Diagnosis and management of congenital dyserythropoietic anemias

ABSTRACT

Congenital dyserythropoietic anemias (CDAs) are inherited disorders hallmarked by chronic hyporegenerative anemia, relative reticulocytopenia, hemolytic component and iron overload. They represent a subtype of the inherited bone marrow failure syndromes, characterized by impaired differentiation and proliferation of the erythroid lineage. Three classical types were defined by marrow morphology, even if the most recent classification recognized six different genetic types. The pathomechanisms of CDAs are different, but all seem to involve the regulation of DNA replication and cell division. CDAs are often misdiagnosed, since either morphological abnormalities or clinical features can be commonly identified in other clinically-related anemias. However, differential diagnosis is essential for guiding both follow up and management of the patients.

KEYWORDS:

• Inherited anemia
• ineffective erythropoiesis
• molecular genetics
• differential diagnosis
• follow up
• patient management

Financial & competing interests disclosure

This work was supported by grants from the Italian Ministero dell’Università e dellaRicerca, by grants MUR-PS 35-126/Ind, by grants from Regione Campania (DGRC2362/07), by EU Contract LSHM-CT-2006-037296, by PRIN to AI (20128PNX83), Italy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Congenital dyserythropoietic anemias (CDAs) are rare/very rare hereditary diseases that are counted as subtypes of bone marrow failure syndromes, with morphological erythroid abnormalities and ineffective erythropoiesis as predominant mechanism of anemia.

• CDA Ia and CDA II show the highest prevalence, particularly in Europe where founder mutations have been identified in CDAN1 and SEC23B genes.

• Three classical types were defined by marrow morphology; however, six different genetic types were recognized.

• The pathomechanisms of CDAs involve the regulation of DNA replication and cell division.

• CDAs can be misdiagnosed with clinically related hemolytic anemias. This is the case of CDA II, which shares several clinical findings with hereditary spherocytosis.

• Differential diagnosis is essential for addressing both follow-up and management of the patients.

• The most harmful complication of CDAs is iron overload, which is due to the increased but ineffective erythropoiesis, but also enhanced by transfusion regimen.

• Follow-up of CDA patients is essential for avoiding the complications related to the chronic anemia.

• The application of new technologies, as next-generation sequencing, will allow understanding the genetic factors that modify disease severity beyond achieving definitive diagnosis.