Congenital Dyserythropoietic Anemias

This is a group of inherited disorders characterized by quantitatively and qualitatively altered erythropoiesis resulting in usually mild-to-moderate anemia. Premature destruction of erythroblasts in the bone marrow reduces the number of them reaching maturity. In addition, there is peripheral destruction of these dysplastic erythroblasts. Three main types of congenital dyserythropoietic anemia (CDA; types I, II, and III) and four other extremely rare types have been described.

For CDA III: Anemia with Multinucleated Erythroblasts; Hereditary Benign Erythroreticulosis.

CDA I: Almost 200 cases of this autosomal recessive inherited disorder have been described. Most cases originate from Europe, and consanguinity is a known risk factor. The defect has been mapped to 15q15.1-q15.3.

CDA II: More than 120 cases have been reported. Inheritance is also autosomal recessive, but the mutations have been mapped to 20q11.2. Consanguinity is present in a few families. Both sexes are equally affected.

CDA III: The rarest of the three well-defined forms of CDA. Most of the knowledge about this type of CDA derives from the Swedish Västerbotten family. Inheritance is autosomal dominant (although sporadic cases have been reported), and the genetic defect has been mapped to 15q21-q25.

Based on the clinical findings, examination of peripheral blood smear and bone marrow biopsy, laboratory results (bilirubin, ferritin, transferrin, haptoglobin), and genealogic tree.

CDA I: Clinically, the spectrum ranges from mild to severe. In approximately half of the cases, the diagnosis is made in the neonatal period secondary to significant anemia. In the other half, the diagnosis is commonly made later in childhood or adolescence secondary to mild anemia with intermittent jaundice, splenomegaly, and sometimes hepatomegaly. The hemoglobin level typically stays at around 90 g/liter (range 66-116 g/liter), so transfusions are rarely required. Macrocytosis may be present, and the reticulocyte count is normal or low. The peripheral blood smear shows anisocytosis (elliptocytosis) and poikilocytosis with dacryocytosis. Serum concentration of bilirubin is elevated, while haptoglobin is decreased. Iron overload (even without transfusions) may result in hepatic cirrhosis and skin and endocrine changes. Biliary complications (e.g., bile duct obstruction, pancreatitis, bile peritonitis) may lead to sepsis. Bone marrow aspirate reveals erythroid hyperplasia with significantly dysplastic nuclei (irregular, karyorrhectic, binucleate, trinucleate appearance). Long chromatin strands surrounded by microtubules forming intercellular bridges and connecting the nuclei of two otherwise almost separated cells are considered typical for CDA I (although it may be seen in other forms of CDA). Erroneously, a β-thalassemia trait can be mimicked by increased percentage of hemoglobin A2 and the α/non-α-globin chain synthesis ratio. Severe forms, usually occurring before or at birth with hemoglobin levels as low as 30 g/liter requiring regular transfusions, have been described. Occasionally, the presenting features are dysmorphic body signs rather than anemia related and may include short stature, platyspondyly, hypoplastic ribs, hearing loss, hypertelorism, micrognathia, large mouth, thick lips, large ears, syndactyly, aplasia/hypoplasia of distal phalanges, onychodysplasia, and brown skin patches. These patients may be on interferon-α therapy.

CDA II: The main clinical features are anemia (which can be absent, mild or severe), jaundice, splenomegaly, and occasionally hepatomegaly. Rarely, frontal and parietal bossing, mental retardation, and posterior mediastinal tumors (extramedullary hemopoietic tissue) may occur. Like in CDA I, iron overload and biliary complications determine the course of this disorder. If CDA II is severe, often other conditions are associated. The combination of CDA II with Gilbert Syndrome results in an almost fivefold increased risk for gallstones compared to patients with isolated CDA II. Hemoglobin levels are usually above the transfusion threshold with normal or decreased reticulocyte count, but occasional drops related to acute infections are common. The peripheral blood cells show normocytosis, anisocytosis, and a varying degree of anisochromasia and poikilocytosis including teardrop poikilocytes. Many erythroblasts are binucleated; less commonly they are multinucleated. Erythroid hyperplasia dominates the bone marrow with an up to 10-fold increase in erythroblasts. Lipid-laden macrophages in the bone marrow lead to a pseudo-Gaucher appearance. The typical feature of CDA II can be detected only with electron microscopy: erythroblasts containing peripheral cisternae with a more or less interrupted double membrane running parallel to the erythroblast cell membrane in a distance of 40 to 60 nm. These cisternae appear to be derived from smooth endoplasmic reticulum and fail to be cleared away as a consequence of dyserythropoiesis. Their persistence can be shown even in circulating red cells. In CDA II, red cells are preferentially destroyed in the spleen, which seems to support the benefit of splenectomy.

