132: Genetic Immunodeficiency Diseases Flashcards
(227 cards)
1
Q
What are the primary immunodeficiency diseases characterized by?
A
Inherited disorders of the immune system that lead to increased susceptibility to infection and increased morbidity and mortality.
2
Q
What are some common cutaneous abnormalities associated with genetic immunodeficiency diseases?
A
Common cutaneous abnormalities include:
- Atopic-like infections
- Seborrheic-like dermatitis
- Macular erythemas
- Alopecia
- Poor wound healing
- Purpura
- Petechiae
- Telangiectasias
- Pigmentary dilution
- Cutaneous granulomas
- Extensive warts
- Angioedema
- Lupus-like changes.
3
Q
What clinical features may indicate a genetic immunodeficiency disorder?
A
Clinical features that may indicate a genetic immunodeficiency disorder include:
- Recurrent infections of increased duration or severity
- Incomplete clearing of infections
- Unexpected or severe complications of infection
- Poor response to antibiotics
- Failure to thrive in infants.
4
Q
What are the most common noncutaneous abnormalities associated with genetic immunodeficiency disorders?
A
The most common noncutaneous abnormalities include:
- Infections
- Diarrhea
- Vomiting
- Hepatosplenomegaly
- Arthritis
- Adenopathy or paucity of lymph nodes/tonsils
- Hematologic abnormalities.
5
Q
How are genetic immunodeficiency disorders classified?
A
Genetic immunodeficiency disorders are classified into:
1. Antibody deficiencies
2. Cellular deficiencies
3. Combined antibody and cellular deficiencies
4. Disorders of phagocytosis and cell killing
5. Complement defects.
6
Q
What is the most important disorder in the differential diagnosis of all genetic immunodeficiency disorders?
A
The most important disorder in the differential diagnosis of all genetic immunodeficiency disorders is HIV infection, which is characterized by an inverted CD4-to-CD8 ratio and hypergammaglobulinemia.
7
Q
What is hypogammaglobulinemia in the context of genetic immunodeficiency?
A
Hypogammaglobulinemia is a condition characterized by low levels of immunoglobulins in the blood, which is a form of genetic immunodeficiency.
8
Q
What are primary immunodeficiency diseases characterized by?
A
Inherited disorders of the immune system leading to increased susceptibility to infection and morbidity and mortality.
9
Q
What are some associated cutaneous abnormalities in genetic immunodeficiency diseases?
A
Cutaneous infections, atopic-like dermatitis, seborrheic-like dermatitis, macular erythemas, alopecia, poor wound healing, purpura, petechiae, telangiectasias, pigmentary dilution, cutaneous granulomas, extensive warts, angioedema, and lupus-like changes.
10
Q
What are common noncutaneous abnormalities in patients with genetic immunodeficiency diseases?
A
Infections, diarrhea, vomiting, hepatosplenomegaly, arthritis, adenopathy or paucity of lymph nodes/tonsils, and hematologic abnormalities.
11
Q
What is the most important disorder in the differential diagnosis of all genetic immunodeficiency disorders?
A
HIV infection.
12
Q
What are the classifications of genetic immunodeficiency disorders?
A
Antibody deficiencies, cellular deficiencies, combined antibody and cellular deficiencies, disorders of phagocytosis and cell killing, and complement defects.
13
Q
What is a common clinical feature that may indicate genetic immunodeficiency diseases?
A
Recurrent infections of increased duration or severity with unusual organisms.
14
Q
What is a significant laboratory finding in patients with HIV infection related to immunodeficiency?
A
Inverted CD4-to-CD8 ratio and hypergammaglobulinemia.
15
Q
What is hypogammaglobulinemia?
A
A genetic immunodeficiency characterized by low levels of immunoglobulins.
16
Q
What are the common patterns associated with primary immune deficiency related to antibody disorders?
A
Common patterns include:
| Disorder | Infection | Other Patterns |
|———-|———-|—————-|
| Antibody | Streptococcus pneumoniae bacteremia | Autoimmune diseases (antibodies, inflammatory bowel disease) |
| | Giardiasis | Mineral growth retardation |
17
Q
What initial steps are taken to diagnose primary immunodeficiency in neonates and infants?
A
The initial steps include:
1. History and physical examination
2. Height & weight measurement
3. Head circumference measurement
4. Suspected primary immunodeficiency?
- If yes, screen for:
- Humoral immunity
- Cellular immunity
- Phagocyte defects
- Complement deficiency.
18
Q
What tests are performed to screen for humoral immunity defects in suspected primary immunodeficiency?
A
To screen for humoral immunity defects, the following tests are performed:
1. Quantitative immunoglobulin levels
- If abnormal, further tests include:
- Specific antibody production (e.g., diphtheria and tetanus)
- Screening for cellular immunity.
19
Q
What is the significance of screening for complement deficiencies in the diagnosis of primary immunodeficiency?
A
Screening for complement deficiencies is crucial because:
- It helps identify specific deficiencies in the complement system that can lead to increased susceptibility to infections.
- Tests include measuring complement components (C3, C4) and assessing the classical pathway function.
20
Q
What are the potential outcomes of the phagocyte defect screen in diagnosing primary immunodeficiency?
A
The potential outcomes of the phagocyte defect screen include:
1. CBC differential
- Normal or abnormal results lead to further testing.
2. Leukocytosis
- If abnormal, consider leukocyte adhesion deficiency (LAD).
3. Dihydrorhodamine test
- Determines if oxidative function is normal or abnormal, indicating possible chronic granulomatous disease.
21
Q
What are the common patterns associated with primary immune deficiency in terms of infections?
A
Recurrent sinopulmonary infections, recurrent viral and/or fungal infections, recurrent skin abscesses, and bacteremia/meningitis with encapsulated bacteria.
22
Q
What is the first step in diagnosing primary immunodeficiency in neonates and infants?
A
History, physical examination, height & weight, head circumference.
23
Q
What tests are included in the phagocyte defect screen for suspected primary immunodeficiency?
A
CBC differential and leukocytosis assessment.
24
Q
What does an abnormal result in the dihydrorhodamine test indicate?
A
Possible phagocyte defect or specific deficiency.
25
What is assessed in the complement deficiency screen?
CH50 levels and specific complement component levels (C3, C4).
26
What should be considered if the cellular immunity screen shows abnormal results?
Consider diagnosis of combined immunodeficiency or specific genetic testing for the underlying defect.
27
What is the significance of measuring immunoglobulin levels in the humoral immunity screen?
To determine if there is a deficiency in antibody production.
28
What is the role of the complement system in immune response?
To enhance the ability of antibodies and phagocytic cells to clear pathogens from an organism.
29
What is indicated by a normal result in the complement deficiency screen?
No evidence of complement pathway deficiency.
30
What is the clinical significance of recurrent skin abscesses in infants?
It may indicate a phagocyte defect or underlying immunodeficiency.
31
What are the clinical features of agammaglobulinemia?
- Recurrent pyogenic infections starting after 6 months of age
- Absent or barely detectable tonsils and cervical lymph nodes
- Common skin infections like furunculosis and impetigo
- Atopic-like eczematous eruption that does not improve with Ig therapy
- Pyoderma gangrenosum and noninfectious cutaneous granulomas
- Recurrent otitis media, sinusitis, bronchitis, and pneumonia
- Untreated pulmonary infections can lead to progressive bronchiectasis
- Chronic enteroviral infections and hearing loss from repeated infections
- Other bacterial infections include conjunctivitis, osteomyelitis, and meningitis
- Protracted diarrhea may be caused by various infections including Giardia and Salmonella.
32
What is the etiology and pathogenesis of agammaglobulinemia?
- Failure of development of B cells
- Most commonly due to gene defects preventing assembly of a full B-cell antigen receptor
- Most common cause: X-linked agammaglobulinemia (XLA) due to defects in Bruton tyrosine kinase
- Approximately 50% of affected boys have a family history
- Autosomal recessive agammaglobulinemia affects both males and females equally.
33
What are the diagnostic criteria for agammaglobulinemia?
- Serum concentrations of IgG, IgA, and IgM far below the 95% confidence limit (usually <100 mg/dL total Ig)
- Virtual absence of B cells in peripheral circulation (<1% of normal)
- Flow cytometry showing absence of Bruton tyrosine kinase protein (XLA)
- Identification of a defect in known genetic causes of agammaglobulinemia confirms diagnosis.
34
What is the clinical course and management for patients with agammaglobulinemia?
- Early Ig replacement, either intravenously or subcutaneously
- Antibiotic use markedly reduces the risk of infections, though it may not help with chronic lung disease or chronic enterovirus infection.
35
What are the clinical features of Common Variable Immunodeficiency (CVID)?
- Heterogeneous group of disorders with both antibody deficiency and T cell abnormalities
- Young adults, with approximately 20% diagnosed before age 21
- Infections similar to those in patients with XLA, particularly sinopulmonary infections
- Less susceptible to enteroviral infections but more susceptible to Giardia infections
- Noncaseating granulomas of skin, lungs, liver, and spleen
- Autoimmune disorders are frequent (28.6%) including thrombocytopenia and hemolytic anemia.
36
How does CVID differ from IgA deficiency?
| Disorder | Features |
|----------|----------|
| IgA Deficiency | Atopic dermatitis without elevated IgE level |
| CVID | Increased psoriasis, skin infections, acne, alopecia, vitiligo, and aphthous ulcers |
37
What are the potential complications associated with CVID?
- Increased risk of lymphoreticular malignancy and gastric carcinoma, particularly in the fifth and sixth decades of life
- Autoimmune disorders such as rheumatoid arthritis and pernicious anemia are common
- Splenomegaly with hypersplenism, with 8.2% undergoing splenectomy.
38
What are the clinical features of agammaglobulinemia?
Characterized by recurrent pyogenic infections, absent or barely detectable tonsils and cervical lymph nodes, and skin infections like furunculosis and impetigo.
39
What is the most common cause of agammaglobulinemia?
X-linked agammaglobulinemia (XLA), caused by defects in the Bruton tyrosine kinase.
40
What is the typical diagnosis for agammaglobulinemia?
Serum concentrations of IgG, IgA, and IgM far below the 95% confidence limit and virtual absence of B cells in the peripheral circulation.
41
What is the management for patients with agammaglobulinemia?
Early Ig replacement and antibiotic use to reduce the risk of infections.
42
What are the clinical features of Common Variable Immunodeficiency (CVID)?
CVID is characterized by infections similar to those in patients with XLA, noncaseating granulomas, and autoimmune disorders.
43
How does CVID differ from IgA deficiency?
CVID is associated with increased psoriasis and skin infections, while IgA deficiency is linked to atopic dermatitis without elevated IgE levels.
44
What is the significance of splenomegaly in CVID patients?
Approximately 8.2% of CVID patients undergo splenectomy due to hypersplenism.
45
What is the risk of malignancy in CVID patients?
There is a markedly increased risk of lymphoreticular malignancy and gastric carcinoma in the fifth and sixth decades of life.
46
A 6-month-old infant presents with recurrent otitis media, sinusitis, and pneumonia caused by pneumococci and Haemophilus. What is the most likely diagnosis, and what genetic defect is associated with this condition?
The most likely diagnosis is agammaglobulinemia, specifically X-linked agammaglobulinemia (XLA), which is caused by defects in the Bruton tyrosine kinase gene.
47
A patient with recurrent bacterial infections and absent tonsils is suspected of having agammaglobulinemia. What diagnostic tests should be performed to confirm the diagnosis?
Diagnostic tests include measuring serum concentrations of IgG, IgA, and IgM (usually less than 100 mg/dL total Ig), assessing the absence of B cells in peripheral circulation (<1% of normal), and flow cytometry to detect the absence of Bruton tyrosine kinase protein.
48
A young adult presents with recurrent sinopulmonary infections and malabsorption syndromes. What immunodeficiency disorder should be considered, and what are its associated risks?
Common variable immunodeficiency (CVID) should be considered. It is associated with an increased risk of lymphoreticular malignancy and gastric carcinoma, as well as autoimmune disorders like autoimmune hemolytic anemia and rheumatoid arthritis.
49
A patient with recurrent bacterial infections and a history of splenectomy is diagnosed with common variable immunodeficiency (CVID). What are the risks associated with this condition?
CVID is associated with an increased risk of lymphoreticular malignancy, gastric carcinoma, and autoimmune disorders such as autoimmune hemolytic anemia and rheumatoid arthritis.
50
What are the clinical features of Chronic Mucocutaneous Candidiasis (CMC)?
- Recurrent, progressive infections of the skin, nails, and mucous membranes, primarily caused by **Candida albicans**.
- Symptoms range from mild erythematous scaling plaques to severe generalized crusted granulomatous plaques.
- Commonly affected areas include intertriginous areas, periorificial sites, and the scalp.
- Nails may appear thickened, brittle, and discolored.
- Scalp infections can lead to scarring and alopecia.
- Oral mucosa is the most frequent site of mucosal alteration, with potential strictures forming in the esophagus, genital, and laryngeal mucosae.
- Patients may develop recurrent or severe infections caused by other organisms, with a significant percentage also having bacterial infections.
51
What is the etiology of Chronic Mucocutaneous Candidiasis (CMC)?
- **T-helper 17 (Th17) cells** play a critical role in immune defense against **Candida** and are impaired in both APECED and non-APECED CMC patients.
- The most common cause is heterozygous mutations activating the **signal transducer and activator of transcription 1 gene (STAT1)**, which represses expression of **interleukin (IL)-17** while promoting interferon signaling.
- Mutations in isoforms of **IL-17**, **IL-17 receptors**, or **TRAF3IP2** also affect responses to IL-17.
- **APECED** is characterized by autosomal recessive loss-of-function mutations in the **autoimmune regulator gene (AIRE)**, which regulates self-antigen expression in thymic epithelial cells.
52
What are the common associated endocrinopathies in patients with APECED?
- **Hypoparathyroidism** (88%)
- **Hypoadrenocorticism** (60%)
- **Gonadal insufficiency** (45%)
- **Alopecia areata** (20%)
- **Pernicious anemia** (16%)
- **Thyroid abnormalities** (12%)
- Other possible conditions include chronic active hepatitis or juvenile cirrhosis (9%), vitiligo, diabetes mellitus, and hypopituitarism.
53
What are the differential diagnoses for Chronic Mucocutaneous Candidiasis (CMC)?
Frequent **Candida** infections in infants, especially thrush.
54
What is hypoadrenocorticism?
A condition affecting the adrenal glands, with a prevalence of 60% in differential diagnoses.
55
What is gonadal insufficiency?
A condition characterized by inadequate function of the gonads, with a prevalence of 45% in differential diagnoses.
56
What is alopecia areata?
An autoimmune condition causing hair loss, with a prevalence of 20% in differential diagnoses.
57
What is pernicious anemia?
A type of anemia caused by vitamin B12 deficiency, with a prevalence of 16% in differential diagnoses.
58
What are thyroid abnormalities?
Conditions affecting thyroid function, with a prevalence of 12% in differential diagnoses.
59
What are other possible conditions associated with chronic mucocutaneous candidiasis?
Conditions include chronic active hepatitis, juvenile cirrhosis (9%), vitiligo, diabetes mellitus, and hypopituitarism.
60
What are the differential diagnoses for Chronic Mucocutaneous Candidiasis (CMC)?
Frequent Candida infections in infants, IPEX syndrome, and autoimmune endocrinopathies in IL-2 receptor α chain deficiency.
61
What is the recommended treatment for Chronic Mucocutaneous Candidiasis (CMC)?
Long-term systemic administration of azole antifungal agents such as itraconazole, fluconazole, or terbinafine.
62
What are alternatives for resistant cases of CMC?
Voriconazole, posaconazole, echinocandins, and/or amphotericin B with or without flucytosine.
63
What is the most common organism causing chronic mucocutaneous candidiasis (CMC)?
Candida albicans.
64
What are the clinical features of chronic mucocutaneous candidiasis?
Recurrent, progressive infections of the skin, nails, and mucous membranes.
65
What is the role of T-helper 17 (Th17) cells in chronic mucocutaneous candidiasis?
They are critical in immune defense against Candida and are impaired in responsiveness in CMC patients.
66
What genetic mutation is commonly associated with APECED?
Loss-of-function mutations in the autoimmune regulator gene (AIRE).
67
What is the typical age of onset for candidal infections in patients with APECED?
By 5 years of age.
68
What are some associated endocrinopathies with APECED?
Hypoparathyroidism, hypoadrenocorticism, and gonadal insufficiency.
69
What is a sensitive and specific marker for APECED?
Autoantibodies against Type I interferons.
70
What is the classic triad of Wiskott-Aldrich Syndrome (WAS)?
Hemorrhage, recurrent pyogenic infections, and recalcitrant dermatitis.
71
What are the common manifestations and complications associated with Wiskott-Aldrich Syndrome?
Bleeding diathesis, recurrent bacterial infections, atopic dermatitis, and autoimmune disorders.
72
What is the etiology and pathogenesis of Wiskott-Aldrich Syndrome?
Defective WASP gene leading to immunological dysfunction.
73
What are the clinical features of Hyper-IgM Syndrome?
Recurrent infections, autoimmune manifestations, and increased susceptibility to infections.
74
What is the incidence of Wiskott-Aldrich Syndrome in male births?
4 per 1 million male births.
75
What is the primary defect in Hyperimmunoglobulin M Syndrome?
Defective CD40 ligand leading to impaired T-cell help for B cells.
