Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter XI.4. Bone Marrow Failure
Desiree Medeiros, MD
March 2002

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This 2-1/2 year old male is referred to the pediatric hematologist with a chief complaint of easy bruising, nosebleeds and decreased activity for one week. He has no history of fever or appetite changes. His past medical history is unremarkable. There is no travel history, history of recent illnesses, or known exposure to toxins.

Exam: He is a well developed, well nourished, pale boy in no acute distress. His conjunctivae are pale. Sclera are anicteric. TMs are normal. His oral mucosa is moist and shows rare petechiae on the buccal mucosa. He has some small palpable posterior cervical lymph nodes. He has a sinus tachycardia with a grade I/VI systolic ejection murmur, without a gallop. His lungs are clear to auscultation. His abdomen is soft and nontender with normoactive bowel sounds. He has no palpable masses, hepatosplenomegaly, or inguinal hernias. His penis and testes are normal (no masses). He has no rashes, but he has ecchymoses present on his left shoulder, chin and both lower extremities. Petechiae are present on his extremities and groin.

Labs: Hemoglobin 7.9 g/dl, hematocrit 24%, platelet count 12,000, WBC 3,000 with 90% lymphocytes (absolute neutrophil count 210). Reticulocyte count 0.5%. A bone marrow aspirate and biopsy show a markedly hypocellular marrow (12% cellularity) with decreased megakaryocytes and erythroid and myeloid precursors. Bone marrow cytogenetics are normal. A diepoxybutane test shows no increase in chromosome breakage. Ham's acid serum test is normal. Serology for CMV, EBV, parvovirus, and hepatitis demonstrates no recent infection.

He is diagnosed with severe acquired aplastic anemia. One of his sisters is a perfect 6 out of 6 HLA match and he undergoes a matched related bone marrow transplant.

Bone marrow failure is a decreased production of one or more cell lines (erythrocytes, granulocytes, and/or platelets) in the bone marrow resulting in peripheral blood cytopenia. These disorders can either be inherited or acquired. The inherited cytopenias are due to a genetic abnormality and may be associated with congenital physical anomalies. The acquired cytopenias may be due to exposure to a toxin, infectious agent (however, a causal agent is usually not identified), or invasion of the bone marrow by a neoplastic process.

The most common type of bone marrow failure not due to neoplastic causes, is aplastic anemia. Acquired aplastic anemia results from an injury to the bone marrow by radiation, drugs (chemotherapy, antibiotics, such as chloramphenicol), insecticides, toxins (benzene, carbon tetrachloride), or infection (hepatitis, HIV, CMV, parvovirus) (1). However, most cases of acquired aplastic anemia are without an identifiable cause (idiopathic). The onset of symptoms is gradual. Signs and symptoms include pallor, fatigue, weakness, loss of appetite, easy bruising, petechiae, mucosal hemorrhage, and fever. Laboratory evaluation demonstrates a normocytic or macrocytic anemia, reticulocytopenia, leukopenia, and thrombocytopenia. A bone marrow biopsy is essential to make the diagnosis and typically shows depression or absence of hematopoietic elements with fatty infiltration of the marrow (2). Severe aplastic anemia is defined as pancytopenia with an absolute neutrophil count <500, platelet count <20,000, reticulocyte count <1%, and <25% bone marrow elements on bone marrow biopsy (2,3).

Without treatment, acquired severe aplastic anemia carries a high mortality rate, with deaths occurring within a year of diagnosis. These are usually due to fatal infection or hemorrhage (2). Supportive care (intravenous antibiotics and transfusion support) has improved outcomes. Early stem cell transplantation with an HLA matched donor is the treatment of choice for severe aplastic anemia (1,2). When transplantation is an option, blood product support should be used sparingly to reduce the risk of sensitization and graft rejection. When stem cell transplantation is not feasible, immunosuppressive therapy with high dose corticosteroids, anti-thymocyte globulin and cyclosporin A is an alternative (1,2).

Fanconi's anemia is inherited in an autosomal recessive pattern (4). Classically, patients have pancytopenia and characteristic congenital anomalies. These include hyperpigmentation and/or cafe-au-lait spots on the trunk, neck and intertriginous areas, short stature, upper limb abnormalities, hypogonadism, skeletal anomalies, eye or eyelid changes, renal malformations, and more rarely, deafness, gastrointestinal and cardiopulmonary malformations. Blood counts start to decrease between 4 and 12 years of age. This usually presents with thrombocytopenia followed by neutropenia then anemia. Severe aplastic anemia develops months to years after initial CBC changes. MCV is often >100 fl. Fetal hemoglobin and i-antigen (an antigen on immature red cells) are increased. Macrocytosis, fetal hemoglobin and the i-antigen are manifestations of a stressed bone marrow. Bone marrow shows patchy hypoplasia. The diagnostic test for Fanconi's anemia is a chromosome breakage analysis using clastogenic agents such as diepoxybutane or mitomycin C (1,4). A high proportion of cells will show chromosomal breaks. Children with Fanconi's anemia have a higher incidence of acute leukemia, squamous cell carcinoma, and hepatocellular carcinoma (4). Therapy consists of supportive care with transfusions and/or antibiotics for infection. Some patients respond to corticosteroid and androgen therapy (4). Stem cell transplantation from a matched sibling donor, or from an unrelated donor if a sibling donor is not available, is recommended in patients who are not responsive to corticosteroid and androgen therapy.

