Shwachman-Diamond Chemotaxis, neutropenia Pancreatic insufficiency, metaphyseal chondrodysplasia; autosomal syndrome
CR3, Complement receptor 3; LFA-1, leukocyte function-associated antigen type 1; Mac-1, macrophage 1 antigen.
disorder of hematopoietic stem cells affecting all bone marrow lineages due to mutations in the AK2 gene.
Isoimmune neutropenia occurs in neonates as the result of transplacental transfer of maternal antibodies to fetal neutrophil antigens. The mother is sensitized to specific neutrophil antigens on fetal leukocytes that are inherited from the father and are not present on maternal cells. Isoimmune neonatal neutropenia, similar to isoimmune anemia and thrombocytopenia, is a transient process (see Chapters 62 and 151). Cutaneous infections are common, and sepsis is rare. Early treatment of infection while the infant is neutropenic is the major goal of therapy. Intravenous immune globulin may decrease the duration of neutropenia.
Autoimmune neutropenia usually develops in children 5 to 24 months of age and often persists for prolonged periods. Neutrophil autoantibodies may be IgG, IgM, IgA, or a combination of these. Usually the condition resolves in 6 months to 4 years. Although intravenous immune globulin and corticosteroids have been used, most patients respond to G-CSF. Autoimmune neutropenia rarely may be an early manifestation of systemic lupus erythematosus, rheumatoid arthritis, or autoimmune lymphoproliferative disease.
Disorders of Neutrophil Migration
Neutrophils normally adhere to endothelium and migrate to areas of inflammation by the interaction of membrane proteins, called integrins and selectins, with endothelial cell adhesion molecules. A hallmark of defects in neutrophil migration is the absence of pus at sites of infection. In leukocyte adhesion deficiency type I (LAD-I), infants lacking the β2 integrin CD18 exhibit the condition early in infancy with failure of separation of the umbilical cord (often 2 months after birth) with attendant omphalitis and sepsis (see Table 74-1). The neutrophil count usually is greater than 20,000/mm3 because of failure of the neutrophils to adhere normally to vascular endothelium and to migrate out of blood to the tissues (Fig. 74-1). Cutaneous, respiratory, and mucosal infections occur. Children with this condition often have severe gingivitis. Sepsis usually leads to death in early childhood. This disorder is transmitted as an autosomal recessive trait. Stem cell transplantation can be lifesaving.
LAD-II results from impairment of neutrophil rolling along the vascular wall, which is the first step in neutrophil migration into tissues and sites of infection. Rolling is mediated by sialylated and fucosylated tetrasaccharides related to the sialylated Lewis X (S-LeX) blood group found on the surface of neutrophils, monocytes, and activated lymphocytes binding to selectin molecules on vascular endothelium (see Fig. 74-1).LAD-II results from a general defect in fucose metabolism leading to the absence of S-LeX blood group on the surface of neutrophils and other leukocytes. LAD-III is a rare disorder caused by defects in the KINDLIN-3 protein resulting in defective neutrophil adhesion as well as platelet defects. Defective migration of neutrophils has also been described in Hyper-IgE syndrome and with mutations in the RAC2 gene (see Chapter 73 and Table 74-1).
Disorders of Neutrophil Function
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