76
What are the clinical features of Cartilage-Hair Hypoplasia Syndrome?
Fine, sparse, hypopigmented hair and short-limbed dwarfism.
77
What is the common treatment for Wiskott-Aldrich Syndrome?
Bone marrow stem cell transplantation.
78
What are the laboratory findings that confirm the diagnosis of Wiskott-Aldrich Syndrome (WAS)?
Thrombocytopenia, defective platelet aggregation, and abnormal immunoglobulin levels.
79
What is the clinical significance of splenectomy in patients with Wiskott-Aldrich Syndrome?
Ameliorates bleeding but increases risk of infections from encapsulated organisms.
80
What are common clinical features of Severe Combined Immunodeficiency (SCID)?
Failure to gain weight, recurrent infections, and persistent mucocutaneous candidiasis.
81
What is the recommended treatment for patients with recurrent problems in SCID?
Bone marrow or stem cell transplantation.
82
What is the prognosis for patients with ectodermal dysplasia with immunodeficiency?
High mortality rate, with 36% dying at a mean age of 6.4 years.
83
What is the estimated incidence of Ataxia-Telangiectasia?
Up to 1:40,000, inherited in an autosomal recessive manner.
84
What are the characteristic clinical features of Ataxia-Telangiectasia?
Oculocutaneous telangiectasias and progressive neurological symptoms.
85
What is the estimated incidence of Ataxia-Telangiectasia and its inheritance pattern?
Ataxia-Telangiectasia, also known as Louis-Bar syndrome, has an estimated incidence of up to 1:40,000 and is inherited in an autosomal recessive manner.
86
What are the characteristic clinical features of Ataxia-Telangiectasia?
Characteristic clinical features include oculocutaneous telangiectasias that begin near the ocular canthi and progress across the bulbar conjunctivae, usually appearing between ages 3 to 6, and cutaneous telangiectasias on malar prominences, ears, eyelids, anterior chest, and other areas, which may resemble fine petechiae.
87
What are the risks associated with being a carrier of Ataxia-Telangiectasia?
Carriers of Ataxia-Telangiectasia have an increased risk of breast cancer, hematologic malignancies, and ischemic heart disease, with a decreased life expectancy of approximately 8 years.
88
What is the most common inheritance pattern of ectodermal dysplasia with immunodeficiency?
X-linked recessive, affecting 1 in 250,000 live male births.
89
What gene mutations are associated with ectodermal dysplasia with immunodeficiency?
Mutations in the nuclear factor kappa B (NF-kB) essential modulator (NEMO).
90
What are the classic clinical features of hypohidrotic ectodermal dysplasia?
Characteristic facies, hypotrichosis or atrichia, hypohidrosis, hypodontia or anodontia with conical incisors, and associated dermatitis.
91
What is the average mortality rate for patients with ectodermal dysplasia with immunodeficiency?
36% mortality at a mean age of 6.4 years.
92
What are the common pathogens associated with bacterial infections in patients with ectodermal dysplasia with immunodeficiency?
Streptococcus pneumoniae, H. influenzae, Klebsiella, Salmonella, and Pseudomonas.
93
What is the inheritance pattern of Ataxia-Telangiectasia?
Autosomal recessive.
94
What are the characteristic features of Ataxia-Telangiectasia?
Oculocutaneous telangiectasias that begin near the ocular canthi and progress across the bulbar conjunctivae, usually appearing between ages 3 to 6.
95
What is the estimated incidence of Ataxia-Telangiectasia?
Up to 1 in 40,000, with a carrier rate of up to 1%.
96
What are the risks associated with being a carrier of Ataxia-Telangiectasia?
Increased risk of breast cancer, hematologic malignancies, and ischemic heart disease.
97
What is the role of NEMO in immune function?
NEMO is a regulatory subunit of the IKK complex, which is essential for NF-κB activation. NF-κB affects inflammation, apoptosis, development, and immunity. Mutations impair NF-κB signaling, leading to immunodeficiency.
98
What are the common clinical features associated with Ataxia-Telangiectasia (AT)?
Common clinical features of Ataxia-Telangiectasia include progeric changes, skin changes, neurological symptoms, infections, growth and endocrine disorders, and neoplasia.
99
What is the prognosis and treatment approach for patients with Ataxia-Telangiectasia?
The prognosis and treatment for Ataxia-Telangiectasia include supportive care, aggressive screening for malignancy, intralesional injections, autopsy findings, and therapeutic interventions.
100
What are the key characteristics of Chronic Granulomatous Disease (CGD)?
Key characteristics of Chronic Granulomatous Disease (CGD) include a heterogeneous group of X-linked and autosomal recessive disorders, incidence of approximately 1 in 200,000 to 250,000 persons, clinical manifestation, and infection susceptibility.
101
What are the common skin manifestations in patients with ataxia-telangiectasia (AT)?
Common skin manifestations include ocular telangiectasias, xerosis, gray hair, and sclerodermatous changes.
102
What is the most common cause of death in patients with ataxia-telangiectasia?
The most common cause of death is pulmonary disease, often from bronchiectasis and respiratory failure.
103
What percentage of patients with ataxia-telangiectasia develop lymphoid malignancies?
Approximately 40% of surviving adolescents or young adults develop lymphoid malignancies.
104
What are the distinctive disorders of phagocytosis and cell killing?
The most distinctive disorders include chronic granulomatous disease (CGD), leukocyte adhesion deficiencies, and Hyperimmunoglobulinemia E syndrome (HIES).
105
What is chronic granulomatous disease (CGD)?
CGD is a heterogeneous group of X-linked and autosomal recessive disorders characterized by defective production of reactive oxygen intermediates, impairing the killing of microorganisms.
106
What is the overall incidence of chronic granulomatous disease?
The overall incidence is 1 in 200,000 to 250,000 persons.
107
What is the typical age of onset for X-linked chronic granulomatous disease?
X-linked chronic granulomatous disease typically manifests in the first year of life.
