There are several forms of congenital neutropenia. Severe congenital neutropenia (Kostmann syndrome) is an autosomal recessive disorder in which myeloid cells fail to mature beyond the early stages of the promyelocyte due to mutations in the HAX-1 gene. The peripheral blood may show an impressive monocytosis. Although endogenous G-CSF levels are increased, exogenous G-CSF produces a rise in the neutrophil count, improving the care of these children. Acute myeloid leukemia has developed in a few patients who have survived into adolescence. Stem cell transplantation may be curative. Defects in G6PC3 and GFI1 have also been shown to cause severe congenital neutropenia. Cyclic neutropenia is a stem cell disorder in which all marrow elements cycle. It may be transmitted as an autosomal dominant, recessive, or sporadic disorder. Because of the short half-life of neutrophils in the blood (6 to 7 hours) compared to platelets (10 days) and red blood cells (120 days), neutropenia is the only clinically significant abnormality. The usual cycle is 21 days, with neutropenia lasting 4 to 6 days, accompanied by monocytosis and often by eosinophilia. Severe, debilitating bone pain is common when the neutrophil count is low. G-CSF results in increasing neutrophil numbers and a shorter duration of neutropenia. Defects in ELA2, the gene encoding for neutrophil elastase, has been found in patients with cyclic neutropenia. Further analysis has demonstrated ELA2 mutations in some cases of severe congenital neutropenia.
Severe congenital neutropenia that may be either persistent or cyclic also is a component of Shwachman-Diamond syndrome, an autosomal recessive syndrome of pancreatic insufficiency accompanying bone marrow dysfunction. This is a panmyeloid disorder in which neutropenia is the most prominent manifestation. Metaphyseal dysostosis and dwarfism may occur. Patients usually respond to G-CSF. Other congenital neutropenia caused by deficient neutrophil production vary in severity and are poorly characterized. A gain of function mutation in the Wiskott-Aldrich syndrome protein has also been associated with an X-linked form of severe congenital neutropenia. Benign congenital neutropenia is a functional diagnosis for patients with significant neutropenia in whom major infectious complications do not develop. Many patients whose ANC ranges from 100 to 500/mm3 have an increased frequency of infections, particularly respiratory infections, but the major problem is the slow resolution of infections that develop. These disorders may be sporadic or familial and, in some instances, are transmitted as an autosomal dominant disorder. Severe congenital neutropenia may be associated with severe combined immunodeficiency in reticular dysgenesis, a
Table 74-1 Phagocytic Disorders NAME DEFECT COMMENT Chronic granulomatous disease Bactericidal X-linked recessive (66%), autosomal recessive (33%); eczema, osteomyelitis, granulomas, abscesses caused by Staphylococcus aureus, Burkholderia cepacia, Aspergillus fumigatus
Chédiak-Higashi syndrome Bactericidal plus chemotaxis; Autosomal recessive; oculocutaneous albinism, neuropathy, giant (1q42I-44) poor natural killer function neutrophilic cytoplasmic inclusions; malignancy, neutropenia
Myeloperoxidase deficiency Bactericidal, fungicidal Reduced chemiluminescence; autosomal recessive (1:4000); persistent candidiasis in diabetic patients
Glucose-6-phosphate Bactericidal Phenotypically similar to chronic granulomatous disease dehydrogenase deficiency
Burns, malnutrition Bactericidal plus chemotaxis Reversible defects