Congenital Hypoplastic Anemia (Diamond-Blackfan Anemia)

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Chapter 442 Congenital Hypoplastic Anemia (Diamond-Blackfan Anemia)

Norma B. Lerner

Congenital hypoplastic anemia (Diamond-Blackfan anemia, DBA) is a rare condition that usually becomes symptomatic in early infancy, often presenting with pallor in the neonatal period. More than 90% of cases are recognized in the 1st year of life. Occasionally the disorder is first diagnosed later in childhood. The most characteristic hematologic features are anemia, usually macrocytic, reticulocytopenia, and a deficiency or absence of red blood cell (RBC) precursors in an otherwise normally cellular bone marrow.

Etiology

The primary defect in DBA is intrinsic to the erythroid progenitor cell and results in increased apoptosis (programmed cell death). High levels of erythropoietin (EPO) are present in serum and urine, although mutations in the EPO receptor gene have not been identified. In about 25% of cases, mutations are seen in the gene RPS19, which codes for a ribosomal protein mapped to chromosome 19q13.2. De novo mutations have also been found in the genes RPS24 and RPS17, located at chromosome 10q22-q23 and 15q25.2, respectively, and also coding for ribosomal proteins. Mutations have also been found in large ribosomal subunit proteins.

Epidemiology

Approximately 40-45% of cases of DBA are familial, with an autosomal dominant pattern of inheritance. The others are either sporadic or familial, with varying inheritance patterns.

Clinical Manifestations

Although hematopoiesis is usually adequate in fetal life, some affected infants appear pale at birth or in the first days after birth; rarely, hydrops fetalis occurs. Profound anemia usually becomes evident by 2-6 mo of age, occasionally somewhat later. Growth retardation (short stature) is recognized in about 30% of children, and congenital malformations are noted in about 35-45%. Craniofacial abnormalities are the most common anomalies and include hypertelorism and snub nose. Thumb abnormalities, including flattening of the thenar eminence and triphalangeal thumb, may be bilateral or unilateral. The radial pulse may be absent. Ophthalmologic, urogenital, cardiac, musculoskeletal, and neuromotor anomalies have also been identified. Overall, the abnormalities are diverse, with no specific pattern emerging among most of those affected.

Laboratory Findings

The RBCs are usually macrocytic for age, but no hypersegmented neutrophils or other characteristics of megaloblastic anemia are appreciated on the peripheral blood smear. Chemical evaluation of the RBCs reveals an enzyme pattern similar to that of a “fetal” RBC population with increased expression of “i” antigen and elevated fetal hemoglobin (HbF). Erythrocyte adenosine deaminase (ADA) activity is increased in most patients with this disorder, a finding that helps distinguish congenital RBC aplasia from acquired transient erythroblastopenia of childhood (Chapter 444

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