The bone marrow failure syndromes include a group of disorders than can be either inherited or acquired. These diseases are disorders of the hematopoietic stem cell that can involve either 1 cell line or all of the cell lines (erythroid for red cells, myeloid for white blood cells, megakaryocytic for platelets). The lymphocytes, which are involved in lymphoproliferative disorders, are usually spared (see the image below). (See Etiology.)
The inherited bone marrow failure syndromes include Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and other genetic disorders. The most common cause of acquired bone marrow failure is aplastic anemia. (See Etiology, Presentation, Workup, and Treatment.) 
Diseases that can present in a manner similar to acquired bone marrow failure include myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, and large granular lymphocytic leukemia. (See DDx.)
For patient education information, see Anemia.
Bone marrow failure can be inherited or acquired and can involve a single hematopoietic stem cell line or all three cell lines. These etiologies involve the following:
- A decrease in or damage to the hematopoietic stem cells and their microenvironment, resulting in hypoplastic or aplastic bone marrow
- Maturation defects, such as in vitamin B-12 or folate deficiency
- Differentiation defects, such as myelodysplasia
Damage to hematopoietic stem cells can be congenital or acquired. Mechanisms include the following:
An acquired stem cell injury from viruses, toxins, or chemicals (eg, chloramphenicol, insecticides  ) that leads to a quantitative or qualitative abnormality
Abnormal humoral or cellular control of hematopoiesis
An abnormal or hostile marrow microenvironment
Immunologic suppression of hematopoiesis (ie, mediated by antibodies, T cells [or cellularly], or lymphokines)
Mutations in genes, causing inherited bone marrow failure syndromes; identification of these relevant mutations has led to progress in defining the precise functions of the corresponding proteins in normal cells
Inherited bone marrow failure syndromes
The genetic abnormalities in the inherited bone marrow failure syndromes (IBMFS) have been identified in the following disorders  :
Fanconi anemia is inherited in either an autosomal recessive or X-linked fashion. Twelve Fanconi anemia (FANC) genes have been identified. These genes collaborate in a complicated pathway (FA pathway) that is responsible for the repair of DNA damage. One of these genes (FANCD1) is the breast/ovarian susceptibility gene (BRCA2).
Dyskeratosis congenita is inherited in an X-linked recessive, autosomal dominant, or autosomal recessive manner. Patients with the X-linked form have mutations in DKC1 at band Xq28, a gene that encodes for dyskenin, in a protein involved in the telomere maintenance pathway. Other patients have mutations in band 3q26 in TERC, a part of the telomerase complex, and still others have mutations in the telomerase reverse transcription (TERT) enzyme. 
Shwachman-Diamond syndrome is an autosomal recessive disorder in which the majority of patients have a mutation in the Shwachman Bodian Diamond syndrome gene (SBDS), located at band 7q11.
Amegakaryocytic thrombocytopenia is an autosomal recessive disorder with biallelic mutations in the thrombopoietin receptor, MPL, at the band 1p34 location.
Diamond-Blackfan anemia is an autosomal dominant disease in which 25% of patients were found to have a mutation in the gene for small ribosomal protein (RPS19), located at band 19q13.2.
In half of the patients, severe congenital neutropenia is associated with dominant mutations in neutrophil elastase (ELA2, located at band 19p13.3), while a few patients have mutations in GFI-1.
Thrombocytopenia absent radii syndrome is associated with bone marrow failure, but no genetic defect for bone marrow failure has been identified in this autosomal recessive disorder.
Constitutional aplastic anemia is associated with chronic bone marrow failure, congenital anomalies, familial incidence, or thrombocytopenia at birth. Constitutional causes of aplastic anemia include the following conditions:
Fanconi anemia - Characterized by familial aplastic anemia, chromosomal breaks, and, in some cases, congenital anomalies of the thumb or kidneys
Dyskeratosis congenita - Another rare disorder, dyskeratosis congenita has a characteristic dermatologic manifestation of nail dystrophies and leukoplakia; patients with this disease develop aplastic anemia in their second decade of life
Shwachman-Diamond syndrome - This disorder consists of exocrine pancreatic insufficiency and bone marrow failure; occasionally, cartilage and hair hypoplasia occur, resulting in short stature and dysostosis
Pure red cell aplasia may be a secondary disorder caused by a thymoma. It may also occur transiently, resulting from a viral infection, as with parvovirus B19. Pure red cell aplasia also may be permanent, as a result of viral hepatitis. Finally, it may arise from lymphoproliferative diseases (eg, lymphomas, chronic lymphocytic leukemia) or collagen vascular diseases (eg, systemic lupus erythematosus, refractory anemia), or it may occur during pregnancy.
