Immunological Pathologies Flashcards
(227 cards)
1
Q
What disorder involves the triad of recurrent infections with encapsulated organisms, eczema and purpura?
A
Wiskott-Aldrich syndrome
A congenital (x-linked recessive, only occurring in males) immunodeficiency that is characterized by the classic triad of eczema, thrombocytopenic purpura, and recurrent opportunistic infections (otitis media).
Caused by a mutation in the WAS gene, which results in impaired signaling to actin cytoskeleton reorganization and therefore impaired T-cell function and thrombocytopenia
Leads to low T Cell counts, normal B cell counts, and low platlets.
2
Q
Which antibodies are decreased in Wiskott-Aldrich syndrome (WAS)?
A
IgG and IgM
can be low or normal values.
3
Q
Which antibodies are elevated in Wiskott-Aldrich syndrome (WAS)?
A
IgE and IgA
In patients with WAS, the rate of IgA synthesis is significantly increased.
4
Q
What gene leads to the x-linked recessive immunodeficiency that is characterized by the classic triad of eczema, thrombocytopenic purpura, and recurrent opportunistic infections?
A
Caused by a mutation in the WAS gene, on the X chromosome, which is inherited in an X-linked recessive manner.
Mutations result in impaired signaling to actin cytoskeleton reorganization and therefore impaired T-cell function and thrombocytopenia.
Diagnosis is confirmed with genetic analysis of the mutated WAS gene.
WATER:
Wiskott-Aldrich:
Thrombocytopenia (purpura)
Eczema
Recurrent (pyogenic) infections
5
Q
Wiskott-Aldrich syndrome (WAS) will show what on a peripheral blood smear?
A
microthromocytes in low amounts (thrombocytopenia).
6
Q
What is the appropriate treatment for the disease causing thrombocytopenia, eczema, and recurring opportunistic infections?
A
Treatment for Wiskott-Aldrich syndrome:
• IV immunoglobulin therapy
• Prophylactic antibiotics
• Platelet transfusions
• Stem cell transplantation (curative)
7
Q
What must be avoided with Wiskott-Aldrich syndrome?
A
Live attenuated vaccines
A group of vaccines containing a modified virus or bacterium that are no longer pathogenic but are able to replicate within the host’s body. These vaccines trigger a humoral and cellular immune response that usually provides lifelong immunity. Contraindicated in pregnancy and immunocompromised patients because of the risk of reverting to virulent forms. Examples include vaccines against mumps-measles-rubella, varicella, zoster, rotavirus, yellow fever, influenza (intranasal), typhoid (oral), smallpox, and adenovirus.
8
Q
What is the prognosis ofWiskott-Aldrich syndrome?
A
Death in the first year with no treatment.
Even with treatment, patients usually have a shortened life expectancy.
Increased risk of autoimmune diseases and hematological malignancies
(e.g., lymphoma, leukemia).
9
Q
Which immunodeficiencies are associated with anaphylaxis during blood transfusion?
A
Selective IgA deficiency, Common Variable Immunodeficiency (CVID), Bruton’s agammaglobulinemia, and Hyper-IgM syndrome.
These conditions may lead to anaphylaxis due to the development of anti-IgA antibodies (common in IgA deficiency and CVID) or exposure to foreign immunoglobulins not native to the host.
10
Q
What is the most common cause for the most common primary immune deficiency?
A
Selective IgA deficiency is the most common primary immune deficiency.
The cause is unknown.
11
Q
What is the prevalence of selective IgA deficiency?
A
It is the most common primary immunodeficiency, with a prevalence of approximately 1 in 300–1,500 individuals, varying by population.
12
Q
What are the hallmark features of selective IgA deficiency?
A
IgA is low or completely absent (<7 mg/dL) with normal levels of IgG and IgM, increasing susceptibility to mucosal infections (e.g., respiratory, gastrointestinal).
Most patients are ASYMPTOMATIC. Clinical manifestations are highly variable and range from asymptomatic to recurrent sinopulmonary (mostly caused by encapsulated bacteria, e.g., S. pneumoniae, H. influenzae) and GI infections (due to Giardia lamblia), as secretory IgA antibodies are a crucial part of mucosal defense.
Atopic diseases.
Sprue-like conditions (gluten-sensitive enteropathy) and fat malabsorption (chronic diarrhea).
Autoimmune diseases.
Anaphylaxis to blood products.
13
Q
Why are nosebleeds common with Selective IgA deficiency?
A
These patients have an increased risk for developing other autoimmune issues like ITP, which can cause ITP (among other autoimmune issues), leading to bleeding diathesis. Additionally, they tend to have increased irritation in their mucosa due to atopy, infection, and inflammation. Combined, this all increases risk for nosebleeds (epistaxis).
14
Q
What differentiates CVID from selective IgA deficiency in the context of transfusion reactions?
A
Both conditions may lead to anti-IgA antibodies, but CVID involves low levels of multiple immunoglobulins (IgG, IgA, and/or IgM), whereas selective IgA deficiency affects only IgA.
15
Q
What must be done while testing for Celiac disease in a patient with selective IgA deficiency?
A
Test with IgG because the condition can cause false-negative celiac disease test, which normally uses IgA antibodies.
16
Q
Selective IgA deficiency is associated with an increased risk of having which comorbidities?
A
Increased risk of:
- inflammatory bowel disease
- gluten sensitive enteropathy
- vitiligo
- thyroiditis
- RA
- immune thrombocytopenia
17
Q
What lab test tends to be falsely positive with selective IgA deficiency?
A
Positive pregnancy tests.
Presumably due to heterophile antibodies interference with β-hCG tests
18
Q
How should blood transfusions be managed in immunodeficient patients at risk of anaphylaxis?
A
Use IgA-depleted blood products or washed red blood cells to prevent exposure to IgA.
19
Q
What laboratory test is used to confirm the presence of anti-IgA antibodies?
A
Enzyme-linked immunosorbent assay (ELISA) or other serological tests specifically for anti-IgA antibodies.
Decreased serum IgA levels (< 7 mg/dL)
Normal IgG and IgM levels
20
Q
What is the primary treatment for anaphylaxis during transfusion in these patients?
A
Immediate administration of epinephrine.
Follow EPI with supportive care (oxygen, antihistamines, corticosteroids).
21
Q
Why is anaphylaxis following transfusion more common in IgA-related deficiencies than other immunodeficiencies?
A
The absence of IgA allows the immune system to produce anti-IgA antibodies, which react to transfused IgA, triggering an allergic or anaphylactic reaction.
22
Q
Why are anti-IgA antibodies formed in selective IgA deficiency?
A
The immune system recognizes IgA as foreign due to its absence in the body and produces IgE-mediated or other antibodies against it, which can trigger anaphylaxis upon re-exposure.
23
Q
How is the management of transfusion anaphylaxis different in IgA deficiency vs. allergic transfusion reactions in general?
A
In IgA deficiency: Use IgA-depleted products.
For allergic transfusion reactions: Pre-medicate with antihistamines and/or corticosteroids.
24
Q
How is selective IgA deficiency managed?
A
Treat infection(s)
Prophylactic antibiotics
Intravenous infusion of IgA is not recommended because of the risk of anaphylactic reactions (caused by the production of anti-IgA antibodies).
To prevent transfusion reactions, IgA-deficient patients must be given washed blood products without IgA or obtain blood from an IgA-deficient donor.
25
Which broader immunodeficiency syndrome can also involve anaphylaxis to transfusion and includes selective IgA deficiency?
Common Variable Immunodeficiency (CVID).
CVID patients may develop anti-IgA antibodies if they are IgA-deficient, similar to those with isolated IgA deficiency.
26
Why should patients with CVID or IgA deficiency avoid live vaccines?
These patients are immunocompromised and at risk for uncontrolled infections due to their inability to mount an adequate immune response.
27
What is the primary defect in CVID?
CVID involves low serum levels of all immunoglobulin classes due to B cells being phenotypically normal but unable to differentiate into immunoglobulin-producing cells.
Total protein will be low as it is a composite of albumin and immunoglobulins.
Patients have normal lymph tissue.
28
At what age does CVID typically present?
CVID usually presents later than other B-cell defects, typically between 20-40 years of age.
May present in childhood but usually diagnosed after puberty.
29
Does CVID affect females more than males?
No.
CVID affects male and female patient populations equally.
30
Is there a genetic component to CVID?
The occurrence is sporadic.
The pathogenesis of autoimmunity is poorly understood. Findings include an increase of CD21-/low cells in patients with CVID, which is thought to be linked to autoimmune reactions. In addition, defects of regulatory immune responses and tolerance to self-antigens have been found in patients with CVID as well as genetic mutations associated with autoimmunity.
31
What are the most common infections in CVID?
Recurrent pyogenic respiratory infections, including sinopulmonary infections.
32
What malignancies are associated with CVID?
Patients are at high risk of developing lymphoma and gastric cancer.
33
What pulmonary issues are associated with CVID?
Bronchiectasis.
Pneumonia.
34
What GI issue is associated with CVID?
Chronic diarrhea.
35
What autoimmune issues are associated with CVID?
* rheumatoid arthritis
* autoimmune hemolytic anemia
* pernicous anemia
* immune thrombocytopenia
36
How is CVID diagnosed?
Diagnosis involves:
- Low immunoglobulin levels (IgG, IgA, IgM).
- Decreased number of plasma cells.
- Poor response to immunizations.
- Flow cytometry showing subsets of normal B and T cells.
37
What is the treatment for CVID?
- Treat active infections.
- IV immunoglobulin (IVIG) to replace deficient immunoglobulins.
- Prophylactic antibiotics to prevent infections.
38
Why are patients with CVID poor responders to vaccines?
Due to defective antibody production despite normal B-cell numbers.
39
Patients with CVID have an increased chance of developing what malignancy?
non-Hodgkin lymphoma.
40
What is Transient Hypogammaglobulinemia of Infancy (THI)?
THI is an age-related delay in immunoglobulin production despite normal B-cell levels, which typically resolves by 2-6 years of age.
41
What is the typical onset age for THI?
Onset is after 6 months of age, as maternal IgG wanes.
42
What are the common clinical features of THI?
- Recurrent infections: sinopulmonary infections, otitis media, bronchitis, tonsillitis, diarrhea.
- Atopic manifestations: asthma, food allergies.
- Failure to thrive or developmental delay (in severe cases).
43
How is THI diagnosed?
- Low IgG levels (≥2 SD below age-appropriate levels).
May also have low IgA and IgM levels.
Presence of specific post-exposure or post-immunization IgG antibodies.
Flow cytometry showing normal B and T-cell subsets.
44
What are the treatments for THI?
- Prophylactic antibiotics for recurrent infections.
IVIG for severe or invasive infections.
Routine immunizations remain appropriate.
45
What are the complications of severe THI?
Rare complications include meningitis and bacteremia.
46
How can THI be differentiated from CVID?
THI resolves spontaneously by 2-6 years of age, whereas CVID persists into adulthood and involves autoimmune and malignant complications.
47
Can patients with SCID experience transfusion-related reactions?
Yes, SCID patients are at risk of graft-versus-host disease (GVHD) from transfused lymphocytes but are less commonly linked to anti-IgA antibody-mediated anaphylaxis.
48
What is the underlying defect in SCID?
SCID is caused by mutations leading to defective development of functional B cells and T cells.
49
What is the most common genetic mutation associated with SCID?
The X-linked recessive mutation in the gene encoding the common gamma chain (IL-2R gamma chain), linked to JAK3.
50
Name three common genetic causes of SCID besides the IL-2R gamma chain mutation.
Autosomal recessive mutations:
- Adenosine deaminase (ADA) deficiency, which causes toxic metabolite accumulation (e.g., dATP).
- Janus-associated kinase 3 (JAK3) deficiency independent of IL-2R.
- RAG mutations that affect V(D)J recombination.
51
What is the subtype of SCID caused by mutations in the RAG or ILRA7 gene?
Omenn syndrome.
52
What are common clinical features of SCID?
Normal at birth.
Severe recurrent infections (bacterial, viral, fungal, protozoal).
Chronic diarrhea.
Failure to thrive.
Absent lymph nodes and tonsils.
53
What are the characteristic clinical features of Omenn syndrome?
Onset before 3 months of age.
Erythroderma, adenopathy, and hepatosplenomegaly.
Severe recurrent infections.
Failure to thrive.
54
What infections are most frequently seen in SCID patients?
Bacterial diarrhea.
Oral thrush (chronic candidiasis).
Viral and protozoal infections.
55
How is Omenn syndrome diagnosed?
Oligoclonal T cells.
Eosinophilia.
Elevated IgE levels.
56
How is SCID typically diagnosed in newborns?
Quantitative PCR for T-cell receptor excision circles (TRECs), used in newborn screening.
Flow cytometry: Absent T cells.
Chest X-ray: Absent thymic shadow.
Lymph node biopsy: Absent germinal centers.
57
Why are lymph nodes and tonsils absent in SCID?
These structures rely on the presence of functional B and T cells, which are deficient in SCID.
58
What are the findings on imaging and biopsy in SCID?
Chest X-ray: Absent thymic shadow.
Lymph node biopsy: No germinal centers.
59
What is a major medical intervention that must be avoided with SCID?
Avoidance of live vaccines.
60
How does ADA deficiency in SCID affect purine metabolism?
ADA deficiency leads to:
Accumulation of toxic metabolites (e.g., deoxyadenosine and dATP).
dATP accumulation inhibits ribonucleotide reductase, impairing the generation of deoxynucleotides.
61
What laboratory finding is essential for newborn screening of SCID?
T-cell receptor excision circles (TRECs) are absent or low.
62
What is the treatment for SCID?
IV immunoglobulins (IVIG) for antibody replacement.
PCP prophylaxis (e.g., trimethoprim-sulfamethoxazole).
Bone marrow transplant or stem cell transplantation (curative).
63
What is the prognosis of SCID without treatment?
Fatal in the first year of life if untreated.
64
How can Hyper-IgM syndrome lead to transfusion-related anaphylaxis?
Patients with Hyper-IgM syndrome often have low IgA and IgG levels, predisposing them to form anti-IgA antibodies. Exposure to IgA-containing blood products can result in hypersensitivity reactions.
65
What is the underlying defect in Hyper-IgM syndrome?
A defect in CD40 ligand (CD40L) on T helper cells, which leads to impaired interaction with B cells, which have the CD40 molecule (receptor) and prevents class switching of immunoglobulins.
66
What is the most common inheritance pattern of Hyper-IgM syndrome?
X-linked recessive.
67
What is the most common mutation associated with Hyper-IgM syndrome?
CD40L deficiency.
68
Why are germinal centers absent in Hyper-IgM syndrome?
The absence of CD40-CD40L interaction prevents B-cell activation and formation of germinal centers in lymph nodes.
69
What are the hallmark clinical features of Hyper-IgM syndrome?
Recurrent severe pyogenic infections starting in childhood.
Opportunistic infections: Pneumocystis jirovecii pneumonia (PCP), Histoplasma infections, Cryptosporidium enteritis, which may lead to biliary disease, cirrhosis, and cholangiocarcinoma, and CMV hepatitis.
Failure to thrive.
70
What is the clinical picture of CMV hepatitis?
Common symptoms are prolonged malaise and fever.
Mild transaminitis (increased LFTs)
Elevated lactate dehydrogenase (LDH)
Normal to elevated bilirubin
71
How does Hyper-IgM syndrome predispose to biliary and liver complications?
Cryptosporidium infections can cause chronic inflammation of the biliary tree, leading to biliary disease, cirrhosis, or cholangiocarcinoma.
72
Which opportunistic infections are unique complications in Hyper-IgM syndrome compared to other immunodeficiencies?
Cryptosporidium enteritis, which can progress to biliary complications.
Fungal infections like Histoplasma and Pneumocystis jirovecii.
73
What are the diagnostic immunoglobulin levels in Hyper-IgM syndrome?
↓↓↓ IgG, IgA, IgE.
Normal or ↑ IgM.
74
What lymph node biopsy finding is associated with Hyper-IgM syndrome?
Absent germinal centers due to impaired B-cell activation and class-switching.
75
What supportive therapies are used in Hyper-IgM syndrome?
IV immunoglobulin (IVIG) replacement.
Prophylactic antibiotics to prevent infections.
Recombinant human granulocyte-colony stimulating factor for neutropenia.
76
What is the definitive treatment for Hyper-IgM syndrome?
Stem cell transplantation.
77
What distinguishes Hyper-IgM syndrome from other hypogammaglobulinemias?
Normal or elevated IgM levels due to impaired class-switching.
Specific susceptibility to opportunistic infections
(e.g., Pneumocystis jirovecii, Cryptosporidium).
78
How does Hyper-IgM syndrome differ from Bruton’s agammaglobulinemia?
Hyper-IgM syndrome involves normal or elevated IgM with low IgG, IgA, and IgE levels due to defects in class-switch recombination. Bruton’s involves low levels of all immunoglobulin classes due to a defect in B-cell maturation.
79
What is the immunoglobulin profile in Bruton’s agammaglobulinemia?
Profoundly low or absent IgG, IgA, and IgM levels due to a defect in B-cell maturation caused by mutations in the BTK gene.
80
What is the genetic defect in X-linked agammaglobulinemia (XLA)?
A mutation in the Bruton tyrosine kinase (BTK) gene, which is required for B-cell maturation.
X-linked recessive, meaning it primarily affects boys.
81
How does Bruton’s agammaglobulinemia affect B cells and immunoglobulins?
Results in absent mature B cells in the blood.
Low levels of all immunoglobulin classes (IgG, IgA, IgM).
82
At what age do symptoms of XLA typically begin, and why?
Symptoms begin between 3 and 6 months of age when maternal IgG wanes.
Suspect XLA in any male infant with recurrent bacterial infections (enteroviral) after 6 months of age.
83
What types of infections are common in Bruton’s agammaglobulinemia?
Recurrent, severe pyogenic infections, including pneumonia, otitis media, and sinusitis caused by encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
Enteroviral infections like hepatitis virus and enterovirus (e.g., Coxsackievirus).
84
Why are encapsulated bacteria a major concern in XLA?
Patients lack antibodies (specifically IgG) required for opsonization and clearance of encapsulated organisms.
85
What physical findings might suggest Bruton’s agammaglobulinemia?
Hypoplasia of lymphoid tissue (e.g., absent or small tonsils and lymph nodes).
Absent germinal centers and primary follicles in lymph node biopsy.
86
How is Bruton’s agammaglobulinemia diagnosed?
Flow cytometry: Absent or low B cells (marked by CD19, CD20, and CD21), leading to low levels of all immunoglobulins.
Absent lymphoid tissue, i.e., no germinal centers and primary follicles.
Normal or elevated T-cell levels.
Family history consistent with X-linked recessive inheritance.
87
Why do patients with Bruton’s agammaglobulinemia have normal T-cell function?
The defect is specific to B-cell maturation; T cells are unaffected and remain functional.
88
What infections should you suspect in a patient with recurrent enteroviral infections?
Bruton’s agammaglobulinemia, as enteroviral infections (e.g., Hepatitis and Coxsackievirus) are common due to poor mucosal immunity.
89
What is the cornerstone of treatment for Bruton’s agammaglobulinemia?
IV immunoglobulin (IVIG) therapy to replace missing antibodies.
Prophylactic antibiotics to prevent infections.
90
Are live vaccines contraindicated in Bruton’s agammaglobulinemia?
Yes, live vaccines (e.g., MMR, varicella) are contraindicated because these patients cannot mount an adequate immune response.
91
What is the difference between Bruton’s agammaglobulinemia and CVID?
Bruton’s occurs early in life (3–6 months) and is caused by a genetic defect in B-cell development.
CVID presents later in life (20–40 years) and involves multiple immunoglobulin deficiencies with no clear genetic cause.
92
How do you distinguish Bruton's from THI?
