Pediatric Blood Disorders: Inherited Bone Marrow Failure Syndromes

Inherited bone marrow failure syndromes can be diagnosed through a series of blood tests to check for genetic defects. In some cases, a physical exam can also reveal signs of genetic blood disorders, which can include short stature, abnormal thumbs, bruising, and other physical changes.

Children, adolescents, and young adults come to Memorial Sloan Kettering for diagnosis of a new inherited bone marrow failure syndrome or with an already established diagnosis. Our team of pediatric experts develops a treatment plan designed to cure the blood and marrow complications of these diseases if possible, address any additional symptoms, and improve the quality of life of children and young adults.

We perform a complete medical work-up of all patients, including blood work for genetic and other tests, bone marrow testing, and tests specific to each of the inherited bone marrow failure syndromes. Management of these diseases includes periodic check-ups, blood work, and other testing. Our multidisciplinary care team includes experts in endocrinology, head and neck oncology, gynecology, and orthopedics to monitor for any additional health problems.

We base the treatment for each child on his or her current condition. Therefore, treatments can vary, and include supportive care, blood transfusions, blood growth factors, immune-based medications, chelation therapy, and allogeneic hematopoietic stem cell transplantation (HSCT), which involves the replenishment of blood-forming stem cells from a donor.

Around the world, there are patient registries for some of the inherited bone marrow failure syndromes to keep track of all patients with a particular diagnosis, study features of the disease, and record the treatment and outcomes of patients to inform future treatments. Investigators at Memorial Sloan Kettering are in contact with these registries as well as with investigators worldwide to stay up-to-date about the latest research studies and treatments for the different disorders. Our experts have also been involved in developing clinical care guidelines, such as indications for Fanconi anemia.

Allogeneic Stem Cell Transplantation

Though inherited bone marrow failure syndromes themselves cannot be cured, the failure of bone marrow to produce the required blood cells can be treated and cured, most often with allogeneic stem cell transplantation. In this treatment, another person’s healthy stem cells are transplanted into your child to stimulate the production of red blood cells, white blood cells, and platelets. The most effective form of transplantation involves using blood stem cells from a child’s sibling who does not have the disease but who is a bone marrow match.

The timing of the treatment depends on whether a stem cell or bone marrow match is found as well as the age of your child (children under age 10 tend to have better outcomes). Blood counts, the child’s overall health, and his or her organ function determine the timing of treatment as well. If your child has developed a severe drop in one or more types of blood cells, another blood disorder such as myelodysplastic syndrome or aplastic anemia requiring blood transfusions, or a blood cancer such as acute myelogenous leukemia, transplantation is required to improve your child’s health.

An allogeneic stem cell transplant is also referred to as a peripheral blood stem cell transplant, bone marrow transplant, or cord blood transplant, depending on the origin of the transplanted cells. The particular type of transplantation used to treat your child depends on the type of syndrome. Regardless of the type of transplantation, the goals are the same: 

  • to limit the risk of graft-versus-host disease, in which the transplanted cells attack the child’s body
  • to decrease the risk that your child will develop infections during the treatment process
  • to reduce the chance that your child will reject the transplanted cells

Our investigators have been performing stem cell transplants in young patients with bone marrow failure syndromes for decades. One of our major advantages is that we are able to perform transplants from any type of donor – related or unrelated, matched or mismatched. The advantages of our program are that for a large number of patients we are able to perform transplants without using total body irradiation. In addition, our use of T-cell-depleted grafts minimizes the chances that white blood cells (T cells) will see the child’s body as foreign and attack healthy cells.

The transplantation process begins with a process called conditioning, in which your child’s abnormal bone marrow and stem cells are destroyed through several days of chemotherapy and/or radiation therapy. The actual stem cell transplant typically takes place a day or two after conditioning is completed. The donor stem cells or bone marrow are given to your child through a catheter or central venous line inserted in the chest or the arm into large veins close to the heart, in a process similar to that of a blood transfusion. The procedure is painless and takes between five and 20 minutes.

After a transplant, it takes about three to six months for a child’s body – especially the immune system – to recover. We ask our patients to remain in the New York area to receive care for about three to six months. After that time, children can return to their primary doctor for most of their care. After one year post transplant, the patient returns for an appointment each year with the internationally recognized experts on our pediatric long-term follow-up team or adult long-term follow-up team.

Management of Fanconi Anemia

After performing a complete medical workup, doctors at Memorial Sloan Kettering communicate with your child’s primary pediatrician or pediatric hematologist to perform regular blood tests, annual bone marrow testing, and monitoring of other organs including the heart, kidneys, gastrointestinal system, and endocrine system.

Some young patients can subsist with borderline blood counts that do not require therapy for many weeks, months, or even years. When treatment is necessary, therapies for managing Fanconi anemia can include transfusions of red blood cells and platelets, and oral administration of male hormones known as androgens to help increase the blood counts. If a child develops a dependence on transfusions or develops a blood cancer such as leukemia or myelodysplastic syndrome, a stem cell transplant is necessary and is the only curative treatment.

