible for causing DNA damage, abnormal cell growth, malignancy, and other blood-related manifestations of Fanconi anaemia.⁶

Clinical manifestation

The symptoms of Fanconi anaemia can appear at birth, during early childhood, or in young adulthood. These symptoms can be associated with conditions such as bone marrow failure syndrome, cancer, and physical abnormalities. Fanconi anaemia can affect both external physical appearance and internal features, and the specific symptoms may vary from person to person. It's important to note that there may not be any specific or obvious symptoms of Fanconi anaemia.⁷

Anaemia symptoms include:³

• Shortness of breath
• Fatigue and dizziness
• Chest pain
• Petechiae - a small red spot under skin
• Excessive bleeding from wound
• Increased risk of infections
• Epistaxis - nosebleed 
• Weight loss

Congenital and physical abnormalities

Around 75% of Fanconi anaemia will have birth defects with symptoms including

• Low birth weight, short stature.
• Skeletal abnormalities like no radius bone or thumb bone.
• Light or dark-coloured spots and birthmarks with skin pigmentation
• Anomalies in the kidney, heart, and GI system⁸

Cancer risk

• A person with Fanconi anaemia has an increased risk of cancer mainly carcinoma, and leukemia with symptoms of fatigue, pale, bruising, and bleeding, increased risk of infection, bumps, sores, or abnormal growths.⁷

Diagnosis

Diagnosis of Fanconi syndrome can be done by physical examination and various laboratory tests like

• Chromosomal breakage test – it is the primary test performed for Fanconi anaemia wherein the suspected blood sample is taken to the clinical cytogenetic laboratory from which lymphocytes are isolated and subjected to DNA cross-linking agents and chromosomes are examined for breakages. A sample with less chromosome breakage is a negative report while the sample having higher breakage is likely to have Fanconi anaemia.
• Genetic testing – It is the secondary test performed after obtaining a positive report for chromosome testing to identify the specific variants that cause FA. The sample is taken and subjected to gene sequencing to find out the FA gene variant that can pose risk to increased risk for malignancy.⁹

Bone Marrow Transplantation (BMT)

Bone marrow transplantation is a process of administering healthy bone marrow stem cells to an individual with depleting bone marrow. This procedure helps to improve bone marrow function by replacing the dysfunctional marrow cells with functional ones. The majority of fatalities from Fanconi anaemia are due to bone marrow failure, leading to haematological conditions such as myelodysplastic syndromes and acute myelogenous leukaemia (a form of blood cancer). The primary treatment for this issue is bone marrow transplantation, which involves replacing the defective bone marrow cells with healthy and functional ones. In addition to replacing unhealthy cells, bone marrow transplantation also helps in combating malignancy by destroying malignant cancer cells that may be caused by Fanconi anaemia.^10,11

There are mainly 3 types of bone marrow transplantation depending on the source of healthy donor cells which includes

• Autologous bone marrow transplant – auto refers to self. This procedure involves the use of one's own stem cells, which are collected after a bone marrow harvest, frozen, and then transplanted. Here the patient himself or herself is a donor.
• Allogeneic BMT- This procedure involves finding a donor with the same genetic type. After matching, healthy cells are harvested, collected, and transplanted. The donor can be a sibling to the patient, or in rare cases, a parent who is half-identical (referred to as haploidentical BMT), or an unrelated individual with genetically matched marrow cells.
• Umbilical cord blood transplant – the cells are collected from the umbilical cord of infant, which are reproduced into a matured functional cell, frozen and then transplanted.¹²

Pre-Transplant Considerations

Bone marrow transplantation is a complex procedure so before undergoing transplantation, the patient must be evaluated to check for the medical condition, and its stage, and to determine if he is fit for the process. A complete medical history, physical examinations, various laboratory tests such as blood tests, and imaging studies for malignancy are performed.

Donor Selection

When undergoing a bone marrow transplant (BMT), it is important to select a suitable donor after an HLA matching. Typically, for allogeneic transplants, a donor is selected from a HLA-matched family member or an unrelated individual. Finding a donor for an unrelated allogeneic transplant can be quite challenging, but national and international registries can be used to find a suitable donor.

Pre-Transplant Conditioning

Before the bone marrow transplantation procedure, patients undergo a special treatment plan known as a conditioning regimen. The goals of this regimen are to provide proper immune support to prevent rejection of the transplanted bone marrow, and to destroy the cancer cell thus creating enough space in bone marrow for stem cell multiplication.  Reduced intensity regimens and nonmyeloablative conditioning regimens are one such regimen for radiation and chemotherapy doses which are used to improve the acceptability of BMT in older and medically challenged patients. This regimen guides the therapeutic options, dosages, and additional interventions for bone marrow transplantation, taking into account factors such as age, remission status, and other medical conditions.¹¹

Transplant Procedure

The transplant procedure involves two steps

• Harvesting the bone marrow/stem cells
• Infusion of stem cells

Harvesting Bone Marrow/Stem Cells

Harvesting and collection of the stem cells can be done from a bone marrow or a peripheral system i.e., the circulating cells in the blood.

• The bone marrow harvest method involves anesthetizing the donor and then isolating the stem cells from the soft part of bone which is the marrow using a needle. This procedure is done under the guidance of an experienced transplant specialist in an operating room. The donor might not experience the pain during the procedure, however, the pain might be seen at the needle site during a post-recovery period. The preferred bones for stem cell collection are the sternum and hip bones.
• The peripheral blood stem cell collection technique involves using a specialized machine for isolation. The stem cells will circulate in the blood which are isolated with the help of a special machine and needle. A needle is inserted into the arm veins of the donor, using which the blood is collected and sent to the machine. This machine separates the required stem cells from the blood and sends back the unwanted blood cells and plasma to the donor via the needle which is connected to another arm vein of the donor. As only a few stem cells are collected due to the limited quantity of blood, this procedure is carried out several times until a required amount of stem cells are isolated. ¹²

Infusion of stem cells

After the successful isolation of the stem cells, they are infused into the patient via an intravenous route like a blood transfusion.¹⁴ This is a convenient mode of transfusion. These cells will restore the body's ability to produce new cells.¹³ Most patients will develop the new marrow cells within 2-3 weeks, however, for a few patients it might take many weeks to a few months to develop the bone marrow cells adequately.¹⁵

The side effects from this procedure are quite rare still, most patients will choose to stay at the hospital for a longer time and are monitored until a new marrow is developed to prevent the infections and side effects. However, few patients will opt for outpatient post-stem cell transplantation services as well.¹⁴

Post-Transplant Care

Bone marrow transplanted patients might experience both acute and long-term side effects. The side effects may differ from patient to patient depending on age, donor type, and conditioning regimen. Acute side effects appear within 3 months include acute graft versus host disease, bacterial infection, fungal infection, etc. Antibiotic prophylaxis will be provided in the hospital to prevent infections.¹⁰

Few side effects will not appear after a few months or even a year after transplantation, some common late complications include chronic graft versus host disease, cognitive problems, insomnia, etc. These are seen in rare cases and can be managed by proper screening and lifestyle changes.¹⁶

Outcomes and Prognosis

The survival rate and success rate for bone marrow therapy show positive statistics, especially with non-malignant cases having a success rate of 70-90% survival, while the malignant cases showed a success rate of 55-68%.BMT has also reduced the reoccurrence of the disease with an increase in quality of life. The factors that influence the success rate include the quality of treatment, pre-transplantation regimen, stem cell donor type, etc.¹⁷

Summary

Bone marrow transplantation (BMT) is the primary treatment for Fanconi anaemia, addressing bone marrow failure and reducing malignancy risks. It involves pre-transplant evaluations, donor matching, and conditioning regimens. The transplant procedure includes harvesting stem cells from bone marrow or peripheral blood, followed by intravenous infusion into the patient. Post-transplant care focuses on monitoring and managing acute and long-term side effects to improve patient outcomes and quality of life.