108
What are the common infections associated with chronic granulomatous disease?
Patients commonly experience recurrent bacterial infections, particularly from skin, mucosa, lungs, and deep tissue abscesses.
109
What is the significance of α-fetoprotein levels in diagnosing ataxia-telangiectasia?
Increased α-fetoprotein levels are significant for diagnosis, particularly after 2 years of age.
110
What is the most likely diagnosis for a 3-year-old child with oculocutaneous telangiectasias and recurrent sinopulmonary infections?
The most likely diagnosis is ataxia-telangiectasia. The serum marker α-fetoprotein is elevated in all patients with this condition, particularly after 2 years of age.
111
What are the common clinical features associated with Chronic Granulomatous Disease (CGD)?
Common clinical features of CGD include pyodermas, staphylococcal abscesses, purulent inflammatory reactions, ecthyma gangrenosum, chronic inflammatory granulomas, intraoral ulcerations, and hepatosplenomegaly.
112
What is the etiology of Chronic Granulomatous Disease (CGD)?
The etiology of CGD involves defects in the reduced NADPH oxidase, responsible for generating superoxide. Key points include X-linked CGD (70%): caused by mutations in the CYBB gene encoding the gp91phox subunit of cytochrome b558; Autosomal recessive CGD: deficiencies in cytosolic factors such as p47phox, p67phox, and p40phox.
113
What are the diagnostic tests used for Chronic Granulomatous Disease (CGD)?
Diagnostic tests for CGD include Dihydrorhodamine flow cytometry-based test (DHR 123 assay), Ferricytochrome c reduction assay, Nitroblue tetrazolium (NBT) reduction assay, Immunoblot analysis, and Biopsy of cutaneous granulomas.
114
What are the differential diagnoses for Chronic Granulomatous Disease (CGD)?
Differential diagnoses for CGD include leukocyte adhesion defects, Shwachman-Diamond syndrome, myeloperoxidase deficiency, and defects in Toll receptor, interferon, or IL-12 signaling.
115
What is the clinical course and prognosis for patients with Chronic Granulomatous Disease (CGD)?
X-linked CGD and p22phox CGD have a more severe clinical course compared to p47phox CGD. Mean age of diagnosis: X-linked CGD: 3 years; Autosomal recessive: 8 years. Over 90% of patients with non-p47phox CGD have undetectable levels of superoxide production.
116
What are the common clinical features of infections in patients with Chronic Granulomatous Disease (CGD)?
Common features include pyodermas, staphylococcal abscesses, purulent inflammatory reactions, and ecthyma gangrenosum.
117
Which organisms are primarily responsible for infections in patients with CGD?
The primary organisms include Staphylococcus aureus, S. marcescens, B. cepacia, Nocardia spp., and Aspergillus spp.
118
What is the role of NADPH oxidase in the immune response?
NADPH oxidase is responsible for producing superoxide and other toxic oxygen metabolites that are crucial for microbial killing.
119
What is the mean age of diagnosis for X-linked Chronic Granulomatous Disease (CGD)?
The mean age of diagnosis for X-linked CGD is 3 years.
120
What are the common symptoms associated with Aspergillus spp. infections in CGD patients?
Aspergillus spp. infections typically present with few symptoms, often lacking fever and showing normal ESR.
121
What is the significance of the CYBB gene in Chronic Granulomatous Disease?
The CYBB gene encodes the gp91 phox subunit of cytochrome b 558, which is crucial for NADPH oxidase function.
122
What are the common noncutaneous areas of involvement in CGD?
Common noncutaneous areas include lymph nodes, lungs, liver, spleen, and GI tract.
123
What is the clinical significance of hepatosplenomegaly in CGD patients?
Hepatosplenomegaly occurs in 80% to 90% of patients and is associated with the development of hepatic abscesses, which are pathognomonic for CGD.
124
What is the preferred diagnostic test for identifying Chronic Granulomatous Disease (CGD)?
The dihydrorhodamine (DHR) flow cytometry-based test is the preferred diagnostic test for identifying CGD, as it measures superoxide production.
125
What are the most common pathogens responsible for infections in CGD?
The most common pathogens include Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, Nocardia spp., and Aspergillus spp.
126
What is the role of prophylactic interferon (IFN)-γ in the management of infections in patients with X-linked and autosomal recessive conditions?
Prophylactic interferon (IFN)-γ decreases the number and severity of infections without increasing the incidence of chronic inflammatory complications.
127
What are the most common causes of death in patients with Chronic Granulomatous Disease (CGD)?
The most common causes of death in patients with CGD are pneumonia and/or sepsis caused by organisms such as Aspergillus or B. cepacia.
128
What are the treatment options for Chronic Granulomatous Disease (CGD)?
Treatment options for CGD include empiric broad-spectrum parenteral antibiotics, IV therapy for at least 10 to 14 days, surgical interventions for deeper infections, trimethoprim-sulfamethoxazole therapy, itraconazole for prophylaxis, granulocyte transfusions, and stem cell transplantation.
129
What is the recommended duration for IV therapy in patients with infections?
At least 10 to 14 days, followed by a several-week course of oral antibiotics.
130
What is the role of trimethoprim-sulfamethoxazole therapy in infection management?
It decreases the incidence of bacterial infection without increasing the incidence of fungal infection.
131
What is the effect of prophylactic interferon (IFN)-γ in patients with X-linked and autosomal recessive conditions?
It decreases the number and severity of infections without increasing the incidence of chronic inflammatory complications.
132
What is the best outcome for stem cell transplantation in CGD patients?
Younger patients without infection at transplantation have the best outcome (survival >95%).
133
What are the clinical features of Hyperglobulinemia E syndrome?
Clinical features include neonatal or infantile rash, papulopustular eruption, and eosinophilic spongiotic dermatitis.
134
What is the incidence of Hyperglobulinemia E syndrome?
1 in 10^6.
135
What are the common manifestations of Hyperglobulinemia E syndrome?