Amegakaryocytic thrombocytopenic purpura has been reported to occur as a result of causes similar to those for pure red cell aplasia.
Early forms of myelodysplastic syndrome initially can manifest as a single cytopenia or, more often, as a bicytopenia.
A decrease in all three cell lines is the most common manifestation of bone marrow failure. Aplastic or hypoplastic anemia can be idiopathic in nature, or it can develop from secondary causes. Myelodysplastic anemia also can cause pancytopenia. Myelophthisic anemia may result from marrow destruction because of tumor invasion or granulomas.
The prevalence of bone marrow failure resulting from hypoplastic or aplastic anemia is low in the United States and Europe (2-6 cases per million persons) compared with the prevalence of bone marrow failure resulting from acute myelogenous leukemia and multiple myeloma (27-35 cases per million persons). The frequency of myelodysplasia, on the other hand, has increased from 143 cases reported in 1973 to about 15,000 cases annually in United States. This is an underestimation of the actual prevalence, which is believed to be about 35,000-55,000 new cases a year.
In Japan and the Far East, the frequency of bone marrow failure is at least 3 times higher than it is in the United States and Europe. Mexico and Latin America also have high occurrence rates, which are attributed to the liberal use of chloramphenicol. Environmental factors and the pervasive use of insecticides have been implicated as causes of this disease. The incidence of myelodysplasia has been estimated to be around 4-5 per 100,000 population per year in Germany and Sweden.
The prognosis of bone marrow failure depends on the duration of the marrow function abnormality. Most inherited forms of bone marrow failure, such as Fanconi anemia, are associated with transformation into leukemia several years later. Viral causes, such as parvoviruses, are usually self-limiting.
Acquired idiopathic aplastic anemia is usually permanent and life threatening. Half of the patients die during the first 6 months.
Morbidity and mortality
Bone marrow failure resulting in failure to produce one, two, or all three blood cell lines increases patient morbidity and mortality.
Morbidity and mortality from pancytopenia are caused by low levels of mature blood cells. Severe anemia can cause high-output cardiac failure and fatigue. Neutropenia can predispose individuals to bacterial and fungal infections. Thrombocytopenia can cause spontaneous bleeding and hemorrhage.
The severity and extent of cytopenia determine prognosis. Severe pancytopenia is a medical emergency, requiring rapid institution of definitive therapy (ie, early determination of supportive care and bone marrow transplant candidates).
Over time, the transfusion of packed red cells increases the patient’s total iron load. Increased levels of iron are toxic to various organs, including the heart, and iron toxicity can cause arrhythmia by blocking the bundle of His, diabetes by damaging the islets of Langerhans in the pancreas, and liver cirrhosis. (Iron can also produce bronze coloration in fair-skinned individuals.) Therefore, it is necessary to measure a patient’s iron stores (in the form of ferritin).
Administering a chelating agent is an effective method of removing excess iron. Chelating agents are composed of molecules that bind tightly with free iron and remove the iron by carrying it as the agents are excreted from the body.
Desferrioxamine is the iron chelator available in parenteral form. If given intravenously, its activity is short and it is excreted rapidly by the kidneys. A subcutaneous infusion given continuously by a portable pump for 3-4 hours every 12 hours is the preferred method. It optimizes the binding of the chelator to the free iron. As more free iron is excreted, storage iron is mobilized into the free form. This treatment can be performed in an outpatient setting.
Monitoring serum ferritin levels and measuring total iron urinary excretion can determine the effectiveness of therapy. Most tissue damage can be reversed with timely chelation, except for cirrhosis of the liver (once it has set in).
What would you like to print?