What Are Common Causes of Congenital Aplastic Anemia?

Patient Presentation
A 15-month-old female had previously come to clinic for her health maintenance examination and the resident was reviewing the patient’s screening laboratories with her attending physician. The hemoglobin was 10.3 mg/dL and hematocrit was 31% with a normal lead level. “I’m going to start her on some iron for probable iron deficiency anemia and follow her up in a month,” the resident said. “I know that iron deficiency anemia is the most common cause of anemia in children, but I was doing some board review questions last night and I got the question wrong about the most common cause of congenital aplastic anemia. I thought it was Shwachman-Diamond syndrome and its really Fanconi anemia,” she continued. The attending said, “It’s been a long time since I reviewed any of those myself. I know there are congenital anomalies associated with them, but I can’t remember them exactly. Drugs, viruses and of course leukemia cause pancytopenia more often than congenital problems.”

Aplastic anemia are disorders where there is inadequate production of erythrocytes, granulocytes and platelets caused by decreased bone marrow production leading to a peripheral blood pancytopenia. Most often it is acquired because of exposures to infections (especially viruses such as Epstein-Barr virus, rubella, herpes, etc.), drugs (e.g. chloramphenicol, chemotherapeutic agents, etc.), toxins or radiation.

Learning Point
The most common congenital bone marrow failure syndromes causing pancytopenia are (in this order) Fanconi anemia, Diamond-Blackfan anemia, and Shwachman-Diamond anemia. Most have a variety of congenital abnormalities. They usually have an increased risk of malignancies. Treatment is usually monitoring, supportive (including colony stimulating factors, transfusions, etc.) and bone marrow and other transplantations.

  • Fanconi anemia
    • Cause is chromosome breakage and defective repair
    • Autosome recessive, few X-linked recessive
    • Pancytopenia is seen first decade of life
    • Congenital abnormalities – cafe-au-lait spots, short stature, abnormal radii and thumbs, microcephaly, renal abnormalities
    • Increased risk of malignancies is 50x general population – leukemia and squamous cell carcinoma
  • Diamond-Blackfan anemia
    • Caused by ribosomal protein mutations
    • Genetics is heterogeneous
    • This is a mainly a congenital red cell aplasia, but often has neutropenia and thrombocytenia. Diagnosed usually in first year of life.
    • Congenital abnormalities – short stature, midline facial defects, renal, thumb abnormalities and cardiac defects
    • Increased risk of malignancy – leukemia, myelodysplastic syndrome, solid tumors
    • Treatment also includes corticosteroids
  • Dyskeratosis congenita
    • Cause is degradation of the telomeres (ends of chromosomes) over replication cycles causing cell death
    • X-linked, autosomal dominant, autosomal recessive
    • Pancytopenia – 50% of individuals have failure by age 50, but often first signs in childhood with death in early adulthood.
    • Congenital abnormalities – nail dystrophy, reticular skin pigmentation, leukoplakia, pulmonary fibrosis, eye abnormalities
    • Increased risk of malignancy is 20-30% by age 50 – squamous cell carcinoma, female genital tract, gastrointestinal tract
  • Shwachman-Diamond Syndrome
    • Cause is ribosomal maturation problem
    • Genetics are heterogeneous
    • Pancytopenia – mainly neutropenia, but also anemia, thrombocytopenia
    • Congenital abnormalities – exocrine pancreatic insufficiency, skeletal abnormalities such as osteoporosis, rib cage dysplasia and metaphyseal dysplasia
    • Increased risk of malignancy is up to 35% – leukemia, myelodysplastic syndrome
  • Congenital amegakaryocytic thrombocytopenia
    • Cause is not completely understood but there is an abnormality in an oncogene on chromosome 1
    • Genetics is autosomal recessive
    • Pancytopenia – mainly thrombocytopenia in infancy and then progression over next 3-5 years of aplastic anemia
    • Congenital abnormalities – does not have them
    • Early death is common

Other bone marrow failures syndromes that have similar features

  • TAR (thrombocytopenia with absent radii)
    • Cause is mRNA processing
    • Genetics is deletion in chromosome 1
    • Hematological problem – severe thrombocytopenia at birth often with megakaryocytes
    • Congenital abnormalities – bilateral absent radii, facial, cardiac and genitorurinary defects, short stature
    • Increased risk of malignancy – leukemias
  • Severe congenital neutropenias
    • A group of disorders
    • Cause is problem with protein folding
    • Genetics is heterogeneous
    • Hematological problem – neutropenia allowing overwhelming bacterial infections to occur.
    • Congenital abnormalities – does not have them
    • Increased risk of malignancy – leukemia, myelodysplastic syndrome
    • Treatment with colony stimulating factors is needed

Questions for Further Discussion
1. What causes increased production of erythrocytes, granulocytes or platelets?
2. What causes increased production of granulocytes?
3. What causes increased production of platelets? (a review can be found here)

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Aplastic Anemia and Bone Marrow Diseases.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Federman N, Sakamoto KM. The genetic basis of bone marrow failure syndromes in children. Mol Genet Metab. 2005 Sep-Oct;86(1-2):100-9.

Leguit RJ, van den Tweel JG. The pathology of bone marrow failure. Histopathology. 2010 Nov;57(5):655-70.

Wilson DB, Link DC, Mason PJ, Bessler M. Inherited bone marrow failure syndromes in adolescents and young adults. Ann Med. 2014 Sep;46(6):353-63.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital