Clinical characteristics: GATA1-related cytopenia is characterized by thrombocytopenia and/or anemia ranging from mild to severe. Thrombocytopenia typically presents in infancy as a bleeding disorder with easy bruising and mucosal bleeding (e.g., epistaxis). Anemia ranges from minimal (mild dyserythropoiesis) to severe (hydrops fetalis requiring in utero transfusion). At the extreme end of the clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are lifelong; at the milder end, anemia and the risk for bleeding may decrease spontaneously with age. One or more of the following may also be present: neutropenia, splenomegaly, cryptorchidism, hypospadias, and rarely additional clinical features of Diamond-Blackfan anemia. Heterozygous females may have mild-to-moderate symptoms such as menorrhagia. Rarely, GATA1-related cytopenia can progress to myelodysplastic syndrome or aplastic anemia.

Diagnosis/testing: The diagnosis of GATA1-related cytopenia is established in a male proband with cytopenia resulting from ineffective hematopoiesis by identification of a hemizygous pathogenic variant in GATA1 by molecular genetic testing. The diagnosis of GATA1-related cytopenia may be established in a female proband with cytopenia by identification of a heterozygous pathogenic variant in GATA1 by molecular genetic testing.

Management: Targeted therapy: For severe disease, hematopoietic stem cell transplantation (HSCT) can be curative.

Supportive care: Platelet transfusions for moderate-to-severe epistaxis, severe gingival bleeding, or other clinically significant bleeding; DDAVP^© may be helpful for short-term management of mild-to-moderate bleeding; platelet transfusion prior to surgical or invasive dental procedures for individuals with a history of pathologic bleeding, thrombocytopenia, and/or platelet dysfunction; red blood cell transfusions for clinical manifestations of anemia (fatigue, tachycardia); iron chelation therapy as needed for chronic red blood cell transfusions; extended pre-transfusion red blood cell phenotyping and consideration of Rh and K antigen matching for those receiving frequent transfusions. Treatment for neutropenia includes counseling regarding infection risk; prophylactic antibiotics when indicated; prompt evaluation when febrile; empiric parenteral antibiotics for febrile individuals with severe neutropenia. HSCT can be curative for those with severe disease.

Surveillance: Complete blood count (CBC) with frequency based on disease severity; annual CBC in those with mild cytopenia(s) and monthly CBC in those with severe cytopenia(s) that require intervention such as red blood cell transfusion. Monitor for iron overload in those with frequent erythrocyte transfusions.

Agents/circumstances to avoid: Those with thrombocytopenia and/or platelet aggregation defects should avoid antiplatelet agents including aspirin and nonsteroidal anti-inflammatory drugs (e.g., ibuprofen) and avoid contact sports or activities with a high risk of trauma. Individuals with severe neutropenia should avoid close contact with persons who have a communicable disease to minimize risk of infection. Individuals with significant splenomegaly should avoid contact sports, which increase the risk of traumatic splenic rupture.

Evaluation of relatives at risk: If a GATA1 pathogenic variant has been identified in the family, molecular genetic testing of at-risk relatives can be offered. At-risk relatives who choose not to have molecular genetic testing should have a CBC to evaluate for thrombocytopenia, anemia, and/or neutropenia.

Genetic counseling: GATA1-related cytopenia is inherited in an X-linked manner. If the mother of the proband has a GATA1 pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and may have mild-to-moderate symptoms. Affected males transmit the GATA1 pathogenic variant to all of their daughters and none of their sons. Once the GATA1 pathogenic variant has been identified in an affected family member, identification of female heterozygotes and prenatal and preimplantation genetic testing are possible.