Confounding factors in the diagnosis and clinical course of rare congenital hemolytic anemias

Abstract

Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis. These rare and heterogeneous conditions may generate several difficulties from the diagnostic point of view. Membrane defects include hereditary spherocytosis and elliptocytosis, and the group of hereditary stomatocytosis; glucose-6-phosphate dehydrogenase and pyruvate kinase, are the most common enzyme deficiencies. Among ultra-rare forms, it is worth reminding other enzyme defects (glucosephosphate isomerase, phosphofructokinase, adenylate kinase, triosephosphate isomerase, phosphoglycerate kinase, hexokinase, and pyrimidine 5′-nucleotidase), and congenital dyserythropoietic anemias. Family history, clinical findings (anemia, hemolysis, splenomegaly, gallstones, and iron overload), red cells morphology, and biochemical tests are well recognized diagnostic tools. Molecular findings are increasingly used, particularly in recessive and de novo cases, and may be fundamental in unraveling the diagnosis. Notably, several confounders may further challenge the diagnostic workup, including concomitant blood loss, nutrients deficiency, alterations of hemolytic markers due to other causes (alloimmunization, infectious agents, rare metabolic disorders), coexistence of other hemolytic disorders (autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc.). Additional factors to be considered are the possible association with bone marrow, renal or hepatic diseases, other causes of iron overload (hereditary hemochromatosis, hemoglobinopathies, metabolic diseases), and the presence of extra-hematological signs/symptoms. In this review we provide some instructive clinical vignettes that highlight the difficulties and confounders encountered in the diagnosis and clinical management of CHAs.

Concomitant Hereditary Spherocytosis and Pyruvate Kinase Deficiency in a Spanish Family with Chronic Hemolytic Anemia: Contribution of Laser Ektacytometry to Clinical Diagnosis

“…( Figure 1 ). The slight differences in clinical expression of SPTB mutation between the different members of this family may be explained by the known intra-family variability of clinical phenotype in HS [ 34 ] or additional factors (even acquired) that may modify clinical phenotype in these patients [ 35 ].…”

Rise of the planet of rare anemias: An update on emerging treatment strategies

“…Congenital hemolytic anemias are characterized by reduced lifespan and early destruction of erythrocytes. They encompass defects of the erythrocyte membrane proteins (hereditary spherocytosis, HS, hereditary elliptocytosis, HE, and hereditary stomatocytosis, Hst) and red cell enzymes metabolism (glucose-6-phosphate dehydrogenase, G6PD, and pyruvate kinase, PK), as well as alterations of erythrocyte precursors, resulting in defective erythropoiesis (congenital dyserythropoietic anemia, CDA) ( 19 ). Current management of CHAs mainly relies on transfusions, iron chelation, and splenectomy.…”

Pyruvate Kinase Deficiency: Current Challenges and Future Prospects

“…1,22 The great overlap with the other congenital anemias challenges the differential diagnosis (Figure 2). 4 Generally, hemolytic features and increased mean corpuscular volume (MCV) typical of CHAs aid the distinction from hemoglobinopathies that are further investigated by searching for pathologic hemoglobin forms through high performance liquid chromatography (HPLC). The distinction from other CHAs may be more difficult and is supported by evaluation of RBC morphology (peripheral blood smear), osmotic fragility tests, and RBC deformability tests by ektacytometry that are usually normal in PKD and altered in membrane defects.…”

“…The latter may have similar phenotypes but may show different outcomes in terms of response to splenectomy and frequency of complications. 4 Finally, the advent of novel treatments aimed at restoring PK activity, including the allosteric PK enzyme activator mitapivat and gene therapy, further advocates for a definite diagnosis in these patients. 5 , 6 In this review, we will provide a clinician insight in the current diagnosis and management of PKD, including challenges in disease identification and treatment, and future prospects on novel targeted therapies and gene therapy.…”