Recurrent staphylococcal skin abscesses, pneumonia with pneumatocele formation, and high serum levels of IgE.
136
What are the safer approaches for gene therapy in X-linked forms of CGD?
Self-inactivating lentiviral vectors or nonviral techniques.
137
What immunodeficiency syndrome should be considered for a neonate with a papulopustular rash and recurrent staphylococcal infections?
Hyperimmunoglobulinemia E syndrome (HIES) should be considered.
138
What is the most consistent finding on skin biopsy for hyperimmunoglobulinemia E syndrome (HIES)?
The most consistent finding on skin biopsy is eosinophilic spongiotic dermatitis.
139
What is the role of gene therapy in the treatment of chronic granulomatous disease (CGD)?
Gene therapy for CGD involves the use of retroviruses or safer approaches like self-inactivating lentiviral vectors to correct the genetic defect.
140
What is the role of systemic glucocorticoids in the treatment of chronic granulomatous disease (CGD)?
Systemic glucocorticoids are helpful for patients with obstructive visceral granulomas in CGD.
141
What are the characteristic features of autosomal recessive Hyper-IgE syndrome (HIES)?
Recurrent viral infections, opportunistic infections, autoimmunity, devastating neurologic complications, and increased risk of mucocutaneous squamous cell carcinoma.
142
What are the diagnostic criteria for autosomal dominant Hyper-IgE syndrome (HIES)?
IgE levels > 1000 IU/mL and a weighted score of 5 clinical features, including typical newborn rash, recurrent pneumonia, pathologic bone fractures, characteristic facies, and high palate.
143
What are the common systemic infections associated with eosinophilic papulopustules in patients with atopic dermatitis?
Pulmonary bacterial pneumonia, abscesses, empyema, and pneumatocele.
144
What are the clinical implications of elevated serum IgE levels in patients with autosomal recessive HIES?
Elevated serum IgE levels are associated with increased susceptibility to infections, chronic eczematous dermatitis, recurrent skin infections, and respiratory tract staphylococcal infections.
145
What are the treatment options for managing infections in patients with autosomal recessive HIES?
Antistaphylococcal antibiotics, oral triazole antifungals, intravenous immunoglobulin therapy, isotretinoin, cyclosporine, and stem cell transplantation for DOCK8-deficient HIES.
146
What is a common superinfection associated with atopic dermatitis in patients with eosinophilic papulopustules?
Superinfection with S. aureus is very common.
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What are the most frequent systemic infections seen in patients with autosomal recessive Hyper-IgE syndrome (HIES)?
Pulmonary bacterial pneumonia, abscesses, and empyema.
148
What distinctive facial features are commonly present in patients with autosomal recessive HIES?
Prominent forehead, broad nasal bridge, and wide nasal tip.
149
What is the significance of elevated serum IgE levels in diagnosing autosomal dominant HIES?
IgE levels > 1000 IU/mL are part of the diagnostic criteria for autosomal dominant HIES.
150
What are the common neurological complications associated with autosomal recessive HIES?
Devastating neurologic complications, especially vasculitis, that are often fatal in childhood.
151
What is the role of Th17 cells in the immune response related to autosomal dominant HIES?
Th17 cells are important for the development of antimicrobial peptides and innate immunity at epithelial surfaces.
152
What treatment is often used to manage recurrent staphylococcal abscesses in patients with HIES?
Isotretinoin is used to eliminate recurrent staphylococcal abscesses.
153
What is the relationship between DOCK8 deficiency and susceptibility to infections?
DOCK8 deficiency leads to a global defect in T-cell activation, increasing susceptibility to viral and bacterial infections.
154
What is the clinical significance of eosinophilia in patients with autosomal recessive HIES?
Eosinophilia is often more severe in autosomal recessive forms, indicating a more severe immune deficiency.
155
What is the impact of intravenous immunoglobulin therapy on IgE levels in patients with HIES?
Intravenous immunoglobulin therapy may influence IgE levels as a consequence of increased Ig catabolism or neutralization of IgE.
156
What are the characteristic facial features of hyperimmunoglobulinemia E syndrome (HIES)?
Characteristic facial features of HIES include a prominent forehead, broad nasal bridge, and wide nasal tip, which are universally present by 16 years of age.
157
What are the diagnostic criteria for autosomal dominant HIES?
Diagnostic criteria include IgE levels >1000 IU/mL, a weighted score of 5 clinical features (e.g., typical newborn rash, recurrent pneumonia, pathologic bone fractures, characteristic facies, high palate), and Th17 cell deficiency.
158
What are the characteristic skeletal abnormalities in hyperimmunoglobulinemia E syndrome (HIES)?
Characteristic skeletal abnormalities include osteopenia, pathologic fractures, scoliosis, and hyperextensibility of joints.
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What is the role of Th17 cells in hyperimmunoglobulinemia E syndrome (HIES)?
Th17 cells are critical for innate immunity at epithelial surfaces through the development of antimicrobial peptides. Their deficiency in HIES leads to increased susceptibility to Candida infections.
160
What are the key clinical features of WHIM syndrome?
WHIM syndrome is characterized by neutropenia, hypogammaglobulinemia, susceptibility to infections (particularly by human papillomavirus), defects in the chemokine receptor gene CXCR4, and mature neutrophils unable to exit the bone marrow (myelokathexis). Treatment includes plerixafor, a CXCR4 antagonist that increases circulating leukocytes and decreases infections.
161
What are the main characteristics of Chédiak-Higashi syndrome?
Chédiak-Higashi syndrome is characterized by an autosomal recessive disorder, silvery sheen to hair and skin, large cytoplasmic granules in blood leukocytes (highly diagnostic), infections that begin in infancy (commonly affecting skin, lungs, and respiratory tract), neurologic manifestations including muscle weakness and progressive neurologic deterioration, and mild coagulation defects leading to easy bruising and petechiae.
162
What is the etiology of Chédiak-Higashi syndrome?