X-linked (Bruton) agammaglobulinemia can be misdiagnosed as transient hypogammaglobulinemia of infancy (THI) because both manifest with high susceptibility to infections occurring at approx. 6 months of age. Differentiation is based on B-cell levels, which are decreased in X-linked (Bruton) agammaglobulinemia and normal in THI.
93
Why is Bruton’s agammaglobulinemia associated with anaphylaxis during transfusion?
Bruton’s agammaglobulinemia results in very low levels of all immunoglobulins, including IgA. Anti-IgA antibodies may develop after exposure to blood products containing IgA, triggering anaphylaxis.
94
What imaging finding might be seen in Bruton’s agammaglobulinemia?
Absent or poorly developed lymphoid structures, such as small or absent tonsils.
95
What is the prognosis for patients with XLA with appropriate treatment?
With IVIG therapy and infection prevention, patients can live relatively normal lives with reduced infection risk.
96
What is the manner by which a patient inherited the disorder that causes late separation (>30 days) of umbilical cord, absent pus, dysfunctional neutrophils recurrent skin and
mucosal bacterial infections?
Autosomal recessive inheritance
Absence of the β2-integrin leukocyte adhesion surface molecule LFA-1 (CD18) prevents leukocytes from migrating to tissues during infection or inflammation.
Causes a defect in LFA-1 integrin (CD18) protein on phagocytes leads to impaired migration and chemotaxis by C5a, IL-8, and leukotriene B4
Flow cytometry will show absent CD18, CD11a, CD11b, and CD11c.
97
Key Clinical Clues for Leukocyte Adhesion Deficiency (LAD)
Recurrent bacterial skin & mucosal infections
Absent pus despite severe infection
Leukocytosis with neutrophilia
(increased neutrophils in blood and an absence of neutrophils at infection sites with impaired wound healing)
Delayed umbilical cord separation (>30 days after birth).
98
What is the genetic mutation responsible for Leukocyte Adhesion Deficiency (LAD)?
Mutation in CD18, part of the β2-integrin complex, impairing neutrophil adhesion and migration.
Type II is due to CD15 (Sialyl-Lewis X) deficiency but is less common and causes less severe disease.
99
What is the triad of clinical features in Leukocyte Adhesion Deficiency (LAD)?
Delayed separation of the umbilical cord
(>30 days)
Recurrent skin and mucosal bacterial infections
(gingivitis, periodontitis, abscesses)
Leukocytosis with neutrophilia
(because neutrophils cannot leave the bloodstream)
100
How is Leukocyte Adhesion Deficiency (LAD) diagnosed?
Flow cytometry for absence of CD18 (CD15 for Type II)
Leukocytosis with neutrophilia.
Biopsy of infected tissue shows absence of inflammatory cells.
101
What infections are common in Leukocyte Adhesion Deficiency (LAD)?
Recurrent bacterial infections, often due to Staphylococcus aureus and Gram-negative bacteria, without the formation of pus.
102
What treatment is used for Leukocyte Adhesion Deficiency (LAD)?
Prophylactic antibiotics to prevent infections.
Bone marrow transplant in severe cases.
For Type II provide fucose supplementation.
103
What is the underlying developmental defect in DiGeorge syndrome?
A 22q11 microdeletion leads to the failure of development of the third and fourth pharyngeal pouches, leading to hypoplastic thymus and parathyroids.
104
What is the genetic defect in DiGeorge syndrome?
A microdeletion at chromosome 22q11.2, most commonly occurring sporadically, though it can also be autosomal dominant.
105
What cardiac anomalies are associated with DiGeorge syndrome?
Conotruncal abnormalities, such as:
Tetralogy of Fallot (TOF).
Persistent truncus arteriosus.
Interrupted aortic arch.
Ventricular septal defect (VSD).
Atrial septal defect (ASD).
106
What are the characteristic craniofacial anomalies in DiGeorge syndrome?
Prominent nasal bridge.
Ocular hypertelorism
Hypoplastic wing of the nose.
Dysplastic ears.
Micrognathia (small lower jaw) and/or retrognathia.
107
What immune dysfunction occurs in DiGeorge syndrome?
T-cell deficiency due to thymic aplasia or hypoplasia
Leads to increased susceptibility to recurrent infections (viral, fungal, and PCP pneumonia).
T-cell deficiency severity: Severity depends on the degree of thymic aplasia; partial DiGeorge syndrome may have milder immune defects.
Partial: Some T-cell function remains; milder symptoms.
Complete: Severe immunodeficiency requiring aggressive interventions like thymus or stem cell transplantation.
108
What endocrine dysfunction is associated with DiGeorge syndrome?
Hypoparathyroidism, resulting in hypocalcemia and potentially tetany or seizures.
Neonatal presentation: Look for seizures due to hypocalcemia and cyanosis from congenital heart disease.
109
What additional anomalies seen on radiographic imaging is commonly seen in DiGeorge syndrome?
Absent thymic shadow on chest X-ray (also seen in SCID).
Additional features are: Cleft palate, flat cheek bones, wide set eyes, epicanthal folds, micrognathia, dysplastic ears, prominent nasal bridge, Developmental delay or intellectual disability, renal agenesis, and anal atresia, and other congenital GI abnormalities.