Diamond-Blackfan anemia (DBA) or congenital pure red cell aplasia is usually inherited in an autosomal dominant pattern (5). Infants present in the first 3 months of life with pallor and poor feeding. Associated physical anomalies are present in 25% of patients and include short stature, craniofacial abnormalities (hypertelorism, flat nasal bridge, and high or cleft palate), thumb abnormalities, skeletal anomalies, deafness, learning difficulties, and renal and cardiac abnormalities (1,5). CBC reveals a normocytic or macrocytic anemia with reticulocytopenia. White cell and platelet counts are normal. Fetal hemoglobin is elevated on hemoglobin electrophoresis and i-antigen is expressed on RBCs. Erythrocyte adenosine deaminase levels are high. Chromosome studies are normal. Bone marrow is cellular with isolated reduction of red cell precursors (1,5). Corticosteroids remain the mainstay of therapy for DBA. Up to 70% of patients have a good initial response to oral corticosteroids (5). The dose can be individualized according to response. However, about one-half of patient with DBA require chronic transfusions, either because they did not respond to corticosteroids or because they developed significant side effects. Rarely, spontaneous remission occurs. Other therapies, such as erythropoietin, interleukin-3, cyclosporin A, intravenous immune globulin, androgens, or splenectomy have been used but have not shown consistent benefit (5). Stem cell transplantation is potentially curative.

Transient erythroblastopenia of childhood (TEC) is an acquired red cell aplasia which occurs in healthy children between 6 months and 5 years old (5). The onset is usually at an older age than that seen in DBA. These children present with a gradual onset of symptoms of anemia, such as pallor and decreased activity. The physical examination is unremarkable except for pallor and tachycardia. A complete blood count (CBC) shows a normocytic normochromic anemia with hemoglobins ranging from 3 to 8 g/dL (5). The reticulocyte count is extremely low. White blood cell and platelet counts are usually normal. Bone marrow examination is not necessary but reveals erythroid hypoplasia (5). Chemistries, such as LDH, bilirubin, and haptoglobin, are normal. During recovery, the reticulocyte count and RDW rise. RDW (measurement of the distribution width of red cells) rises when there is a spectrum of older (smaller) and younger (larger) red cells. Spontaneous recovery occurs within weeks to months. Recurrence of TEC is rare. Packed red blood cell transfusion may be necessary in patients who exhibit associated cardiac compromise, but is usually not necessary since the onset of the anemia is gradual (5).

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by hemolytic anemia, thrombosis and progression to pancytopenia (6). It is rarely seen in the pediatric population but should be considered in any child with anemia and "dark urine". The classic presentation is paroxysmal episodes of hemolysis, hemoglobinuria and abdominal and back pain. Pain is due to intravascular hemolysis or small vessel thrombosis. Diagnosis is confirmed by laboratory testing designed to show RBC sensitivity to complement lysis. The Ham's (acid hemolysis) and sugar-water lysis tests show selective lysis of PNH RBCs (3,6). Therapy is controversial. Corticosteroids seem to decrease hemolysis in adult patients (6). Iron supplementation may be necessary because of significant daily iron losses. However, it is thought to exacerbate hemolysis (6). Long term anticoagulation to prevent thrombosis may be required. Stem cell transplantation may play a role in patients with markedly hypoplastic marrows.

Dyskeratosis congenita is a rare X-linked recessive disorder characterized by the triad of: 1) hyperpigmentation of the face, neck and shoulders, 2) mucous membrane leukoplakia, and 3) dystrophic nails (3). Approximately 50% of patients will develop refractory pancytopenia and severe bone marrow hypoplasia. They are also at risk of developing acute myeloid leukemia (3). Stem cell transplantation is an effective therapy.