Chédiak-Higashi syndrome is caused by mutations in the LYST gene located on chromosome 1q42, which encodes a protein necessary for vesicle trafficking and secretion. This leads to giant granules in leukocytes due to altered granule maturation and fusion, and diminished chemotaxis of neutrophils and monocytes, resulting in delayed intracellular microorganism killing.
163
What are the differential diagnoses for the silvery hair sheen observed in Chédiak-Higashi syndrome?
The differential diagnoses for silvery hair sheen include Griscelli Syndrome (GS), Hermansky-Pudlak Syndrome, Pseudo-Chédiak Syndrome, X-linked lymphoproliferative disorder, Familial hemophagocytic lymphohistiocytosis, and Canale-Smith syndrome.
164
What is the prognosis and treatment for Chédiak-Higashi syndrome?
The prognosis and treatment for Chédiak-Higashi syndrome include an accelerated phase of hemophagocytic lymphohistiocytosis occurring in approximately 85% of cases, often triggered by Epstein-Barr virus infection. Treatment may involve stem cell transplantation to manage immunodeficiency and associated complications.
165
What is WHIM syndrome characterized by?
WHIM syndrome is characterized by neutropenia, hypogammaglobulinemia, and susceptibility to infection by human papillomavirus.
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What gene is mutated in Chédiak-Higashi syndrome?
LYST gene.
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What are the clinical findings in Chédiak-Higashi syndrome?
Silvery hair sheen, pigment abnormalities, ocular hypopigmentation, and recurrent infections.
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What is a highly diagnostic feature of Chédiak-Higashi syndrome?
Large cytoplasmic granules in blood leukocytes.
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What is the prognosis for patients with hemophagocytic lymphohistiocytosis associated with Chédiak-Higashi syndrome?
85% have an accelerated phase triggered by Epstein-Barr virus infection.
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What are common infections in Chédiak-Higashi syndrome?
Skin, lungs, and respiratory tract infections.
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What is the inheritance pattern of Chédiak-Higashi syndrome?
Autosomal recessive disorder.
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What are the neurological manifestations of Chédiak-Higashi syndrome?
Muscle weakness, cranial and peripheral neuropathy, and progressive neurologic deterioration.
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What is the treatment for Chédiak-Higashi syndrome?
Transplantation.
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What is the genetic mutation responsible for Chediak-Higashi syndrome?
Chediak-Higashi syndrome is caused by mutations in the LYST gene, which encodes a protein required for vesicle trafficking and secretion.
175
What is the genetic defect in WHIM syndrome?
WHIM syndrome is caused by defects in the CXCR4 gene, which leads to myelokathexis (retention of neutrophils in the bone marrow).
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What is the characteristic finding in blood leukocytes in Chediak-Higashi syndrome?
The characteristic finding in blood leukocytes is the presence of large cytoplasmic granules.
177
What are the clinical features of Griscelli Syndrome?
Griscelli Syndrome is characterized by pigmentary dilution, hair shaft abnormalities, skin pigmentary dilution, neurologic disorders, and immune disorders.
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What is the treatment of choice for Griscelli Syndrome?
The treatment of choice for Griscelli Syndrome is early transplantation, which corrects the immunologic status but does not affect the pigment abnormality.
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What genetic mutations are associated with Griscelli Syndrome?
Griscelli Syndrome is associated with mutations in MYO5A, RAB27A, and Slac2-a/melanophilin.
180
What is Griscelli syndrome and how is it inherited?
Griscelli syndrome is an autosomal recessive disorder characterized by pigmentary dilution and immune dysfunction.
181
What are the clinical findings associated with Griscelli syndrome?
Clinical findings include pigmentary dilution in hair, a silver-gray sheen, and accumulation of melanosomes in melanocytes.
182
What is the mean age of death for untransplanted patients with Griscelli syndrome?
The mean age of death is 6 years, usually from overwhelming infection or hemorrhage during the accelerated phase.
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What are the three genetic subtypes of Griscelli syndrome?
The three genetic subtypes are GS1 (neurologic disorder), GS2 (hemophagocytic syndrome), and GS3 (solely pigmentary abnormalities).
184
What gene mutations are associated with GS2 of Griscelli syndrome?
GS2 is associated with mutations in the RAB27A gene, which is involved in the function of the intracellular-regulated secretory pathway.
185
What is the prognosis for patients with GS2 of Griscelli syndrome?
The prognosis is uniformly fatal, but can be reversed by successful hematopoietic stem cell transplantation.
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What is the role of the MYO5A gene in Griscelli syndrome?
The MYO5A gene encodes myosin-5a, a motor protein responsible for intracellular organelle transport, and is involved in the pathogenesis of GS1.
187
What is the significance of prenatal diagnosis in Griscelli syndrome?
Prenatal diagnosis can be performed by examining hair from fetal scalp biopsies and leukocytes from fetal blood samples to identify the disorder early.
188
What is the inheritance pattern of hereditary angioedema?
Hereditary angioedema is almost always autosomal dominant.
189
What are the three types of hereditary angioedema?
The three types of hereditary angioedema are Type I (85%: Low antigenic levels of C1 inhibitor), Type II (15%: Low functional levels but normal/high antigenic levels of C1 inhibitor), and Type III (does not show a deficiency of C1 inhibitor).
190
What is a significant risk for mortality in hereditary angioedema?
Laryngeal edema is a significant risk for mortality in hereditary angioedema.
191
What are the treatment modalities for hereditary angioedema?
The treatment modalities for hereditary angioedema include attenuated androgens, antifibrinolytic agents, plasma-derived C1 inhibitor, kallikrein inhibitor, and bradykinin receptor antagonist.
192
What is the most common cause of agammaglobulinemia?
The most common cause of agammaglobulinemia is X-linked agammaglobulinemia (XLA).
193
What is the most common manifestation of WAS mutation?
The most common manifestation of WAS mutation is thrombocytopenia (~ 90%).
194
What are the two most commonly associated endocrinopathies in APECED?