110
What infections are patients with DiGeorge syndrome prone to?
Viral infections (e.g., CMV, EBV).
Fungal infections (e.g., Candida).
Pneumocystis jirovecii pneumonia (PCP).
111
What is the mnemonic "CATCH-22" used for in DiGeorge syndrome?
Cardiac (conotruncal) anomalies.
Abnormal facies.
Thymic aplasia/hypoplasia.
Cleft palate.
Hypocalcemia.
22: Chromosome 22 deletion.
112
How is DiGeorge syndrome diagnosed?
Low CD3 T Cells.
Detection of 22q11.2 deletion via fluorescence in situ hybridization (FISH).
Low levels of PTH and calcium.
Absolute T-lymphocyte count showing reduced T cells.
Delayed hypersensitivity skin testing (absent or reduced T-cell response).
CXR: Absence of the thymic shadow.
113
What are the treatment options for DiGeorge syndrome?
Antibiotics for infections.
PCP prophylaxis (e.g., trimethoprim-sulfamethoxazole).
Antiviral and antifungal therapy as needed.
Hypocalcemia management: Calcium supplementation and calcitriol.
IVIG for antibody deficiencies.
HCT for severe immunodeficiencies.
Surgical correction for cardiac defects and cleft palate.
Consideration of thymus transplantation or bone marrow transplant in severe T-cell deficiency, although this is only available in a few centers world-wide.
114
What is the prognosis for untreated patients with DiGeorge syndrome?
Variable depending on the severity of symptoms and degree of thymus impairment
Overall, poor, with most patients not surviving beyond childhood without treatment.
The most significant prognostic factor is degree of cardiac involvement.
With treatment, patients can have a normal life expectancy.
115
What are long-term complications of DiGeorge syndrome?
Developmental delays and intellectual disabilities.
Chronic infections.
Risk of autoimmune diseases due to immune dysregulation.
Hearing loss.
116
What are the psychological comorbidities associated with DiGeorge syndrome?
Learning disabilities, ADHD, and Schizophrenia
117
What is the underlying defect in Autosomal Dominant Hyper-IgE Syndrome (Job Syndrome)?
A defect in neutrophil chemotaxis due to a mutation in the STAT3 gene, leading to impaired development of Th17 cells.
118
What is the inheritance pattern of Job Syndrome?
Autosomal dominant (STAT3), but sometimes autosomal recessive (DOCK8).
The autosomal dominant form (STAT3) is in many cases a de novo mutation.
Most patients have unaffected parents.
119
Why is the STAT3 mutation significant in Job Syndrome?
It disrupts the differentiation of Th17 cells, leading to impaired neutrophil recruitment and chemotaxis, which explains the susceptibility to bacterial and fungal infections.
120
What are the characteristic clinical features of Job Syndrome?
Coarse facial features.
Recurrent cold abscesses (typically caused by Staphylococcus aureus and Candida).
Retained primary teeth (failure of normal exfoliation).
Hyper-IgE (with associated eosinophilia).
Dermatologic features (severe eczema).
Bone fragility, with increased risk of fractures due to decreased bone density.
121
Other than retained primary teeth, what other orthodontic issue is seen in Hyper-IgE (Job Syndrome)?
Gingival hypertrophy is also commonly associated.
Retained primary teeth is the more known orthodontic issue accompanying Job Syndrome.
122
What is the mnemonic FATED used for in Job Syndrome?
Facies (coarse facial [Leonine] features).
Abscesses (cold, recurrent).
Teeth (retained primary teeth).
Eosinophilia/Hyper-IgE.
Dermatologic findings (eczema).
123
What laboratory findings are characteristic of Job Syndrome?
Elevated IgE levels.
Eosinophilia (variable).
Reduced levels of IFN-γ, contributing to impaired neutrophil recruitment.
124
Why are the abscesses in Job Syndrome described as "cold"?
They lack typical signs of inflammation (e.g., warmth, redness) because of defective neutrophil chemotaxis and cytokine signaling.
Cold abscesses are pathognomonic for Job Syndrome and differentiate it from other primary immunodeficiencies.
125
What infections are common in Job Syndrome?
Recurrent bacterial infections of the skin, especially Staphylococcus aureus and Candida.
Recurrent (cold) abscesses, lung infections, and skin infections.
Pneumatoceles (thin-walled lung cysts) may develop after infections.
126
How is bone health affected in Job Syndrome?
Patients have decreased bone density.
Increased risk of pathological fractures following minor trauma.
127
What dermatologic findings are common in Job Syndrome?
Severe eczema, often present from infancy.
128
What color are patients' hair with Job Syndrome?
Red.
129
How is Job Syndrome diagnosed?
Clinical features (FATED criteria).
Elevated IgE levels (often > 2000 IU/mL).
Variable eosinophilia.
Reduced IFN-γ levels.
130
What is the treatment for Job Syndrome?
Antibiotics (penicillinase-resistant antibiotics for recurrent bacterial infections).
- dicloxacillin or cephalexin
IV immunoglobulin (IVIG) therapy for immune support.
Management of eczema with emollients and topical steroids.
131
What are the long-term complications of Job Syndrome?
