Page 818 - Hematology_ Basic Principles and Practice ( PDFDrive )

704 Part VI Non-Malignant Leukocytes

Hyperimmunoglobulin E Syndrome Most cases of HIES result from inherited or sporadic autosomal
dominant (AD) mutations in signal transducer and activator of
Hyperimmunoglobulin E syndrome (HIES) is a complex disorder transcription 3 (STAT3), a Janus kinase (JAK)-activated transcription
characterized by markedly elevated serum IgE levels, serious recurrent factor activated in response to many cytokines and growth factors.
staphylococcal infections, mucocutaneous candidiasis, chronic derma- These mutations, which are located primarily in regions of the protein
titis, and skeletal and dental abnormalities. 20,21 Although not a primary that interact with other proteins or with DNA, inhibit the activity
phagocyte defect, neutrophils from patients with this syndrome exhibit of the wild-type STAT3 allele and result in a complex pattern of
a variable and at times profound chemotactic defect. HIES was first altered cytokine signaling and impaired T helper type 17 (Th17) cell
described in 1966 and was called Job syndrome, in reference to the differentiation. Mutations in DOCK8, a guanine nucleotide exchange
biblical description of Job as being affected by “sore boils from the soles factor, or TYK2, a JAK family member, result in the more rare AR
of his feet unto his crown.” The skin abscesses in patients with HIES forms of HIES that have more profound impairments in lymphocyte
lack the erythema that is typical of such lesions and are referred to as function, leading to a broader risk of infection and other immune
cold abscesses. The key features of HIES are described in Table 50.8. dysregulation. Approximately 96% of DOCK8-deficient patients
suffered life-threatening infection (58%), malignancy (17% by
median age of 12 years) or noninfectious cerebral events (10%) by
TABLE Summary of Hyperimmunoglobulin E Syndrome age 30 years. Only 33% of these patients who were not transplanted
50.8 survived to 30 years of age. 20
Insights into how STAT3 signaling defects lead to the clinical
Incidence More than 200 patients reviewed in the syndrome characteristic of AD HIES are now emerging. Defective
literature
responses to IL-6 may account for the minimal inflammatory
Inheritance AD with incomplete penetrance; sporadic responses characteristic of HIES, and the enhanced IgE production
forms, AR (rare) may reflect dysregulated immune responses secondary to impaired
Molecular defect Dominant-negative mutations in STAT3 (AD signaling by IL-10, a negative regulator. Th17 cells are important for
inheritance; sporadic), Dock8, or Tyk2 control of mucocutaneous Candida infection, which is problematic
kinase (AR) in many patients. In addition, keratinocytes and bronchial epithelial
Clinical manifestations Staphylococcal pneumonia cells are particularly dependent on Th17 cytokines to produce che-
Pneumatoceles mokines and antimicrobial peptides, which may explain the predilec-
Fungal superinfection of lung cysts tion for skin and lung infections. The dental and skeletal abnormalities
“Cold” cutaneous skin abscesses and may be related to defective STAT3 signaling in osteoblasts and
furuncles osteoclasts.
Chronic eczematoid dermatitis
Mucocutaneous candidiasis
Chronic cutaneous viral infections (AR) Diagnosis of Chemotactic Disorders
Severe allergies (AR)
Coarse facies, growth retardation (AD) The direct measurement of neutrophil chemotaxis in a clinical setting
Osteopenia, recurrent fractures (AD) is very difficult and requires a specialized research laboratory. Because
Sinusitis, keratoconjunctivitis the assays are biologic assays, the laboratory must run the tests at
Scoliosis (AD) least monthly to maintain competence and have acceptable normal
ranges. Neutrophil chemotaxis is significantly affected by inflamma-
Hyperextensible joints (AD) tion, complement activation, and medications, making it very difficult,
Delayed shedding of primary teeth (AD) especially in a patient with infection, to determine if the infection is
Vascular disease (AD) attributable to a chemotactic defect or if the defect is attributable to
Malignancy (AR) the infection. This is further complicated by the fact that inflammation
Stroke/CNS vasculitis (AR) activates the neutrophils and affects which populations actually come
Laboratory evaluation Serum IgE >2500 IU/mL off of the density gradients required to separate the cells for assay.
Unlike the respiratory burst, chemotaxis must be done on fresh cells,
Peripheral blood eosinophilia
so samples cannot be reliably shipped.
Differential diagnosis Atopic dermatitis The neutrophils from patients with primary chemotactic defects have
Wiskott-Aldrich syndrome, DiGeorge almost no motility in standard biologic assay systems. Some chemotactic
syndrome disorders can be diagnosed by assays of other characteristic features.
Hypergammaglobulinemia LAD I
Chronic granulomatous disease • LAD I has a significant chemotactic defect as well as phagocytic
Therapy Prophylactic anti-Staphylococcus aureus defect, and is characterized by leukocytosis. The diagnosis can
antibiotics be made by flow cytometry of the CD11b complex on the surface.
Aggressive treatment of acute infections • Fig. 50.6 indicates surface expression of C3b and CD11b on
with parenteral antibiotics neutrophils. C3b is used as a positive control and is normal in
LAD1. With stimulation, CD11b increases (top panel).
Surgical drainage of deep infections and • The results in this assay are expressed as percent of normal
resection of lung cysts stimulated control mean channel number. It is important to note
Monitor for scoliosis, fractures, vascular that this is not the percent positive cell, as is the case for most
disease flow cytometry assays.
Prognosis Generally good if managed aggressively • Severe LAD1 has no increase with stimulation.
Some patients develop lymphoid • Moderate LAD1 shows some shift of fluorescence with
stimulation.
malignancies; patients with AR HIES • Genetic analysis for this disorder is clinically available.
have an increased risk and broader Other chemotactic disorders: Genetic analysis is available for several
spectrum of cancer susceptibility primary neutrophil defects, and this approach should be pursued
30% survival by 30 years of age without before attempting assay of chemotaxis in a clinical setting.
bone marrow transplant (AR) No other primary chemotactic defects are readily diagnosed by a
AD, Autosomal dominant; AR, autosomal recessive; HIES, hyperimmunoglobulin routine clinical laboratory. Measurement of neutrophil chemotaxis itself
E syndrome; IgE, immunoglobulin E; STAT3, signal transducer and activator of to look for secondary defects for any kind of clinical decision making
transcription 3. is difficult if not impossible to interpret.