It is extremely rare to have primary defects in neutrophil actin polymerization as a cause of abnormal chemotaxis and recurrent infections. An apparent AR disorder of actin polymerization has been described in a male infant of Tongan descent who presented with severe skin infections, recurrent pulmonary infiltrates, thrombocytopenia, and invasive Candida tropicalis infection (MIM %257150). Neutrophil actin polymerization was markedly abnormal and associated with increased expression of the actin-binding protein LSP-1. In another single case, a heterozygous point mutation in β-actin affecting binding to actin regulatory proteins was discovered in a female patient with recurrent infections, photosensitivity, and mental retardation. Neutrophils had a marked impairment in chemotaxis and in the formyl peptide-induced respiratory burst. Finally, the use of unbiased exome sequencing has identified the genetic basis for several “actinopathies” due to defects in various actin regulatory proteins, resulting in impaired chemotaxis of neutrophils and other immune cells. Affected patients suffer from recurrent bacterial and other infections, but each disorder also has distinctive laboratory and clinical features. For example, in patients with genetic defects in the actin-binding protein WDR1, which is important for depolymerizing actin via cofilin, about 50% of neutrophils show herniation of the nuclear lobes, which colocalize with increased F-actin staining. These patients also often have severe stomatitis resulting in acquired microstomia and oral stenosis.
A syndrome of severe neutrophil dysfunction caused by a DN mutation in Rac2, a small GTPase expressed in blood cells that acts in many signal transduction pathways, was described in an infant boy born to unrelated parents. This baby presented with rapidly progressive and deep-seated soft tissue infections, along with neutrophilia and poor formation of pus. The clinical phenotype resembles LAD, but there is normal expression of β2 integrins and fucosylated proteins. Neutrophils had marked defects in actin polymerization, chemotaxis, degranulation, and the respiratory burst in response to chemoattractants. Neutrophil responses to other agonists were normal, suggesting that the DN Rac2 mutation produces a selective intracellular signaling defect.
Localized juvenile periodontitis (LJP) is a heterogeneous dis order of unknown etiology characterized by chronic and recurrent periodontal infections and severe alveolar bone loss with onset at the time of puberty. Many patients with LJP have been reported to have defective neutrophil chemotaxis in vitro. At present, it appears that LJP is an acquired disorder in some patients and a genetic disorder in others. It may also be a combination of both in certain patients because they may inherit an unusual sensitivity to the chemotactic inhibitors released by certain periodontal microorganisms. The diagnosis of the disorder is made on the basis of severe periodontal disease and destructive alveolar bone loss involving the first molars and incisors developing during adolescence. It is important to note that many qualitative and quantitative neutrophil disorders are also associated with severe periodontal disease. Therefore the differential diagnosis should include neutropenia (both chronic and cyclic), LAD, CGD, and Chédiak-Higashi syndrome (CHS).
One of the most consistently observed chemotactic abnormalities is seen in neonatal neutrophils. These cells exhibit impaired chemotaxis in vitro in response to a wide variety of chemotactic factors. It appears as though this abnormality is caused, at least in part, by defects in cellular adhesion as a result of diminished mobilization of intracellular adhesion-promoting molecules to the cell surface. Defective neutrophil chemotaxis can be seen in normal neonates between birth and 5 days of age. In severely ill infants, the defect may persist for a longer time.
