Page 830 - Hematology_ Basic Principles and Practice ( PDFDrive )

716 Part VI Non-Malignant Leukocytes

heterozygous for null NEMO mutations suffer from incontinentia poor migration of T and B lymphocytes in response to chemokines,
pigmenti. Typically, males with NEMO deficiency present with NKT-cell deficiency, and markedly reduced secretion of interferon-
ectodermal dysplasia and immunodeficiency (EDA-ID). The phe- alpha (IFN-α) by plasmacytoid dendritic cells represent the major
notypic manifestations of EDA-ID are largely restricted to epithelial immunological abnormalities. Low TREC levels at birth have been
tissues and the immune system, with sparse hair, shiny skin, lack of reported in two patients. The prognosis is very severe, but definitive
sweat glands and other appendages, and rare conical-shaped teeth. cure may be achieved with HCT. Use of systemic IFN-α may help
There is often frontal bossing and a characteristic facies. Typical in the treatment of severe viral infections.
infections are caused by bacteria, including sepsis and meningitis,
especially Streptococcus pneumoniae, Staphylococcus, and Haemophilus
influenzae; DNA viral infections such as CMV and herpes simplex DOCK8 Deficiency
virus (HSV); and atypical mycobacterial infection. Pneumocystis and
other opportunistic infections may also occur. Inflammatory colitis DOCK8 deficiency is an autosomal recessive combined immunode-
is a frequent manifestation of immune dysregulation. Lymphedema ficiency characterized by severe and recurrent infections, particularly
and osteopetrosis have been reported in some patients. Occasionally, systemic and cutaneous viral infection (molluscum contagiosium,
manifestations of ectodermal dysplasia may be modest or even absent, HSV-1 and HSV-2, human papillomavirus), allergic manifestations
thus adding to phenotypic heterogeneity. Immunological abnormali- (early-onset eczema, food allergies) with elevated serum IgE, impaired
ties include variable defects in T-cell proliferation to mitogen and humoral immunity (with frequent sinopulmonary infections), and
antigens, hypogammaglobulinemia with normal or high IgM, defec- increased risk for squamous cell carcinoma and lymphoma. Large
tive antibody production (especially against polysaccharides), and intragenic deletions account for the majority of the mutations.
impairment of NK-cell cytotoxicity. Finally, monocytes from patients Affected patients have low numbers of naive CD8 T cells, and
with NEMO deficiency fail to elaborate inflammatory cytokines accumulation of CD8 memory cells with an “exhausted phenotype”.
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such as tumor necrosis factor (TNF)α in response to stimulation A profound impairment in the generation of CD8 memory T cells
by a variety of Toll-like receptor ligands. A similar clinical and in response to influenza or other viral infections has been reported.
immunological phenotype is observed in patients with autosomal Humoral immunity is also compromised, with loss of germinal center
dominant EDA-ID caused by gain-of-function mutations of the B cells and defective immunoglobulin affinity maturation. The
IKBA gene. In these patients, the mutated IKB-α protein cannot disease has a severe prognosis, with considerable mortality. HCT
be phosphorylated at residues that are critical for its degradation. represents the only definitive treatment. Use of systemic IFN-α may
This prevents release of the cytoplasmic components of NF-κB, ameliorate manifestations of severe cutaneous viral infection.
which cannot translocate to the nucleus and mediate transcription of
target genes.
