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Purpose of review: This review summarizes the recent advances in the diagnosis and molecular characterization of isolated and syndromal forms of severe congenital neutropenia.

Recent findings: It has become evident that severe congenital neutropenia comprises several genetically distinct entities. In 1999, mutations were identified in the neutrophil elastase gene ELA2. ELA2 mutations have been found in cyclic, sporadic and autosomal dominant neutropenia. Recently, homozygous mutations in the antiapoptotic gene HAX1 were found in patients with autosomal recessive severe congenital neutropenia. Ongoing linkage studies suggest that more and, as yet unidentified, genes may be involved in the pathophysiology of severe congenital neutropenia. In other patients, congenital neutropenia is not an isolated finding but is associated with other abnormalities, in particular, lymphoid immunodeficiency and pigmentation defects such as Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2, or deficiency of the endosomal adaptor p14. The molecular identification of these disorders originating from mutations in lysosome (related) proteins has advanced our knowledge of intracellular protein trafficking.

Summary: Recent insights into the molecular etiology of severe congenital neutropenia provide the opportunity for a definitive genetic classification system. Based on this knowledge, disease-related risks may be recognized and optimized therapeutic options may become available.

(C) 2007 Lippincott Williams & Wilkins, Inc.