Thrombocytopenia with absent radii (TAR) is usually diagnosed at birth because of the characteristic physical finding of bilateral absence of the radii and presence of thumbs. These infants also present with petechiae and bloody stools. Associated problems include additional bony deformities, facial hemangiomas, congenital heart disease, and cow's milk allergy (1,7). The platelet count is typically below 50,000 at diagnosis (1,7). Bone marrow studies demonstrate markedly decreased or absent megakaryocytes and normal erythroid and myeloid cell lines. TAR has an autosomal recessive inheritance pattern. The risk of hemorrhage is greatest in the first year of life with mortality being due to intracranial or gastrointestinal hemorrhage (1). Therapy includes platelet support for bleeding symptoms and as prophylaxis for infants with severe symptomatic thrombocytopenia. Dietary modifications are required for those with cow's milk allergy. The prognosis for patients with TAR is very good. After the first year of life, the platelet count rises to above 100,000 which is adequate for necessary orthopedic intervention (1).

Bone marrow infiltration due to leukemia or diseases metastatic to the bone marrow potentially results in pancytopenia by crowding out the normal bone marrow elements. Patients will often first present with symptoms related to the suppression of one or more of the cell lines (RBCs, WBCs, or platelets). Patients present with lethargy (from anemia), bruising and bleeding (from thrombocytopenia) and/or unexplained fever. They may also complain of bone pain or present with a limp. A CBC shows pancytopenia or anemia, thrombocytopenia and leukocytosis. Depending on the underlying malignancy, the physical examination, and laboratory or radiographic studies will demonstrate other abnormalities.


1. What is the treatment of choice for severe acquired aplastic anemia?

2. What laboratory study is diagnostic for Fanconi's anemia?

3. How can one differentiate between Diamond Blackfan anemia and transient erythroblastopenia of childhood?

4. What is the triad associated with dyskeratosis congenita?

5. Which two factors are associated with gastrointestinal hemorrhage in infants with TAR syndrome?

6. Name some viruses and drugs which cause aplastic anemia?

7. What is the i-antigen and what hematologic problems is it associated with?


1. Alter BP, Young NS. Chapter 7 - The Bone Marrow Failure Syndromes. In: Nathan DG, Orkin SH (eds). Nathan and Oski's Hematology of Infancy and Childhood, fifth edition. 1998, Philadelphia: W.B. Saunders Company, pp. 237-335.

2. Doyle JJ, Freedman MH. Chapter 2 - Acquired Aplastic Anemia. In: Lilleyman J, Hann I, Blanchette V (eds). Pediatric Hematology, second edition. 1999, London: Churchill Livingstone Inc., pp. 51-63.

3. Lanzkowsky P. Chapter 6 - Bone Marrow Failure. In: Lanzkowsky P (ed). Manual of Pediatric Hematology Oncology, second edition. 1995, New York: Churchill Livingstone Inc., pp. 77-96.

4. Freedman MH, Doyle, JJ. Chapter 1 - Inherited Bone Marrow Failure Syndromes. In Lilleyman J, Hann I, Blanchette V (eds). Pediatric Hematology, second edition. 1999, London: Churchill Livingstone Inc., pp. 23-49.

5. Ball SE, Gordon-Smith, EC. Chapter 3 - Failure of Red Cell Production. In: Lilleyman J, Hann I, Blanchette V (eds). Pediatric Hematology, second edition. 1999, London: Churchill Livingstone Inc., pp. 65-81.

6. Sapp MV, Bussel JB. Chapter 10 - Immune hemolytic anemias. In: Lilleyman J, Hann I, Blanchette V (eds). Pediatric Hematology, second edition. 1999, London: Churchill Livingstone Inc., pp. 203-218.

7. Sola MC, Christensen, RD. Chapter 13 - Developmental Aspects of Platelets and Disorders of Platelets in the Neonatal Period. In: Christensen RD (ed). Hematologic Problems of the Neonate, first edition. 2000, Philadelphia: WB Saunders Company, pp. 273-309.

Answers to questions

1. Stem cell transplantation from a matched sibling donor or other compatible stem cell source.

2. Diepoxybutane induced chromosome breakage (increased in patient with Fanconi's anemia).

3. Diamond Blackfan anemia presents at an earlier age (<1 year) and may have associated physical anomalies. At diagnosis, MCV, hemoglobin F and i-antigen are increased. TEC presents at an older age (>1 year). Since it is acquired, there are no associated anomalies. MCV, hemoglobin F and i-antigen should be normal.

4. Skin hyperpigmentation, mucous membrane leukoplakia, dystrophic nails.

5. Cow's milk allergy and thrombocytopenia.

6. Viruses: hepatitis, HIV and parvovirus. Drugs: Chemotherapy, chloramphenicol.

7. The i-antigen is a marker found on immature red cells. It, along with fetal hemoglobin and macrocytosis are manifestations of the fetal-like hematopoiesis seen in the stressed bone marrows of patients with acquired aplastic anemia, Fanconi's anemia, and Diamond Blackfan anemia.

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