Kostmann Syndrome - Pathophysiology

Pathophysiology

Homozygous mutations in the HAX1 gene are associated with Kostmann disease, i.e. the "classical," autosomal recessive form of severe congenital neutropenia (SCN3).

In patients with the autosomal dominant form of severe congenital neutropenia (SCN1), although the underlying genetic defect in myeloid precursor cells is not entirely elucidated, mutations in the gene (ELA2) encoding neutrophil elastase appear to be present in most patients. These mutations may be responsible for the untimely initiation of apoptosis in myelocytes, producing their premature destruction, and interrupting the normal cycle of maturation. There may be, in addition, other underlying molecular/genetic changes producing DNA mutations and genome instability, which contribute to initiation and progression of this disease. Regular administration of exogenous granulocyte colony-stimulating factor (Filgrastim) clinically improves neutrophil counts and immune function and is the current mainstay of therapy, although this may increase risk for myelofibrosis and acute myeloid leukemia in the long term.