The two most commonly associated endocrinopathies in APECED include adrenal insufficiency and hypoparathyroidism.
195
What is the poor prognostic factor in WAS?
The poor prognostic factor in WAS is severe thrombocytopenia.
196
What is the most common infection in Chronic Granulomatous Disease (CGD)?
The most common infection in Chronic Granulomatous Disease (CGD) is catalase-positive organisms.
197
What are the most common causes of death in CGD?
The most common causes of death in CGD are severe infections and complications from infections.
198
What is the spontaneous mutation rate for hereditary angioedema?
Approximately 25%.
199
What is the prevalence of hereditary angioedema in the population?
1 in 150,000 persons.
200
What percentage of hereditary angioedema cases are Type I?
85%.
201
What characterizes Type II hereditary angioedema?
Low functional levels but normal/high antigenic levels of C1 inhibitor.
202
What is a significant risk factor for mortality in hereditary angioedema?
Laryngeal edema.
203
What treatment modalities are used for hereditary angioedema?
Attenuated androgens, antifibrinolytic agents, plasma-derived C1 INH, kallikrein inhibitor, bradykinin receptor antagonist.
204
What is the most common cause of agammaglobulinemia?
X-linked agammaglobulinemia (XLA).
205
What is the most common manifestation of WAS mutation?
Thrombocytopenia.
206
What is the poor prognostic factor in WAS?
Low platelet count.
207
What is the most common infection in Chronic Granulomatous Disease (CGD)?
Catalase-positive organisms.
208
What are the most common causes of death in CGD?
Severe infections, particularly from catalase-positive organisms.
209
What treatment options are available for acute attacks of hereditary angioedema?
Treatment options for acute attacks include plasma-derived C1 inhibitor.
210
A patient with hereditary angioedema presents with laryngeal edema. What treatment options are available for acute attacks?
Treatment options for acute attacks include plasma-derived C1 inhibitor, kallikrein inhibitors, and bradykinin receptor antagonists.
211
What are the clinical features associated with Severe Combined Immunodeficiency (SCID)?
Clinical features of SCID include:
- **Recurrent infections**: Frequent bacterial, viral, and fungal infections.
- **Failure to thrive**: Poor growth and weight gain in infants.
- **Chronic diarrhea**: Persistent gastrointestinal issues.
- **Lymphadenopathy**: Swelling of lymph nodes.
- **Hepatosplenomegaly**: Enlargement of the liver and spleen.
- **Skin rashes**: Various dermatological manifestations.
212
What are the associated features of Severe Combined Immunodeficiency (SCID)?
Associated features of SCID include:
- **Absence of T and B lymphocytes**: Low or absent levels of these immune cells.
- **Elevated serum immunoglobulin levels**: Often seen in some subtypes.
- **Family history of immunodeficiency**: Genetic predisposition may be present.
- **Positive newborn screening**: Early detection through screening programs.
213
What are the genetic defects associated with Severe Combined Immunodeficiency (SCID)?
Genetic defects associated with SCID include:
- **IL2RG gene mutation**: Affects T and NK cell development.
- **ADA deficiency**: Leads to toxic accumulation of metabolites.
- **RAG1/RAG2 mutations**: Impair V(D)J recombination necessary for lymphocyte development.
- **JAK3 mutations**: Disrupt signaling pathways for lymphocyte maturation.
214
What are the subtypes of Severe Combined Immunodeficiency (SCID)?
Subtypes of SCID include:
- **X-linked SCID**: Caused by mutations in the IL2RG gene.
- **Adenosine deaminase (ADA) deficiency**: Autosomal recessive disorder.
- **RAG1/RAG2 deficiency**: Impairs lymphocyte development.
- **JAK3 deficiency**: Affects signaling in lymphocyte maturation.
215
What is a common laboratory finding in patients with SCID?
Lymphopenia is a common laboratory finding in SCID patients.
216
What are the genetic causes of Severe Combined Immunodeficiency?
Genetic causes include mutations in genes such as IL2RG, ADA, and JAK3.
217
What is the significance of T-cell receptor excision circles (TRECs) in SCID diagnosis?
TRECs are used as a biomarker for T-cell development and can indicate SCID when absent or low.
218
What are the associated features of X-linked SCID?
Associated features include absent or reduced T cells and normal or increased B cells.
219
What is the role of gene therapy in treating SCID?
Gene therapy aims to correct the underlying genetic defect in SCID patients.
220
What is the typical age of presentation for SCID?
SCID typically presents in infancy, often within the first few months of life.
221
What is the impact of SCID on the immune system?
SCID results in a severely compromised immune system, leading to increased susceptibility to infections.
222
What are the clinical features associated with Griscelli syndrome?
Griscelli syndrome is characterized by:
- **Partial oculocutaneous albinism**
- **Immunodeficiency**
- **Neurological abnormalities**
- **Silvery hair**
- **Lymphohistiocytosis**
223
What are the key characteristics of Chédiak-Higashi syndrome?
Chédiak-Higashi syndrome includes:
- **Immunodeficiency**
- **Partial oculocutaneous albinism**
- **Neurological problems**
- **Increased susceptibility to infections**
- **Giant granules in leukocytes**
224
What are the clinical manifestations of other disorders of phagocytosis and cell killing?
Other disorders of phagocytosis and cell killing may present with:
- **Recurrent infections**
- **Impaired wound healing**
- **Granuloma formation**
- **Increased susceptibility to certain pathogens**
225
What is the clinical presentation of Chédiak-Higashi syndrome?
Chédiak-Higashi syndrome presents with immunodeficiency, partial oculocutaneous albinism, and neurological issues.
226
What is a common feature of both Griscelli and Chédiak-Higashi syndromes?
Both syndromes involve immunodeficiency and partial oculocutaneous albinism.
227
What is the significance of the clinical features listed for these syndromes?
The clinical features help in diagnosing and understanding the implications of these genetic immunodeficiencies.
