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What are the inherited Bone Marrow Failure Syndromes?

Inherited BMFS (iBMFS) usually present during childhood. These syndromes involve genetic hereditable defects that reduce blood forming stem cell survival or stem cell proliferation. The syndromes include multiple other non-blood forming (non-haematopoietic) manifestations.

Fanconi Anaemia

Fanconi Anaemia is the most common of the iBMFS, with a reported incidence of 1 in 130,000. 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.

Dyskeratosis Congenita

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

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.

Shwachman Diamond Syndrome

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

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

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

Congenital Amegakaryocytic Thrombocytopenia (CAMT) 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.

CAMT 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.