Neutrophil SGD is an extremely rare congenital disorder characterized by recurrent bacterial and fungal infections, primarily involving the skin, ears, and lungs. Infections are often indolent and smoldering, and S. aureus, P. aeruginosa, enteric gram-negative bacteria, and C. albicans are the major pathogens. Family studies suggest that it is inherited in an AR manner. Neutrophils from patients with SGD have atypical bilobed nuclei, absent specific granules, and multiple deficiencies of secondary and tertiary granule mRNAs and proteins, including lactoferrin, vitamin B12–binding protein, and gelatinase B; although azurophil granules in this disorder are present and contain MPO and lysozyme, they are markedly deficient in defensins. Monocytes display cell surface and functional defects, eosinophils lack eosinophil-specific granule proteins such as eosinophil cationic protein, and platelets have abnormal α granules, suggesting that the underlying defect may be related to regulation of the synthesis of certain granule and membrane proteins. This defect in synthesis is con fined to BM-derived cells because lactoferrin secretion is normal in the glandular epithelia of SGD patients despite the severe deficiency in the neutrophils.
The recurrent skin and pulmonary infections characteristic of SGD appear to be caused by two fundamental defects in the neutrophils. One defect is the marked deficiency of at least two important microbicidal granule proteins, lactoferrin and defensins. The other defect is a relatively severe chemotactic abnormality presumably caused by the absence of the intracellular pool of leukocyte adhesion molecules that normally resides in the specific granules. As discussed earlier, these β2 integrins play a key role in phagocyte chemotaxis.
The molecular defect responsible for most cases of SGD has recently been shown to involve a myeloid transcription factor known as C/EBPε, which regulates expression of certain genes activated during granulocyte differentiation. This came about serendipitously when it was recognized that mice with a targeted deletion in the C/EBPε gene displayed characteristics similar to those of SGD patients, including neutrophils with bilobed nuclei, absent secondary granules, and impaired chemotaxis along with increased susceptibility to bacterial infections. To date, mutations in the C/ EBPε gene have been identified in two SGD patients that encode truncated, nonfunctional proteins. However, DNA sequencing of the C/EBPε gene of several other SGD patients has not revealed abnormalities, suggesting that SGD is a genetically heterogeneous disorder.
The diagnosis of SGD can be readily made by microscopic examination. Wright-stained neutrophils are devoid of specific granules but contain normal numbers of azurophilic granules. Electron microscopy reveals small peroxidase-negative vesicles, which presumably represent empty specific granules. The diagnosis of SGD can also be established by demonstrating a severe deficiency in either lactoferrin or vitamin B12–binding protein. An acquired form of SGD can be seen in burn patients or in individuals with various myeloproliferative neoplasms. The treatment for SGD is similar to that for other neutrophil disorders. If medical management is aggressive, the prognosis appears quite good, with patients surviving into their adult years.