Memorial Sloan Kettering is one of the leading centers in the United States and is known for its success in performing allogeneic stem cell transplants in children with Fanconi anemia. The process can be difficult because young patients with Fanconi anemia have genetic defects that result in fragile DNA and chromosomes that break easily. This can result in organ damage from the chemotherapy or radiation therapy used during the conditioning process prior to the transplant, and can increase a child’s risk for rejecting the transplanted stem cells.

Through a careful combination of transplantation and supportive care measures designed by our experts, many children with Fanconi anemia can begin to produce healthy blood cells.(1) This includes a chemotherapy drug called fludarabine, which is used during conditioning to limit DNA damage that could further harm your child’s already fragile DNA. In addition, instead of transplanting stem cells from a donor’s bone marrow, our doctors use stem cells from circulating blood (known as peripheral blood stem cells), which can contain a concentration of up to 20 times more stem cells than the bone marrow. These high numbers of stem cells help prevent the child from rejecting the transplant. Our center has been the leading institution of a multicenter trial for transplantation of patients with Fanconi anemia. This trial has involved five different centers and has been recognized and partially funded by the Fanconi Anemia Research Fund.

Management of Dyskeratosis Congenita

Children with dyskeratosis congenita have a number of organ issues or damage. They are also at risk for developing aplastic anemia, myelodysplastic syndrome, or acute myelogenous leukemia.

Patients are often treated with stem cell transplantation. However, we recognize that children with this disease have especially fragile skin, lungs, and livers. We aim to cure the bone marrow failure and blood disorder with transplantation, but at the same time minimize the risks of both graft-versus-host disease that can affect these organs and toxicity to these organs from the chemotherapy delivered prior to transplantation.

We have transplanted several patients with this disease using this approach – low dose chemotherapy and T-cell depleted transplant – and the results have been promising.

Management of Shwachman-Diamond Syndrome

The bone marrow and blood cell complications of Shwachman-Diamond Syndrome can sometimes be cured with an allogeneic transplantation. Typically, however, supportive care is provided unless your child’s doctor recommends that transplantation is necessary.

Supportive care can include follow-up care with a gastroenterologist to address the liver and pancreas problems associated with the disorder. Enzyme replacement therapy can help with pancreatic dysfunction, as can daily multivitamins including A, D, E, and K. In general, your child’s bleeding problems and low blood cell counts can be treated with red blood cell and platelet transfusions.

Transplantation has been used successfully at Memorial Sloan Kettering for patients with Shwachman-Diamond Syndrome who have gone on to develop severe aplastic anemia and/or myelodysplastic syndrome that requires frequent blood transfusions. We have been able to perform successful T-cell depleted transplants for such patients using mismatched, unrelated donors, and these patients have avoided the complication of graft-versus-host disease.

Management of Congenital Amegakaryocytic Thrombocytopenia

This disorder may be severe from the time of birth and lead to life threatening complications. Although it affects usually only the platelets, it often progresses to severe aplastic anemia involving red blood cells and white blood cells as well, and may also lead to acute myelogenous leukemia.

The treatment of choice for these complications is allogeneic stem cell transplantation. As with the other inherited bone marrow failure syndromes, we have successfully performed T-cell depleted transplants for patients with congenital amegakaryocytic thrombocytopenia using matched or mismatched unrelated donors with chemotherapy only – to avoid the high risks of irradiation in such young children – and avoiding graft-versus-host disease.(2)

Management of Severe Chronic Neutropenia

Chronic neutropenia, which affects white blood cells known as neutrophils, includes a number of different disorders, some of them benign and some more severe. The standard treatment for severe chronic neutropenia is to use granulocyte colony-stimulating factor (G-CSF), which stimulates the bone marrow to produce blood stem cells. Memorial Sloan Kettering investigators developed this drug.(3),(4) The goal of this treatment approach is to achieve and maintain a neutrophil count of more than 1,000/mm3.

For patients who are resistant to G-CSF or who develop complications such as myelodysplastic syndrome or leukemia secondary to the disease, the only curative treatment option is a stem cell transplant. This can be performed with stem cells from a matched sibling or an unrelated donor.

We have successfully performed T-cell depleted transplants for patients with severe chronic neutropenia using matched or mismatched unrelated donors with chemotherapy only – to avoid the high risks of irradiation in such young children – and these patients have remained free of graft-versus-host disease.

Management of Diamond-Blackfan Anemia

Typically, supportive care is provided for the treatment of this disease, unless your child’s doctor recommends transplantation.

When Diamond-Blackfan Anemia only affects red blood cells, which is usually the case early in life, it can be treated with steroid medications, including cortisone and prednisone. These hormones can help stimulate the bone marrow to make red blood cells. Some children respond to this treatment for a period of time. Other medications have been used with mixed responses.

If other therapies are not successful, the red blood cell deficiency can be treated with red blood cell transfusions, which may need to occur every three to four weeks.

For patients with Diamond-Blackfan anemia who have siblings who are stem cell matched, the standard treatment is stem cell transplantation early in life. This therapy has been successful for several patients at Memorial Sloan Kettering over the past few years.

Management of Thrombocytopenia-Absent Radii

For patients with thrombocytopenia-absent radii, management of the disease typically involves supportive care. Only rarely is a stem cell transplant performed.