What is Bone Marrow Failure?
Bone marrow failure (BMF) is a condition where the bone marrow produces fewer or no blood cells, leading to low levels of blood cell precursors in the bone marrow, resulting in various health problems. It can be either acquired (developed over time) or inherited (passed down from parents).
Inherited bone marrow failure (IBMF) occurs when a person inherits certain defects in their genes from their parents, or new defects happen for the first time in a person. This not only leads to symptoms like extreme fatigue, abnormal bleeding, and frequent bacterial infections (similar to aplastic anemia) but also can present with unique characteristics depending on the specific syndrome.
The most commonly seen inherited bone marrow failure syndromes (IBMFSs) include Fanconi anemia (FA), dyskeratosis congenita (DC), Shwachman-Diamond syndrome (SDS), congenital amegakaryocytic thrombocytopenia (CAMT), Blackfan-Diamond anemia (BDA), and reticular dysgenesis (RD). There are others too but they are rarer and often share traits with the listed IBMFSs, such as short telomerase, which is a part of the chromosome that affects how cells age.
What Causes Bone Marrow Failure?
Inherited bone marrow failures are health conditions that occur due to specific changes or mutations in a person’s genes. These mutations are usually passed down from parents, or they can sometimes happen spontaneously. Several of these conditions, like Fanconi anemia, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, and reticular dysgenesis, are generally inherited in a way that is called “autosomal recessive”. This means that for the condition to develop, a person needs to get a mutated gene from both parents.
A small number of these conditions, such as dyskeratosis congenita and 2% of FC, are inherited in an “X-linked recessive” manner. Here, the mutated gene is located on the X chromosome, and typically, males are more affected than females.
Blackfan-Diamond anemia and reticular dysgenesis are examples of conditions that are recovered in an “autosomal dominant” way. In this case, just one mutated gene from either parent is enough for a person to develop the condition.
Risk Factors and Frequency for Bone Marrow Failure
Bone marrow failure tends to occur in three main age groups: 2 to 5 years old, 20 to 25 years old, and those over 65 years old. In young children, it’s usually inherited, while in the elderly, it’s often due to other causes. Out of all cases of bone marrow failure, 10% to 15% are inherited and this is even higher (30%) in children with bone marrow issues. Each year, about 65 in every million newborns will have this condition.
Most of the time (75%), it’s possible to identify why a child has inherited bone marrow failure. Even though these inherited conditions can show up in adults. The most common one is called Fanconi anemia. This condition happens in 1 to 5 out of every million people and is more common in certain populations: Spanish Gypsies (1 in 64), Afrikaners in South Africa with a certain mutation (1 in 83), and Ashkenazi Jews (1 in 89). Interestingly, 10% of people who have bone marrow failure weren’t aware they had Fanconi anemia.
Signs and Symptoms of Bone Marrow Failure
Inherited bone marrow failure syndromes are health conditions that mainly affect blood cells production. Common symptoms include constant tiredness and pale skin due to anemia, easy bruising or bleeding caused by low platelet count (thrombocytopenia), and fever with mouth sores or bacterial infections resulting from low white blood cell count (neutropenia). Some people with these syndromes also have features that aren’t related to blood cells, but these aren’t always present.
Fanconi anemia is one of these syndromes, usually seen in children. Symptoms include:
- Low birthweight
- Birthmarks that are the color of coffee with milk (cafe au lait spots)
- Being shorter than average
- A smaller than normal head (microcephaly)
- Kidney or heart abnormalities
- Delayed puberty
- Missing or unusually formed forearms and thumbs
- History of bone marrow failure or certain cancers in the patient or family members, often at an early age (before 40 years old).
