CLINICAL CHARACTERISTICS: DBA syndrome is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50% of affected individuals, 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 or no anemia with only subtle erythroid abnormalities and/or physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA syndrome is associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma. DIAGNOSIS/TESTING: The clinical diagnosis of DBA syndrome can be established in a proband with characteristic laboratory, histopathology, and clinical features. The molecular diagnosis of DBA syndrome can be established in a proband by identification of a heterozygous pathogenic variant in a gene associated with autosomal dominant DBA syndrome or biallelic pathogenic variants in associated with autosomal recessive DBA syndrome. Rarely, the molecular diagnosis can be established in a male proband by identification of a hemizygous pathogenic variant in or associated with X-linked DBA syndrome. MANAGEMENT: Corticosteroid treatment, recommended in children at age 12 months or older, improves the red blood cell count in approximately 60%-80% of affected individuals. Hematopoietic stem cell transplantation, the only curative therapy for the hematologic manifestations of DBA syndrome, is often recommended for those who are transfusion dependent or develop other cytopenias. Chronic transfusion with packed red blood cells is necessary during the first year of life to avoid steroid-induced growth deficiency. At age 12 months start an initial trial of steroids. Toxicity in individuals unresponsive to corticosteroids and individuals who relapse include transfusion-related iron overload, which 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. Deferiprone is only used in individuals with severe cardiac iron overload due to side effects. Cleft lip/palate and 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. Complete blood counts several times a year, then one to two times per year once hemoglobin is stable; 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, assess growth throughout childhood and monitor blood pressure. Endocrine evaluation for those who are steroid dependent and those at risk for transfusion iron overload. Ophthalmology evaluation for glaucoma and cataracts. Assessment of liver iron for those on chronic red blood cell transfusions. 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. Deferiprone for the treatment of iron overload (which can cause neutropenia); infection (especially in individuals on corticosteroids). It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual to allow early diagnosis and appropriate monitoring for bone marrow failure, physical abnormalities, and related cancers. 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 vasculoplacental complications in women with a history of a problematic pregnancy. GENETIC COUNSELING: Most often, DBA syndrome is inherited in an autosomal dominant manner. -related DBA syndrome is inherited in an autosomal recessive manner. - and -related DBA syndrome are inherited in an X-linked manner. Approximately 40%-45% of individuals diagnosed with autosomal dominant DBA syndrome inherited a DBA syndrome-causing variant from a parent; approximately 55%-60% have a pathogenic variant. Each child of an individual with autosomal dominant DBA syndrome has a 50% chance of inheriting the pathogenic variant. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family. If the mother of an affected male has a or pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually not be affected. Affected males transmit the or pathogenic variant to all of their daughters and none of their sons. Identification of female heterozygotes is possible once a or pathogenic variant has been identified in an affected family member. Once the DBA syndrome-causing variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.