Page 1250 - Williams Hematology ( PDFDrive )

1224 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1225

in gain-of-function–impaired actin polymerization, causing X-linked Other abnormal laboratory tests include eosinophilia, abnormal B-cell
neutropenia (Chap. 65). 186 maturation and defective antibody responses to neoantigens, che-
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motactic defects of neutrophils, and reduced lymphocyte proliferation
Clinical and Laboratory Features to specific antigens.
By definition, WAS and XLT patients have congenital thrombocytope- Most patients with HIES were noted to arise sporadically from unaf-
nia in the range of 20,000 to 60,000/μL and microplatelets, but normal fected, healthy parents. With the advent of improved antibiotic therapy,
numbers of megakaryocytes. Hemorrhagic problems may be mild, con- patients survived into adulthood and had affected children, suggesting
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sisting of bruises and petechiae, or serious, including gastrointestinal AD inheritance. This observation was validated by the finding that
and central nervous system hemorrhages. Patients with classic WAS are heterozygous mutations of the gene encoding the transcription factor
susceptible to bacterial, fungal, and viral infections. STAT3 are the cause of AD-HIES. All STAT3 mutations identified to
date in patients with AD-HIES are either amino acid substitutions or
Treatment in-frame deletions strongly supporting the concept that coexpression of
Patients may require antibiotic prophylaxis and IVIG replacement wild-type and mutant STAT3 protein is required to cause the syndrome.
therapy. Immunosuppressive therapy may be needed if autoimmune The notable lack of nonsense or frameshift mutations strengthens the
symptoms occur. Splenectomy ameliorates the bleeding tendency by notion that AD-HIES is a result of a dominant-negative effect. 196–198 The
increasing the number of blood platelets. However, splenectomy sub- molecular analysis of a large cohort of patients (n = 38) with “classic”
stantially increases the risk of septicemia, sometimes in spite of antibi- HIES and a score of greater than 40 points using the National Insti-
otic prophylaxis, and often results in fatal bacterial infections. Because tutes of Health clinical scoring system, identified STAT3 mutations
of the poor long-term outcome of WAS, early allogeneic HSCT is the in all but one individual. The mutations clustered in three domains
treatment of choice. The outcome is excellent if a matched-related or of the STAT3 protein known to have distinct functional characteris-
matched-unrelated donor can be identified, or if a partially matched tics, the DNA-binding, and the SH2 and the transactivation domains.
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cord blood unit is available. Haploidentical transplantation is not This finding suggests that more than one molecular mechanism causes
recommended. Patients with XLT have an excellent prognosis, but may the AD-HIES phenotype. This notion is supported by the observation
develop complications including serious bleeding, autoimmune dis- that mutations in the SH2 domain, but not those in the DNA-binding
eases, and malignancies. 144,185 Therefore, allogeneic HSCT for XLT may domain, affect tyrosine phosphorylation of STAT3, whereas muta-
be considered if an appropriate donor is available. Because complete tions in the DNA-binding domain interfere with nuclear import and
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myeloid and lymphoid engraftment is required to correct all aspects DNA-binding. Because STAT3 plays a key role in the development of
of WAS/XLT, standard-conditioning using myeloablative protocols IL-17 producing Th17 cells, AD-HIES patients have a marked decrease
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(busulfan, cyclophosphamide, with or without antithymocyte globulin) in circulating Th17 cells. Given that IL-17 plays an important role
are required. A European followup study of WAS patients who received in host defense against extracellular bacteria and fungi and upregu-
HSCT reports a strong association of autoimmunity with mixed chime- lates production of β defensins and S100 proteins by neutrophils, the
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rism, clearly demonstrating that reduced intensity conditioning is not absence of Th17 cells may directly affect susceptibility to S. aureus and
sufficient. 188 Candida albicans.
WASp-INTERACTING PROTEIN DEFICIENCY Treatment
To prevent progressive lung destruction, prophylactic antibiotic ther-
A syndrome exhibiting symptoms and laboratory abnormalities typical apy to decrease the frequency of S. aureus infections is important. Anti-
for classic WAS has been observed in a female infant with a homozy- fungal therapy is indicated to prevent recurrent Candida infections. A
gous nonsense mutation in WIPF1 that encodes WASp-interacting surgical approach to treating chronic lung disease should be avoided, if
protein (WIP). The patient presented at 11 days of age with eczema, possible. Allogeneic HSCT has been performed in a few patients with
thrombocytopenia (but normal platelet size) and infections. Both variable benefits. 201,202
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WIP and WASp were absent in patient leukocytes, demonstrating that
WIP is required for stabilization of WASp. The patient was successfully
transplanted at age 4.5 months. Autosomal Recessive Hyperimmunoglobulin E Syndromes
In 2004, a cohort of 13 patients from consanguineous families were
THE HYPERIMMUNOGLOBULIN E SYNDROMES reported to have marked eosinophilia, elevated serum IgE levels, eczema,
skin abscesses, recurrent bacterial, fungal, and viral infections including
Autosomal Dominant Hyperimmunoglobulin E Syndrome herpes simplex, therapy-resistant molluscum contagiosum, and recur-
HIES (or Job syndrome) is a rare AD or sporadic multisystem immuno- rent varicella zoster. Lymphopenia and decreased lymphocyte prolifera-
deficiency characterized by eczema, S. aureus-induced skin abscesses, tion suggested a significant T-cell defect. In contrast to HIES caused by
recurrent pneumonia with abscess and pneumatocele formation, STAT3 mutations, autosomal recessive hyper-IgE syndrome (AR-HIES)
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Candida infections, and skeletal and connective tissue abnormalities. patients frequently present with neurologic complications but do not
In 1966, two girls suffering from eczema, recurrent respiratory tract develop skeletal abnormalities or postpneumonia pneumatoceles. Most
infections, and “cold” staphylococcus skin abscesses were described as have large deletions in the DOCK8 gene, resulting in absent DOCK8
having Job syndrome because of the phenotypic similarity to the biblical protein. 138,139 (See DOCK8 deficiency in “Other Combined Immunode-
figure Job, who had been “smitten with sore boils from the soles of his ficiencies” above.) Because of a high incidence of malignancies and early
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feet unto his crown.” Subsequently, patients with similar clinical find- death, HSCT is recommended. A single adult patient with eczema;
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ings were reported to have very-high serum IgE concentrations and moderately elevated serum IgE; a history of bacterial (BCG complica-
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additional characteristic abnormalities were recognized, including dis- tions, salmonellosis), fungal, and viral infections, including molluscum
tinct facial features, often described as “coarse,” hyperextensive joints, contagiosum; and a mild T-cell deficiency was found to have a muta-
pathologic bone fractures, scoliosis, craniosynostosis, and retained pri- tion in tyrosine kinase 2 (TYK2), a receptor-associated cytoplasmatic
mary teeth. 193,194 Serum IgE levels of greater than 2000 IU/mL have been tyrosine kinase that plays an important role in multiple cytokine signal-
used as arbitrary diagnostic values, but often are greater than 10,000 IU/mL. ing of T cells. 204

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