Page 821 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 50 Disorders of Phagocyte Function 707

lymphadenopathy, and progressive pancytopenia, that is now recog- molecules that normally reside in the specific granules. As discussed
nized to be a genetic form of HLH caused by impaired lymphocyte earlier, these β2 integrins play a key role in phagocyte chemotaxis.
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and NK cell function. The development of HLH can sometimes The molecular defect responsible for most cases of SGD has
be precipitated by Epstein-Barr virus infection. A reactive-appearing recently been shown to involve a myeloid transcription factor known
lymphohistiocytic proliferation occurs in the liver, spleen, lymph as C/EBPε, which regulates expression of certain genes activated
nodes, and BM, and the prognosis is uniformly fatal unless patients during granulocyte differentiation. 3,27 This came about serendipi-
undergo BMT. tously 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
Diagnosis granules, and impaired chemotaxis along with increased susceptibility
to bacterial infections. To date, mutations in the C/EBPε gene have
The diagnosis of CHS is made on the basis of the giant peroxidase- been identified in two SGD patients that encode truncated, nonfunc-
positive lysosomal granules in the peripheral blood granulocytes or tional proteins. However, DNA sequencing of the C/EBPε gene of
in BM myeloid cells. Identification of large, acid phosphatase-positive several other SGD patients has not revealed abnormalities, suggesting
lysosomes in amniocytes and chorionic villus cells has been used to that SGD is a genetically heterogeneous disorder.
diagnose CHS prenatally. Other clinical features characteristic of The diagnosis of SGD can be readily made by microscopic
CHS can support the diagnosis, including mild oculocutaneous examination. Wright-stained neutrophils are devoid of specific gran-
albinism; silvery hair, in which microscopic examination reveals giant ules but contain normal numbers of azurophilic granules. Electron
melanin granules; and a bleeding diathesis. The development of HLH microscopy reveals small peroxidase-negative vesicles, which presum-
is characterized by diffuse infiltrates of lymphohistiocytic cells seen ably represent empty specific granules. The diagnosis of SGD can also
on biopsy and by pancytopenia. Occasionally, giant granules that be established by demonstrating a severe deficiency in either lactofer-
resemble those of CHS can be seen in both acute and chronic rin or vitamin B 12-binding protein. An acquired form of SGD can
myelogenous leukemias. be seen in burn patients or in individuals with various myeloprolifera-
tive disorders. The treatment for SGD is similar to that for other
neutrophil disorders. If medical management is aggressive, the prog-
Therapy nosis appears quite good, with patients surviving into their adult
years.
The treatment for the stable phase of CHS is similar to that for other
neutrophil disorders. Prophylactic antibiotics such as TMP-SMX
appear to be beneficial. Parenteral antibiotics are indicated for acute MISCELLANEOUS INHERITED AND ACQUIRED
infections, and responses are often slow. Treatment with high-dose DISORDERS OF PHAGOCYTE FUNCTION
ascorbic acid (200 mg/day for infants; 6 g/day for adults) has been
found to improve the clinical status of some patients. Although there Rare inherited defects in phagocyte production or response to inflam-
is some controversy regarding the efficacy of ascorbic acid, given the matory cytokines are manifested as recurrent infections. 28,29 HIES
safety of this medication, it seems prudent to administer it to all also falls into this category (see earlier discussion). A distinctive group
patients. The treatment of HLH (accelerated phase) includes combi- of disorders referred to as Mendelian susceptibility to mycobacterial
nations of drugs that suppress the function of activated macrophages diseases (MSMD) involve inherited defects in macrophage IL-12/23–
and T cells followed by allogeneic hematopoietic stem cell transplan- dependent IFN-γ–mediated immunity. Macrophage production of
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tation. Indeed, transplantation is ideally performed before or at the IL-12 and IL-23 after ingestion of mycobacteria triggers IFN-γ
beginning of the accelerated phase. Note that transplantation does production by T and NK lymphocytes, which in turn activates crucial
not prevent the progressive neuropathy of CHS. genes in macrophages. MSMD (MIM 20990) can be caused by
inherited AR, AD, or X-linked defects leading to impaired T-cell
production of IFN-γ, expression of the IFN-γ receptor, or down-
Specific Granule Deficiency stream signaling, which results in a spectrum of recurrent and severe
atypical mycobacterial infections, as well as susceptibility to Salmo-
Neutrophil SGD is an extremely rare congenital disorder character- nella and, in some subgroups, viral infections. 28,29 As mentioned
ized by recurrent bacterial and fungal infections, primarily involving earlier, recessive point mutations in X-linked CYBB that selectively
the skin, ears, and lungs. 3,27 Infections are often indolent and smol- impair expression of the NADPH oxidase subunit gp91 phox in mac-
dering, and S. aureus, P. aeruginosa, enteric gram-negative bacteria, rophages but not neutrophils are also considered a subgroup of
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and C. albicans are the major pathogens. Family studies suggest that MSMD. A variety of genetic defects in a scaffolding protein known
it is inherited in an AR manner. Neutrophils from patients with SGD as IKK-γ or NEMO that is important for activation of the nuclear
have atypical bilobed nuclei, absent specific granules, and multiple factor kappa-B (NFκB) signaling pathway have been reported in
deficiencies of secondary and tertiary granule mRNAs and proteins, patients with anhydrotic ectodermal dysplasia and immunodeficiency;
including lactoferrin, vitamin B 12 -binding protein and gelatinase B; affected children have recurrent pyogenic infections with a minimal
although azurophil granules in this disorder are present and contain systemic inflammatory response and can also develop opportunistic
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MPO and lysozyme, they are markedly deficient in defensins. Mono- infections with atypical mycobacteria or Pneumocystis carinii. Several
cytes display cell surface and functional defects, eosinophils lack other kindred have been described with genetic deficiency of another
eosinophil-specific granule proteins such as eosinophil cationic protein, IRAK-4, important for NFκB activation by pyogenic bacte-
protein, and platelets have abnormal α granules, suggesting that the ria via the Toll-like receptor/IL-I receptor superfamily. Affected
underlying defect may be related to regulation of the synthesis of children also had recurrent infections with S. pneumonia and S.
certain granule and membrane proteins. This defect in synthesis is aureus, and a poor inflammatory response but no dysmorphic features
confined to BM-derived cells because lactoferrin secretion is normal or opportunistic infections. Finally, with the increasing use of low-
in the glandular epithelia of SGD patients despite the severe defi- cost gene sequencing, it is likely that new inherited disorders of
ciency in the neutrophils. phagocyte function will be identified in the coming years.
The recurrent skin and pulmonary infections characteristic of Patients with glycogen storage disease type Ib (GSD-Ib), which
SGD appear to be caused by two fundamental defects in the neutro- results from absence of a glucose-6-phosphate transporter, have
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phils. One defect is the marked deficiency of at least two important impaired neutrophil functions and neutropenia. Neutrophil defects
microbicidal granule proteins, lactoferrin and defensins. The other include depressed chemotaxis, phagocytosis, and NADPH oxidase
defect is a relatively severe chemotactic abnormality presumably activity. Although neutropenia appears to result from increased
caused by the absence of the intracellular pool of leukocyte adhesion neutrophil apoptosis, how impaired glucose homeostasis leads to