Aside from supportive therapy with intravenous immunoglobulin Wiskott-Aldrich Syndrome
replacement, antibiotic prophylaxis and treatment of infections,
HCT for these disorders has been used with variable success. Because Wiskott-Aldrich syndrome (WAS) is an X-linked disorder, character-
of the role of NF-κB signaling in nonhematopoietic tissues, certain ized by thrombocytopenia with small-sized platelets, eczema, and
manifestations of the disease, such as colitis, may not be uniformly immunodeficiency. Autoimmune manifestations are common, and
ameliorated by HCT. there is an increased risk of hematologic malignancies (primarily
Mutations of the IKBKB gene are responsible for an autosomal non-Hodgkin lymphoma, sometimes EBV driven). The estimated
recessive disease, characterized by a SCID-like phenotype without incidence is 1 in 100,000 births. The defect is due to mutations in
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ectodermal dystrophy. Patients lack regulatory T cells and TCRγδ T the WAS gene, which encodes for an intracytoplasmic protein (WAS
cells. The MAP3K14 gene encodes for NIK, a component of the protein [WASp]) expressed in hematopoietic cells and involved in
noncanonical NF-κB signaling pathway. Patients with NIK deficiency cytoskeleton reorganization and immune synapse formation. Defi-
suffer from recurrent infections. Immunological abnormalities ciency of WASp results in impaired T-cell activation, poor produc-
include reduced T-cell proliferation, hypogammaglobulinemia with tion of antibodies, particularly to carbohydrate antigen, defective
reduced number of total and switched memory B cells, and NK NK function, impaired phagocytic cell migration, and defective
deficiency. antigen presentation, thus explaining the immunodeficiency of the
The CARD11–BCL10–MALT1 complex regulates NF-κB signal- disease.
ing. Deficiency of any of these proteins causes combined immune The clinical phenotype may range from typical and severe WAS
deficiency with increased susceptibility to infections. T-cell prolifera- to isolated thrombocytopenia; milder phenotypes are often associated
tion is impaired. Defective antibody responses are observed in patients with residual expression of WASp. Rarely, mutations occurring in the
with BCL10 and CARD11 deficiency; the latter condition is also GTPase binding domain of the protein results in a hyperactive form
characterized by an increase in the proportion of transitional B cells. of WASp, resulting in X-linked neutropenia and myelodysplasia
without thrombocytopenia, eczema, or immunodeficiency.
Boys with WAS typically present in infancy with bleeding,
DOCK2 Deficiency prompting the discovery of low numbers of platelets with a low mean
platelet volume. Bleeding manifestations can range from petechiae
The dedicator of cytokinesis (DOCK) proteins are atypical guanine and bruising, to severe gastrointestinal and intracranial hemorrhages.
exchange factors containing a phosphatidylinositol (3,4,5)-triphos- Eczema can be mild to severe. Common infections in WAS patients
phate (PIP3) binding domain and a Rho-family GTPase binding include otitis, sinusitis, pneumonia, and cellulitis. Viral infections
domain with guanine exchange factor activity. DOCK2 is predomi- (especially from herpesviruses, including CMV, EBV, and HSV-1)
nantly expressed in various hematopoietic cell lineages (including T, and opportunistic infections, such as P. jiroveci pneumonia, are also
B, NK, and NKT lymphocytes, as well as granulocytes and other frequent. Approximately 40% of patients with WAS develop autoim-
myeloid cells), and is activated in response to engagement of the munity, including autoimmune hemolytic anemia, autoimmune
TCR, BCR, and chemokine receptors. DOCK2 activation allows thrombocytopenia, thyroiditis, colitis, vasculitis, nephropathy, and
formation of GTP-Rac1, thereby promoting reorganization of the arthritis. In addition to thrombocytopenia, typical laboratory find-
cellular cytoskeleton, and intracellular signaling. DOCK2 deficiency ings include inability to mount responses to polysaccharide antigens,
is an autosomal recessive combined immunodeficiency characterized low or absent isohemagglutinin titers, high IgE, and poor prolifera-
by increased susceptibility to severe infections starting early in life. tion of T cells when stimulated with anti-CD3 antibody. Other
Severe varicella has been reported in multiple patients. T-cell lym- immune findings are more variable, including progressive T lympho-
phopenia, with marked reduction of naive T cells and impaired T-cell penia with age, low IgM, and high IgA. Analysis of WASp expression
proliferation, defective antibody responses, reduced NK cell function, and demonstration of WAS gene mutations confirm the diagnosis.