Severe congenital neutropenia (SCN) consists of a group of inherited diseases that are characterized by severely impaired neutrophil counts ( <500 polymorphonuclear leukocytes [PMN]/μL of blood). The condition is usually manifested from birth. SCN may also be cyclic (with a 3-week periodicity), and other neutropenia syndromes can also be intermittent. Although the most frequent inheritance pattern for SCN is autosomal dominant, autosomal recessive and X-linked recessive conditions also exist. Bacterial infections at the interface between the body and the external milieu (e.g., the orifices, wounds, and the respiratory tract) are common manifestations. Bacterial infections can rapidly progress through soft tissue and are followed by dissemination in the bloodstream. Severe visceral fungal infections can also ensue. The absence of pus is a hallmark of this condition.
Diagnosis of SCN requires examination of the bone marrow. Most SCNs are associated with a block in granulopoiesis at the promyelocytic stage (Fig. 1). SCN has multiple etiologies, and to date, mutations in 21 different genes have been identified. Most of these mutations result in isolated SCN, whereas others are syndromic. The most frequent forms of SCN are caused by the premature cell death of granulocyte precursors, as observed in deficiencies of GFI1, HAX1, and elastase 2 (ELANE), with the latter accounting for 50% of SCN sufferers. Certain ELANE mutations cause cyclic neutropenia syn drome. A gain-of-function mutation in the WASP gene (see the section “Wiskott-Aldrich Syndrome” below) causes X-linked SCN, which is also associated with monocytopenia.
Fig1. Differentiation of phagocytic cells and related primary immunodeficiencies (PIDs). Hematopoietic stem cells (HSCs) differentiate into common myeloid progenitors (CMPs) and then granulocyte-monocyte progenitors (GM prog.), which, in turn, differentiate into neutrophils (MB: myeloblasts; Promyelo: promyelocytes; myelo: myelocytes) or monocytes (monoblasts and promonocytes). Upon activation, neutrophils adhere to the vascular endothelium, transmigrate, and phagocytose the targets. Reactive oxygen species (ROS) are delivered to the microorganism-containing phagosomes. Macrophages in tissues kill using the same mechanism. Following activation by interferon γ (not shown here), macrophages can be armed to kill intracellular pathogens such as mycobacteria. For sake of simplicity, not all cell differentiation stages are shown. The abbreviations for PIDs are contained in boxes placed at corresponding stages of the pathway. CGD, chronic granulomatous diseases; GATA2, zinc finger transcription factor; LAD, leukocyte adhesion deficiencies; MSMD, Mendelian susceptibility to mycobacterial disease; SCN, severe congenital neutropenia; WHIM, warts, hypogammaglobulinemia, infections, and myelokathexis.
As mentioned above, SCN exposes the patient to life-threatening, disseminated bacterial and fungal infections. Treatment requires careful hygiene measures, notably in infants. Later in life, special oral and dental care is essential, along with the prevention of bacterial infection by prophylactic administration of trimethoprim/sulfamethoxazole. Subcutaneous injection of the cytokine granulocyte colony-stimulating factor (G-CSF) usually improves neutrophil development and thus pre vents infection in most SCN diseases. However, there are two caveats: (1) a few cases of SCN with ELANE mutation are refractory to G-CSF and may require curative treatment via allogeneic hematopoietic stem cell transplantation (HSCT); and (2) a subset of G-CSF-treated patients carrying ELANE mutations are at a greater risk of developing acute myelogenous leukemia associated (in most cases) with somatic gain of-function mutations of the G-CSF receptor gene.
A few SCN conditions are associated with additional immune defects involving leukocyte migration as observed in the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (gain-of-function mutation of the chemokine CXCR4) or in moesin deficiency.
