Genetic and molecular diagnosis of severe congenital neutropenia

Severe congenital neutropenia has been a well known hematological condition for over 50 years. Over this long period of time, the variable genetic causes and associated sequelae of the disease have been ascertained, and successful treatment strategies developed. Over the past 2 years, however, new studies have added greatly to our understanding of the molecular basis of the disease, details of which are presented in this review.

Recent studies have elucidated a role for the unfolded protein response in mediating the pathogenic effects of ELA2 mutations, the most common mutation in severe congenital neutropenia (SCN) as well as cyclic neutropenia. Genetic lesions in HAX1 have also been identified in the original Kostmann pedigree representing the autosomal recessive form of SCN. An emerging theme is the convergence of these and other genetic lesions underlying SCN in enhancing neutrophil apoptosis. Other studies have revealed the importance of multiple independent mutations in these and other genes in SCN. Finally, the key role for signal transducer and activator of transcription 5 in mediating the effects of granulocyte colony-stimulating factor receptor truncation mutations in the development of myelodysplastic syndrome/acute myeloid leukemia following SCN has been elucidated.

As the full spectrum of molecular mutations causing neutropenia emerges, it is becoming possible to differentiate patients into subtypes with different prognoses, for whom tailored therapies are indicated.