CDA III: Clinical features are variable but usually well tolerated, with some fatigue and mild jaundice. Splenomegaly may be present. Hemoglobin levels are commonly above the transfusion threshold with a normal or low reticulocyte count. Peripheral blood smears show anisocytosis and basophilic stippling. Bone marrow examination reveals erythroid hyperplasia with sometimes impressive giant, multinucleated erythroblasts. The haptoglobin concentration is decreased, while serum bilirubin and lactic dehydrogenase (LDH) concentrations are elevated. Iron overload is rarely an issue in these patients. Hemosiderinuria may be present and partially explain the absence of iron overload. There seems to be an increased prevalence of lymphoproliferative disorders (Hodgkin lymphoma, T-cell lymphoma, monoclonal gammopathy, multiple myeloma). Other rare clinical features may include mental retardation, visual problems with macular degeneration and angioid streaks, mongoloid facial appearance, “hair-on-end” skull phenomenon on radiographs (expansion of the diploetic portion of the calvarium), and elevated serum thymidine kinase levels.

CDA IV: Severe, transfusion-dependent, autosomal recessive inherited form with nonspecific, moderately megaloblastic erythroid dysplasia and mild-to-moderate splenomegaly.

CDA V: Extremely rare, autosomal dominant inherited form with mild anemia and jaundice, unconjugated hyperbilirubinemia, and normoblastic erythroid hyperplasia without evidence of dyserythropoiesis.

CDA VI: Extremely rare form of CDA (only five cases have been described) characterized by vitamin B12- and folate-independent megaloblastic and dysplastic erythropoiesis. Anemia is usually mild with marked macrocytosis, slight hyperbilirubinemia, and absent splenomegaly.

CDA VII: Extremely rare form of CDA presenting with severe, transfusion-dependent anemia and prominent erythroid hyperplasia, anomalies of the erythroblast nuclei, and characteristic inclusions in polychromatophilic erythroblasts.

Obtain a complete blood count with differentiation. Check for signs of secondary hemochromatosis (as a result of iron overload). Assess cardiac function (clinically, echocardiography, electrocardiogram) and liver function (serum concentrations of bilirubin, transaminases, albumin, and clotting factors). Evaluate for endocrinopathies. Correct anemia if necessary prior to surgery. Check for dysmorphic features that sometimes are associated with this disorder (e.g., micrognathia, short stature, vertebral anomalies) and may have an impact on the anesthetic management.

Airway management may be challenging in the presence of micrognathia. Central neuraxial anesthesia techniques are not contraindicated but should be expected to be difficult in patients with vertebral anomalies. However, if hepatic function appears to be compromised, coagulation status should be checked beforehand. Depending on the procedure, ensure that blood is easily available for transfusion because patients with repeated transfusions may have antibodies that may delay the availability of matching blood units.

There are no specific implications for these conditions.

Blackfan-Diamond Syndrome: Congenital hypoplastic anemia manifesting in the first year of life with an increased risk for leukemia.

Fanconi Anemia: Spontaneous chromosomal aberrations associated with hypocellular marrow, pancytopenia, and constitutional aplastic anemia presenting in the first years of life associated with growth retardation. In older patients, a variety of cancers (head and neck, esophageal, gastrointestinal, vulvar, anal) have been described.