Chediak-Higashi syndrome is characterized by
Ans. a (Defects in phagolysosome function) (Ref. H - 17th/pg. Table 61-4)CHRONIC GRANULOMATOUS DISEASEChronic Granulomatous Disease presents before the age of 2 and can be transmitted through X-linked or autosomal pattern of inheritance. The defect lies in the inability to generate oxidative burst to kill organisms after being phagocytosed. The neutrophils lack enzyme NADPH oxidase, which plays an important role in production of microbicidal oxygen radicles. In the lab, the diagnosis can be confirmed through Nitro blue Tetrazolium reduction dye test, which will be negative. B cell and T cell functions are normal. Recurrent infections with catalase producing organisms are common. The NBT test is a measure of the respiratory burst in neutrophils and is used to screen for CGD. Neutrophils will reduce the dye NBT, a clear yellow water-soluble compound, to formazan upon stimulation of the respiratory burst. Formazan thus forms precipitates as a dark blue granular substance, which remains trapped in the cytoplasm. Patients with CGD lack a component of the oxidase system, which produces super oxide anion and thus cannot reduce NBT to formazan. Results are interpreted as follows: Normal (positive test) - cells with an orange-red nucleus and blue cytoplasm; Abnormal (negative test) - cells with an orange-red nucleus and colorless cytoplasm.Phagocytic cell deficiency:Leukocyte adhesion deficiency syndrome (type 1): Defect in LFA-1 integrin proteins on phagocytes. Presents early with recurrent bacterial infections, absent pus formation, and delayed separation of umbilicus.Chediak-Higashi disease:Autosomal recessive. Defect in microtubular function and lysosomal emptying of phagocytic cells. Presents with recurrent pyogenic infections by staphylococci and streptococci, partial albinism, and peripheral neuropathy.Chronic granulomatous disease:Defect in phagocytosis of neutrophils owing to lack of NADPH oxidase activity or similar enzymes. Presents with marked susceptibility to opportunistic infections with bacteria, especially S. aureus, E. coli, and Aspergillus. Diagnosis confirmed with negative nitroblue tetrazolium dye reduction test. Rx:Gamma Interferon.Inherited Disorders of Phagocyte Function: Differential FeaturesClinical manifestationsCellular or molecular defectsDiagnosisChronic Granulomatous Diseases (70% X-linked, 30% Autosomal Recessive)Severe infections of skin, ears, lungs, liver, and bone with catalase-positive microorganismsSuch as S. aureus, BurkholderiaChromobacterium violaceum; often hard to culture organism; excessive inflammation with granulomas, frequent lymph node suppuration; granulomas can obstruct GI or GU tracts; gingivitis, aphthous ulcers, seborrheic dermatitisNo respiratory burst due to the lack of one of four NADPH oxidase subunits in neutrophils, monocytes, and eosinophilsNBT or DHR test; no superoxide and H2O2 production by neutrophils; immunoblot for NADPH oxidase components; genetic detectionChediak-Higashi Syndrome(Autosomal Recessive)Recurrent pyogenic infections, especially with S. aureus; many patients get lymphoma-like illness during adolescence; periodontal disease; partial oculocutaneous albinism, nystagmus, progressive peripheral neuropathy, mental retardation in some patientsReduced chemotaxis and phagolysosome fusion, increased respiratory burst activity, defective egress from marrow, abnormal skin window; defect in LYSTGiant primary granules in neutrophils and other granule-bearing cells (Wright's stain); genetic detectionSpecific Granule Deficiency(Autosomal Recessive)Recurrent infections of skin, ears, and sinopulmonary tract; delayed wound healing; decreased inflammation; bleeding diathesisAbnormal chemotaxis, impaired respiratory burst and bacterial killing, failure to upregulate chemotactic and adhesion receptors with stimulation, defect in transcription of granule proteins; defect in C/EBPLack of secondary (specific) granules in neutrophils (Wright's stain), no neutrophil- specific granule contents (i.e., lactoferrin), no defensins, platelet granule abnormality; genetic detectionMyeloperoxidase Deficiency(Autosomal Recessive)Clinically normal except in patients with underlying disease such as diabetes mellitus; then candidiasis or other fungal infectionsNo myeloperoxidase due to pre- and posttranslational defectsNo peroxidase in neutrophils; genetic detectionLeukocyte Adhesion DeficiencyType 1: Delayed separation of umbilical cord, sustained neutrophilia, recurrent infections of skin and mucosa, gingivitis, periodontal diseaseImpaired phagocyte adherence, aggregation, spreading, chemotaxis, phagocytosis of C3bi-coated particles; defective production of CD18 subunit common to leukocyte integrinsReduced phagocyte surface expression of the CD18-containing integrins with monoclonal antibodies against LFA-1 (CD18/CD11a), Mac-1 or CR3 (CD18/CD11b), pl50,95 (CD1S/ CD11c); genetic detectionType 2: Mental retardation, short stature, Bombay (hh) blood phenotype, recurrent infections, neutrophiliaImpaired phagocyte rolling along endotheliumReduced phagocyte surface expression of Sialyl-Lewisx, with monoclonal antibodies against CD15s; genetic detectionPhagocyte Activation Defects(X-linked and Autosomal Recessive)NEMO deficiency: mild hypohidrotic ectodermal dysplasia; broad based immune defectrpyogenic and encapsulated bacteria, viruses, Pneumocystis, mycobacteria; X-linkedImpaired phagocyte activation by IL-1, IL-18, TLR, CD40 TNF-leading to problem with inflammation and antibody productionPoor in vitro response to endotoxin;lack of NF-B activation; genetic detectionClinical manifestationsCellular or molecular defectsDiagnosisIRAK4 deficiency: susceptibility to pyogenic bacteria such as staphylococci, streptococci, Clostridia; resistant to mycobacteria; autosomal recessiveImpaired phagocyte activation by endotoxin through TLR and other pathway; TNF-signaling preservedPoor in vitro response to endotoxin; lack of NF-B activation by endotoxin; geneticdetectionHyper IgE-Recurrent InfectionSyndrome (Autosomal Dominant)(Job's Syndrome)Eczematoid or pruritic dermatitis, "cold" skin abscesses, recurrent pneumonias with S. aureus with bronchopleural fistulae and cyst formation, mild eosinophilia, mucocutaneous candidiasis, characteristic facies, restrictive lung disease, scoliosis, delayed primary dental deciduationReduced chemotaxis in some patients, reduced suppressor T cell activityClinical features, involving lungs, skeleton, and immune system; serum IgE > 2000 IU/mL
Defects in phagolysosome function
Defects in macrophage production
Defects in leukocyte adhesion
Defects in microbicidal activity
Immunity