Another syndrome known as Dyskeratosis congenita also chiefly affects children, and while it shares many of the same features, it has some unique distinctions, including:
- Lacy skin pigmentation and small, widened blood vessels (telangiectasias) generally affecting the upper body
- Abnormal teeth
- Hair loss
- Early onset of gray hair
- Nail disorders
- Excessive sweating of the non-hairy (glabrous) skin
- Scarring and thickening of lung tissue (pulmonary fibrosis)
Other syndromes include Blackfan-Diamond anemia, presenting at varying ages with bone marrow failure, exocrine pancreatic dysfunction, and skeletal abnormalities, and Congenital amegakaryocytic thrombocytopenia that exhibits history of low platelet count in infancy, progressing to anemia in later childhood and increased risk of certain types of cancer. Blackfan-Diamond anemia often appears early in life with isolated erythroid failure (or red blood cell production) than anemia and other features like low birth weight, bone deformities, and short stature. Reticular dysgenesis patients exhibit early onset of infections, extremely low white blood cell count, and deficient T and NK cells with almost no B cells.
Testing for Bone Marrow Failure
If you’re a patient with pancytopenia, which is a reduction of all your blood cells, doctors will first examine your blood for any abnormalities, like certain deficiencies. Then, a sample may be taken from your bone marrow to look for any signs of myelodysplastic morphology or cloned abnormal cells. These signs could show that your bone marrow is not producing blood cells as it’s supposed to.
Your doctor will then rule out acquired bone marrow failure by stopping any possibly harmful medications, treating any active infections, and testing you for hepatitis, pregnancy, or paroxysmal nocturnal hemoglobinuria (PNH – a rare, life-threatening blood disease). If you have bone marrow failure and a family history of MDS/AML (types of blood cancer) or squamous cell carcinoma (a type of skin cancer), or if you’re under 40, your doctor may also check if your bone marrow failure is a condition you inherited.
One of the things the doctor may check for is Fanconi anemia. This involves looking for abnormal chromosome breakage in particular cells. The test may involve the use of certain chemical agents. If Fanconi anemia is suspected, they’ll confirm it by sequencing your genes – essentially, reading your DNA for abnormalities.
If they suspect dyskeratosis congenita, a rare inherited bone marrow failure syndrome, they’ll perform a quantitative analysis of the length of certain parts of your chromosomes, and confirm their suspicion with gene sequencing. They’ll also simultaneously test for chromosomal fragility since it has similarities with Fanconi anemia.
For other disorders – such as Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, Diamond-Blackfan anemia, and reticular dysgenesis – your doctor will have to sequence the genes because there are no screening tests. Diamond-Blackfan anemia, for example, is associated with high levels of adenosine deaminase, an enzyme in our body.
Last but not least, your doctor will consider acquired causes for bone marrow failure, meaning causes that are not inherited. These may include drugs, chemicals, radiation, viral infections, immune disorders, MDS, PNH, or large granular lymphocytic leukemia, a rare type of chronic leukemia.
Treatment Options for Bone Marrow Failure
The best treatment for inherited bone marrow failure syndromes, which are conditions where the bone marrow cannot create enough blood cells, involves a procedure called a hematopoietic stem cell transplant (HSCT). In this procedure, damaged stem cells are replaced by healthy ones. Someday, gene cell therapy might be able to cure these conditions, but that technology is not quite ready yet.
Before a patient undergoes the stem cell transplant, there are several factors to consider. For instance, patients with these conditions can be at higher risk if they are treated using traditional methods. Some patients, especially those with Fanconi anemia, can’t tolerate certain types of treatments like radiation therapy and crosslinking agents — chemicals that can damage or disrupt DNA. These treatments are usually part of a conditioning regimen that prepares the body for the transplant.
People with conditions called dyskeratosis congenita and Shwachman-Diamond syndrome can face serious complications after the transplant, including liver and lung problems. Therefore, less intense treatments, such as fludarabine, are often used instead. But, there is still much more to learn about these treatments.
In cases where a sibling of the patient is a good match for a stem cell donation, it’s important for them to be tested for these conditions as well. If the donating sibling has the condition, the patient could die from the transplant due to the effect of toxic treatments intended to prepare their body for the transplant. Therefore, family members who are potential stem cell donors should be screened for these conditions and referred for genetic counselling if needed.
