Anemia, Fanconi (Constitutional Aplastic Anemia)

Key Features

Essentials of Diagnosis

• Progressive pancytopenia

• Macrocytosis

• Multiple congenital anomalies

• Increased chromosome breakage in peripheral blood lymphocytes

General Considerations

• Most common inherited bone marrow failure syndrome; 75–90% of affected individuals develop bone marrow failure in the first 10 years of life

• Characterized by defective DNA repair that is caused by a variety of genetic mutations

• Inheritance is autosomal recessive

• Occurs in all ethnic groups

Clinical Findings

Symptoms and Signs

• Symptoms are determined principally by the degree of hematologic abnormality

• Thrombocytopenia may cause purpura, petechiae, and bleeding

• Neutropenia may cause severe or recurrent infections

• Anemia may cause weakness, fatigue, and pallor

• Congenital anomalies are present in at least 50% of patients; most common include

  • Abnormal pigmentation of the skin (generalized hyperpigmentation, café au lait or hypopigmented spots)

  • Short stature with delicate features

  • Skeletal malformations (hypoplasia, anomalies, or absence of the thumb and radius)

• More subtle anomalies are hypoplasia of the thenar eminence or a weak or absent radial pulse

• Associated renal anomalies include

  • Aplasia

  • Horseshoe kidney

  • Duplication of the collecting system

• Other anomalies

  • Microcephaly

  • Microphthalmia

  • Strabismus

  • Ear abnormalities

  • Hypogenitalism

Differential Diagnosis

• Idiopathic thrombocytopenic purpura (ITP)

• Other more common causes of thrombocytopenia

Diagnosis

Laboratory Findings

• Thrombocytopenia or leukopenia typically occurs first, followed over the course of months to years by anemia and progression to severe aplastic anemia

• Macrocytosis

  • Virtually always present

  • Usually associated with anisocytosis and an elevation in fetal hemoglobin levels

• Bone marrow reveals hypoplasia or aplasia

• Diagnosis is confirmed by demonstration of an increased number of chromosome breaks and rearrangements in peripheral blood lymphocytes

  • Use of diepoxybutane to stimulate these breaks and rearrangements provides a sensitive assay that is virtually always positive in children with Fanconi anemia, even before the onset of hematologic abnormalities

• Specific Fanconi genes (FANCA, B, C, and others) have been identified and transmission is generally autosomal, although FANCB is on the X chromosome

Treatment

• Attentive supportive care is critical

• Parenteral broad-spectrum antibiotics are required for patients with neutropenia in whom fever develops

• Transfusions

  • Should be used judiciously, especially in the management of thrombocytopenia, which frequently becomes refractory to platelet transfusions as a consequence of alloimmunization

  • Transfusions from family members should be discouraged because of the negative effect on the outcome of bone marrow transplant

• Oxymetholone

  • At least 50% of patients respond, albeit incompletely

  • Many experts recommend institution of androgen therapy before transfusions are needed

  • Side effects associated with therapy include hepatotoxicity, hepatic adenomas, and masculinization

• Reduced intensity hematopoietic stem cell transplant

  • Definitive treatment

  • Ideally, should come from an HLA-identical sibling donor

  • Although matched unrelated and cord transplant may be considered

Outcome

Complications