Types of Bone Marrow Failure Syndromes

What is Aplastic Anaemia?

Aplastic Anaemia is a rare and life-threatening haematological disorder that predominantly affects children and young adults. The major causative mechanism is an immunological attack on one’s blood forming stem cells, known as haematopoietic stem cells, that leads to bone marrow destruction and bone marrow failure.

Aplastic Anaemia can develop either rapidly or slowly and there is no way to prevent its development. Sometimes, individuals with acquired Aplastic Anaemia also develop other disorders, such as paroxysmal nocturnal hemoglobinuria (PNH) or myelodysplasia (MDS).

What causes Aplastic Anaemia?

In most cases where a person is diagnosed with Aplastic Anaemia, the cause isn’t known. A number of chemicals, environmental toxins and viral infections have been implicated in precipitating Aplastic Anaemia, but in the majority of circumstances, there is no specific agent responsible for the immune system malfunction.

How is Aplastic Anaemia diagnosed?

There is no single definitive test to diagnose Aplastic Anaemia, rather it is a diagnosis of exclusion, with the inherited Bone Marrow Failure Syndromes among the main differential diagnoses.

Routine clinical assessments include reviewing the patient’s history, blood tests, and more invasive investigations procedures such as a bone marrow biopsy. A bone marrow biopsy is a surgical procedure which collects a small specimen of bone marrow tissue to review it’s functionality under the microscope.

Additional tests may be necessary to rule out other disorders such as leukemia and to determine if there is an inherited or genetic cause.

Severity of Aplastic Anaemia is determined by the number of one of the types of white blood cells (neutrophils) present and is classified as very severe, severe and mild.

What are the signs and symptoms of Aplastic Anaemia?

While Aplastic Anaemia can be present without symptoms, some people who have Aplastic Anaemia may experience:

• An increase in bruising
• Weakness, paleness
• Fatigue and tiredness
• Shortness of breath
• Headaches
• Increased infections
• Nosebleeds

How common is Aplastic Anaemia?

Aplastic Anaemia is rare, affecting approximately 2-3 million people per year in North America and Europe, and approximately 5 per million per year in Southeast Asia.

What are the current treatments?

Based on the severity of Aplastic Anaemia (including factors of age and general health), treatments aim to cure the bone marrow failure and to treat the patient’s immediate signs and symptoms.

• Immunosuppressants– first line immunosuppressive treatments include anti-thymocyte globulin (ATG) and cyclosporin (CsA)
• Granulocyte colony stimulating factor(G-CSF) – a medication that stimulates the bone marrow to produce white blood cells (granulocytes) and blood forming stem cells (haematopoietic stem cells) and release them from the bone marrow into the blood stream
• Thrombopoietin receptor agonists(TPO mimetics) – Eltrombopag and Avatrombopag are medications that stimulate the production of platelets
• Androgens– sex hormone therapies are more likely to be used in older patients
• Bone marrow transplantation– the only current curative option available is bone marrow transplantation. In younger patients with a matched sibling donor, bone marrow transplantation may be considered as first line treatment in the setting of very severe or severe Aplastic Anaemia.

Fanconi Anaemia is the most common inherited Bone Marrow Failure Syndrome. As it’s a rare genetic condition, it’s passed from the parents to their children.

Genetic mutations in 22 different genes have currently been identified as causing Fanconi Anaemia. As these genes play an integral role in the repair of DNA damage and the stability of the genetic code in cells, mutations result in not only bone marrow failure, but a much higher risk of developing both solid organ cancers and haematological (blood) cancers.

For some of these cancers, for example head and neck squamous cell cancers, the risk is hundreds fold higher than in the normal population. It is very possible there are further genes responsible, and scientists are working hard to discover additional genes that may play a role.

Whilst improved overall survival has occurred over the last few decades, particularly with improvements in the administration of bone marrow transplantation, the median survival of Fanconi Anaemia is still horrifically less than 30 years.

For more information on Fanconi Anaemia, visit Fanconi Anaemia Support Australasia (FASA).

Dyskeratosis Congenita is characterised by bone marrow failure, dystrophic (malformed) nails and abnormalities of the skin. Increased incidence of solid and haematological (blood) cancers occurs. The incidence of Dyskeratosis Congenita is approximately 1 in 1,000,000.

Currently, mutations in 11 genes have been identified as causing Dyskeratosis Congenita. Many of the genetic mutations that have been discovered are located within genes that are responsible for the integrity and lengthening of telomeres. Telomeres are the ‘fluffy’ tips that cap our chromosomes, protecting the essential genetic code stored within the chromosome. It is natural for our telomeres to shorten as part of the ageing process, but unfortunately in conditions like Dyskeratosis Congenita, telomeres are prematurely shortened.

Diamond Blackfan Anaemia is characterised by deficiencies of red blood cells and a moderate to severe anaemia. The majority of genes that have been identified as causing Diamond Blackfan Anaemia are in ribosomal protein genes. Ribosomes are mini factories that reside in all cells, and are responsible for producing proteins.

Diamond Blackfan Anaemia affects approximately 5 per million people per year. Associated issues may include short stature, heart, eye and kidney problems.

Schwachman Diamond Syndrome is typically characterised by bone marrow failure and abnormal development of the pancreas. Reduced production of pancreatic enzymes results in digestive issues and malabsorption. Additional issues may include short stature, abnormal bone development and liver problems.

Schwachman Diamond Syndrome is mainly inherited in an autosomal recessive pattern, whereby in order to be affected an individual receives a copy of the mutated gene from each parent. The SBDS gene has been implicated in the majority of cases. Reported incidence is approximately 1 in 75,000 individuals.

Severe Congenital Neutropenia is characterised by very low neutrophil counts. Neutrophils are the white cells responsible for fighting bacteria, and as a result, affected individuals are particularly susceptible to infections of the skin, digestive tract and respiratory system. These infections can be life threatening.

There are 2 genes that have currently been found to cause Severe Congenital Neutropenia. Approximately 1 person per 1,000,000 is estimated to be affected.

Thrombocytopenia with Absent Radii Syndrome is characterised by low levels of platelets (thrombocytopenia) and the absence of the radius bone, the long bone of the forearm. Other abnormalities may also be present, including short stature, heart and kidney issues.

Thrombocytopenia with Absent Radii Syndrome is inherited in an autosomal recessive manner, and thus far two different types of mutations in the RBM8A gene have been identified. Estimated prevalence is less than 1 per 100,000.

Congenital Amegakaryocytic Thrombocytopenia is characterised by very low numbers of megakaryocytes, the bone marrow cells responsible for producing platelets. Patients are susceptible to bleeding difficulties. In some circumstances bleeding can be life threatening. Patients may also have other abnormalities of the central nervous system and the heart.

Congenital Amegakaryocytic Thrombocytopenia is understood to be inherited in an autosomal recessive pattern, and a single gene has currently been identified as causative. It is extremely rare and worldwide prevalence and incidence is unknown. Approximately 100 cases have been reported in the literature.