Chronic lung disease (e.g., bronchiectasis and pneumatoceles).
Skeletal abnormalities (fractures and scoliosis).
Recurrent infections leading to significant morbidity.
132
How does Job Syndrome differ from Hyper-IgM Syndrome?
In Job Syndrome, IgE levels are elevated, and Th17 cells are defective, whereas in Hyper-IgM Syndrome, IgM is elevated, and class switching is defective.
Dermatologic findings like eczema are specific to Job Syndrome.
133
What is the prognosis for patients with Job Syndrome?
With proper management, including prophylactic antibiotics and immune support, patients can lead relatively normal lives, though recurrent infections and fractures remain challenges.
Retained primary teeth can lead to dental malocclusion and require dental intervention.
Early recognition and prophylactic treatment significantly improve quality of life and reduce complications.
134
What deficiency is associated with a disseminated mycobacterial and/or fungal infection, that may present after administration of the BCG vaccine?
Impaired Th1 response due to defective IL-12 receptors, resulting in reduced activation of macrophages by IFN-γ.
The condition is autosomal recessive.
135
What is the inheritance pattern of IL-12 receptor deficiency?
Autosomal recessive.
136
What is the underlying pathology in most cases of Mendelian susceptibility to mycobacterial disease (MSMD)?
IL-12 receptor deficiency.
A rare genetic condition that causes primary immunodeficiency. Affected individuals have defects in IFN-γ mediated immunity. This increases susceptibility to infection with weakly virulent mycobacteria (e.g., environmental mycobacteria, BCG vaccine)
137
What is the normal role of IL-12 in the immune system?
IL-12, released by antigen-presenting macrophages, activates Th1 cells to produce IFN-γ, which stimulates macrophages to kill intracellular pathogens.
138
What pathogens are patients with IL-12 receptor deficiency especially susceptible to?
Mycobacterial infections (e.g., Mycobacterium tuberculosis, Salmonella).
Disseminated infections from weakly virulent mycobacteria, such as environmental mycobacteria or the BCG vaccine.
Fungal infections.
139
Why are individuals with IL-12 receptor deficiency at increased risk for disseminated infections?
They have defects in IFN-γ-mediated immunity, which is critical for intracellular pathogen clearance.
140
At what age do symptoms of IL-12 receptor deficiency typically present?
Symptoms usually appear around 1–3 years of age, depending on the age of exposure to pathogens.
141
What clinical features are associated with IL-12 receptor deficiency?
Disseminated mycobacterial infections (e.g., severe reaction to the BCG vaccine).
Recurrent fungal infections.
Poor immune response to intracellular pathogens.
142
How is IL-12 receptor deficiency diagnosed?
Low levels of IFN-γ in response to IL-12 stimulation.
Genetic testing may confirm the IL-12 receptor mutation.
143
What is the treatment for IL-12 receptor deficiency?
Antibiotics for active infections.
IFN-γ therapy to enhance macrophage activation and intracellular pathogen clearance.
144
Why does IL-12 receptor deficiency increase susceptibility to tuberculosis after BCG vaccination?
The defective IL-12-IFN-γ axis prevents effective macrophage activation, allowing even attenuated mycobacteria (e.g., in the BCG vaccine) to cause disseminated disease.
145
What are the key intracellular pathogens cleared by the IL-12/IFN-γ pathway?
Mycobacteria.
Salmonella.
Listeria monocytogenes.
146
How does IL-12 receptor deficiency differ from chronic granulomatous disease (CGD)?
IL-12 receptor deficiency affects IFN-γ-mediated Th1 activation and macrophage function, while CGD involves defective NADPH oxidase and impaired intracellular killing by phagocytes.
IL-12 deficiency primarily leads to mycobacterial infections, whereas CGD leads to catalase-positive bacterial and fungal infections.
147
What are the complications of untreated IL-12 receptor deficiency?
Disseminated infections leading to organ damage.
Potential death from overwhelming infections if not treated.
148
What screening should be avoided in patients suspected of having IL-12 receptor deficiency?
Avoid live vaccines like BCG, as they can cause disseminated infections.
149
What is the primary immune defect in Chronic Mucocutaneous Candidiasis (CMC)?
Impaired or absent T-cell response to Candida antigens, leading to chronic Candida infections.
150
What is the most common genetic mutation associated with CMC?
A gain-of-function mutation in the STAT1 gene.
151
What congenital immune defect is commonly associated with CMC?
Autoimmune regulator (AIRE protein) deficiency, leading to autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).
152
What cytokine pathways are defective in CMC?
IL-17 and IL-17 receptor pathways, resulting in an insufficient cell-mediated immune response to Candida infections.
153
What are the characteristic clinical features of CMC?
Persistent or recurrent noninvasive Candida infections of the skin, mucous membranes (e.g., oral thrush), and nails.
Associated autoimmune disorders, such as: immune thrombocytopenic purpura (ITP) and Rheumatoid arthritis.
154
How is CMC diagnosed?
Clinical diagnosis based on recurrent Candida infections.
Absent in vitro T-cell proliferation in response to Candida antigens.
