Clinical characteristics: Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild anemia or no anemia with only subtle erythroid abnormalities, physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma.
Diagnosis/testing: The clinical diagnosis can be established in a proband with macrocytic anemia with onset prior to age one year, no other significant cytopenias, reticulocytopenia, normal marrow cellularity with a paucity of erythroid precursors, and no evidence of another acquired or inherited disorder of bone marrow function.
The molecular diagnosis can be established in a female proband by identification of a heterozygous pathogenic variant in one of the 22 genes associated with DBA.
The molecular diagnosis can be established in a male proband by identification of a heterozygous pathogenic variant in a gene associated with autosomal dominant DBA or identification of a hemizygous pathogenic variant in GATA1 or TSR2 (associated with X-linked inheritance).
Management: Treatment of manifestations: Corticosteroid treatment, recommended in children older than age 12 months, improves the red blood cell count in approximately 80% of affected individuals. Chronic transfusion with packed red blood cells is necessary during the first year of life to avoid steroid-induced toxicity in those not responsive to a trial of corticosteroids at age 12 months and in individuals who relapse. Hematopoietic stem cell transplantation, the only curative therapy for the hematologic manifestations of DBA, is often recommended for those who are transfusion dependent or develop other cytopenias. Ocular, skeletal, genitourinary, cardiac, and endocrine complications are best managed in collaboration with appropriate subspecialists. Treatment of malignancies should be coordinated by an oncologist. Chemotherapy must be given cautiously as it may lead to prolonged cytopenia and subsequent toxicities.
Prevention of secondary complications: Transfusion-related iron overload is the most common complication in transfusion-dependent individuals. Iron chelation therapy with deferasirox orally or desferrioxamine subcutaneously is recommended after ten to 12 transfusions. Corticosteroid-related side effects must also be closely monitored, especially as related to risk for infection, growth deficiency, and loss of bone density in growing children. Often individuals will be placed on transfusion therapy if these side effects are intolerable.
Surveillance: Complete blood counts several times a year; bone marrow aspirate/biopsy to evaluate morphology and cellularity only in the event of another cytopenia or a change in response to treatment. In steroid-dependent individuals: monitor blood pressure and (in children) growth. Evaluation by an endocrinologist for those who are steroid dependent and those at risk for transfusion iron overload. Cancer surveillance includes history, physical examination, and blood counts every four to six months. If red blood cell, white blood cell, or platelet counts fall rapidly, bone marrow aspirate with biopsy and cytogenetic studies (including karyotype and FISH analysis) to look for acquired abnormalities in chromosomes 5, 7, and 8 that are associated with myelodysplastic syndrome or leukemia.
Agents/circumstances to avoid: Deferiprone for the treatment of iron overload (which can cause neutropenia); infection (especially in individuals on corticosteroids).
Evaluation of relatives at risk: Molecular genetic testing of at-risk relatives of a proband with a known pathogenic variant allows for early diagnosis and appropriate monitoring for bone marrow failure, physical abnormalities, and related cancers.
Pregnancy management: Management by an obstetrician with expertise in high-risk pregnancies and hematologists with experience in bone marrow failure syndromes. During pregnancy the maternal hemoglobin level must be monitored. Use of low-dose aspirin up to 37 weeks' gestation may help prevent vasculo-placental complications in women with a history of a problematic pregnancy.
Genetic counseling: DBA is most often inherited in an autosomal dominant manner; GATA1-related and TSR2-related DBA are inherited in an X-linked manner.
Autosomal dominant. Approximately 40%-45% of individuals with autosomal dominant DBA have inherited the pathogenic variant from a parent; approximately 55%-60% have a de novo pathogenic variant. Each child of an individual with autosomal dominant DBA has a 50% chance of inheriting the pathogenic variant.
X-linked. Males with GATA1- or TSR2-related DBA pass the pathogenic variant to all of their daughters and none of their sons. Women heterozygous for a GATA1 or TSR2 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Carrier testing of at-risk female relatives is possible if the GATA1 or TSR2 pathogenic variant has been identified in the family.
Once the DBA-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
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