One exception to this is Diamond-Blackfan anemia (DBA). People with DBA often respond well to standard treatment and steroids. These steroids can help to manage the disease in about 80% of DBA patients.
Prior to and after the transplant, patients need special supportive care, which may include infection prevention treatments and blood transfusions. Blood products should not be used from family members as this can increase the risk of an immune reaction called alloimmunization. Iron supplement chelators may be needed to prevent a condition called secondary hemochromatosis, which results from too much iron in the body.
In terms of future family planning, in vitro fertilization can be successful in patients affected by these conditions. Cord blood transplantation from a healthy child has shown promising results in treating Fanconi anemia.
What else can Bone Marrow Failure be?
There are various reasons why bone marrow failure (BMF) can develop. BMF can often be caused by:
- Certain drugs or medications
- Exposure to specific chemicals
- Radiation exposure
- Viral infections
- Disorders of the immune system
- Myelodysplastic syndromes (MDS), a group of disorders caused by poorly formed or dysfunctional blood cells
- Paroxysmal nocturnal hemoglobinuria (PNH), a rare and life-threatening blood disease
- Large granular lymphocytic leukemia, a type of blood cancer
What to expect with Bone Marrow Failure
Survival rates for people with inherited bone marrow failure syndromes (IBMFSs) largely depend on three things: the age at the time of transplant, how severe the disease is, and how the body responds to initial therapy. It’s reported that the survival rates 10 years after hematopoietic stem cell transplantation (HSCT, a procedure that replaces damaged or diseased bone marrow with healthy new stem cells) are 83%, 73%, 68%, and 51%, in the first, second, third and fifth decades of life, respectively.
When considering Fanconi anemia (FA, a rare genetic disorder that primarily affects the bone marrow), the 3-year survival rate is 85% with matched sibling donors and 50% with unmatched donors. In regards to Blackfan-Diamond anemia (BDA, another rare inherited bone marrow failure syndrome), the chances of living to 40 years increase almost to 100% in patients who show improvement following steroid use, 75% if the use of steroids produces long-term improvement, and 50% for those who continue to show signs of illness despite steroid use.
However, it’s important to understand that HSCT only treats the marrow disease. This means that patients with IBMFSs remain vulnerable to early-onset squamous cell carcinomas (SCC, a common kind of skin cancer). Furthermore, secondary cancers and complications from pancytopenia (a medical condition that causes a reduction in the number of red and white blood cells and platelets in the blood) remain the most common causes of death among this group of patients. These complications can include bleeding (hemorrhage) and infections.
Possible Complications When Diagnosed with Bone Marrow Failure
The main problems people with inherited bone marrow failure often encounter include bleeding, infections, cancer (like squamous cell carcinoma), and conditions resulting in an abnormal increase in lymph cells. The best way to manage these complications is to keep a close watch on health changes and address symptoms when they occur. This might include using antibiotics, chemotherapy, and/or blood transfusions.
Common Complications:
- Bleeding
- Infections
- Squamous Cell Carcinoma (a type of cancer)
- Abnormal increase in lymph cells
Possible Treatments:
- Health Monitoring
- Antibiotics
- Chemotherapy
- Blood Transfusions
Preventing Bone Marrow Failure
Inherited bone marrow failure is a range of conditions where the body can’t produce certain blood cells needed for fighting infections, repairing injuries, and transporting oxygen. These diseases are often passed down in families, but they can also appear in individuals with no family history. Besides affecting the blood, patients might also have problems with other body parts like their bones. These conditions typically show up early in life.
Diagnosis is usually done through personal medical history, a physical checkup, and lab tests. To manage these conditions, treatments may include bone marrow transplants and additional medications. These medicines help to control the immune system and supply the body with the necessary blood components.
Patients with inherited bone marrow failure may face complications such as bleeding, cancers, and infections. Therefore, they should continuously keep their doctors updated about any changes in their health.
