Congenital dyserythropoietic anaemia with novel intra‐erythroblastic and intra‐erythrocytic inclusions

Abstract

A hitherto undescribed form of congenital dyserythropoietic anaemia is reported. The patient was severely anaemic and hydropic at birth and is now 8 years old. She has a moderate normochromic normocytic anaemia. HbF level of 50%, reticulocyte count of 5-12% and hyperbilirubinaemia. Bone marrow smears showed intense normoblastic erythroid hyperplasia with morphological evidence of dyserythropoiesis; the most common dysplastic features were basophilic stippling of polychromatic erythroblasts and erythrocytes and marked abnormalities of nuclear shape in polychromatic erythroblasts. Electron microscope studies showed that some polychromatic erythroblasts and several erythrocytes contained inclusions which were rounded, elongated or irregular in outline or were doughnut-shaped. These inclusions consisted of compact masses of tubules and saccules which may represent smooth endoplastic reticulum together with Golgi cisternae. The ultrastructural studies also revealed peculiar membrane-bound cylindrical structures in a rare late erythroblast, and phagocytosed erythroblasts within some macrophages. The technique of combined Feulgen microspectrophotometry and 3H-thymidine autoradiography demonstrated a pile-up of early polychromatic erythroblasts in the G1 and G2 phases of the cell cycle, indicating a prolongation of, or an arrest at, these phases. Furthermore, nearly a quarter of all erythroblasts failed to incorporate 3H-leucine into protein. Thus the anaemia appeared to be due to a combination of disordered erythroblast function, increased ineffectiveness of erythropoiesis and peripheral haemolysis. The primary defect may be an excessive synthesis or impaired degradation of intracytoplasmic membranes.

Severe anemia in theNanmutant mouse caused by sequence-selective disruption of erythroid Krüppel-like factor

“…Studies of this transfusion-dependent patient in the 1990s revealed severe anemia with high hemoglobin F and reticulocyte levels, membrane abnormalities, altered cell-cycle parameters, deficient protein synthesis (42,43), and increased embryonic ζ-and ε-globin expression (44,45). These effects are consistent with our observations of the Nan mutant mouse and demonstrate that carrying a single KLF1 allele mutated at this site can lead to a human disease phenotype.…”

Dyserythropoiesis and Congenital Dyserythropoietic Anaemias

“…There are descriptions of novel types of CDA in single patients. For example, in one patient, large, rounded intraerythroblastic inclusions of tightly-packed double membranes were found associated with a deficiency of CD44, Co (a¹b¹) blood group, reduced expression of aquaporin-1 (CHIP) and the presence of z-and e-globin chains in some red cells (Wickramasinghe et al, 1991;Parsons et al, 1994;Agre et al, 1994). In this case the primary defect may lie in a hitherto unidentified erythroid transcription factor.…”

Investigating the Molecular Pathogenesis of Inherited Childhood Anaemia

“…The team then discovered the same mutation in another patient described many years beforehand (patient SF) (Agre et al, 1994, Parsons et al, 1994, Tang et al, 1993, Wickramasinghe et al, 1991.…”

“…The patients show slightly variant phenotypes but the overall clinical characteristics are severe normocytic anaemia, highly elevated HbF, the presence of nucleated RBCs in the peripheral blood, and erythroid hyperplasia in the bone marrow (Mitchell et al, 2011). The patients also display mild dyserythropoiesis, splenomegaly, and growth delay (Arnaud et al, 2010, Jaffray et al, 2013, Ravindranath et al, 2011, Wickramasinghe et al, 1991.…”

“…CDAIV patients present with severe normocytic anaemia, highly elevated HbF, the presence of nucleated RBCs in the peripheral blood, and erythroid hyperplasia (Mitchell et al, 2011). The patients display mild dyserythropoiesis in the bone marrow, splenomegaly, and growth delay (Arnaud et al, 2010, Jaffray et al, 2013, Ravindranath et al, 2011, Wickramasinghe et al, 1991. In all patients, the causative mutation results in a single amino acid change in the highly conserved DNA-binding domain of KLF1.…”