Absent cutaneous reaction to Candida antigen during delayed hypersensitivity testing.
155
What is the typical presentation of Candida infections in CMC?
Infections are persistent and involve the skin, nails, and mucous membranes, but they remain noninvasive.
156
How does CMC differ from systemic Candida infections seen in immunocompromised patients?
CMC involves localized, noninvasive infections due to a specific T-cell defect.
Systemic Candida infections involve invasive disease due to neutropenia or broader immunosuppression.
157
What autoimmune syndromes are associated with CMC?
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a triad of mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency.
Autoimmune diseases such as ITP and rheumatoid arthritis.
158
Why are IL-17 and IL-17 receptors important in preventing Candida infections?
They mediate the cellular immune response by recruiting neutrophils and macrophages to combat Candida infections.
When the IL-17 pathway is affected, Candida infections in CMC are noninvasive because neutrophil function is preserved, even though T-cell-mediated immunity is impaired.
159
How does a STAT1 gain-of-function mutation lead to CMC?
The mutation disrupts IL-17 signaling, impairing T-cell and neutrophil responses against Candida. Candida infections in CMC are noninvasive because neutrophil function is somewhat preserved, even though T-cell-mediated immunity is impaired.
160
What diagnostic test can assess T-cell functionality in response to Candida?
In vitro T-cell proliferation assay with Candida antigens.
161
What conditions should be screened in patients with CMC and AIRE deficiency?
Associated autoimmune endocrinopathies such as:
Hypoparathyroidism.
Adrenal insufficiency (Addison's disease).
Type 1 diabetes mellitus.
162
What is the prognosis for untreated CMC?
Without treatment, patients face significant morbidity from recurrent infections and associated autoimmune diseases.
163
What is the treatment for CMC?
Antifungal therapy (e.g., fluconazole for mucocutaneous infections).
Treatment of associated autoimmune conditions (e.g., corticosteroids or other immunosuppressive agents for autoimmune disorders).
164
What other considerations should be acknowledged when a patient has CMC?
Patients with recurrent Candida infections should be evaluated for underlying immunodeficiencies like HIV.
165
What is the underlying defect in IPEX syndrome?
Dysfunctional regulatory T cells due to a mutation in the FOXP3 transcription factor, leading to unchecked T-cell activation and autoimmunity.
166
What is the inheritance pattern of IPEX syndrome?
X-linked recessive, meaning it predominantly affects males.
Because it is X-linked recessive, females are typically carriers and are less likely to exhibit the disease.
167
What is the role of FOXP3 in the immune system?
FOXP3 is critical for the development and function of CD4+CD25+ regulatory T cells, which suppress autoimmune responses.
168
What are the classic clinical features of IPEX syndrome?
Early infancy presentation. Male infants presenting with early-onset type 1 diabetes mellitus and chronic diarrhea should be evaluated for IPEX.
Lymphadenopathy or chronic lymphoid tissue hypertrophy (e.g., enlarged tonsils).
Eczema, often associated with other autoimmune skin conditions.
Autoimmune endocrinopathies, such as: Type 1 diabetes mellitus, Hypothyroidism or hyperthyroidism, Enteropathy, presenting as chronic diarrhea, Nail dystrophy, and Failure to thrive.
169
Which autoimmune endocrine conditions are associated with IPEX syndrome?
Type 1 diabetes mellitus (in male individuals).
Hypothyroidism.
Hyperthyroidism.
170
What gastrointestinal findings are characteristic of IPEX syndrome?
Chronic diarrhea due to autoimmune enteropathy.
171
How is IPEX syndrome diagnosed?
Clinical examination and family history.
Genetic testing to identify mutations in FOXP3.
Flow cytometry: Markedly reduced or absent CD4+CD25+ regulatory T cells with otherwise normal T-cell populations.
172
What laboratory findings might support a diagnosis of IPEX syndrome?
Evidence of autoimmune-mediated tissue destruction, such as:
Elevated autoantibodies (e.g., anti-GAD antibodies in type 1 diabetes).
Malabsorption markers in chronic diarrhea.
173
What is the treatment for IPEX syndrome?
Nutritional support for failure to thrive and enteropathy.
Immunosuppression, using: Tacrolimus, Cyclosporine, and/or Sirolimus.
Rituximab (in refractory cases).
Definitive treatment: Bone marrow transplantation.
174
What dermatologic features are associated with IPEX syndrome?
Severe eczema.
Possible co-occurrence of other autoimmune dermatoses.
175
A 4-year-old boy is brought to the pediatric clinic by his parents due to recurrent infections. The child has a history of multiple episodes of pneumonia, chronic suppurative lymphadenitis, and two episodes of liver abscesses. He has also been hospitalized twice for severe skin infections caused by Staphylococcus aureus. His infections are notable for being caused by catalase-positive organisms. Family history reveals that his maternal uncle died in childhood from a similar pattern of recurrent infections.
Physical examination reveals cervical lymphadenopathy and several healed scars on the skin from previous abscesses. Laboratory studies show normal leukocyte and platelet counts, but flow cytometry with dihydrorhodamine (DHR) reduction testing reveals decreased fluorescence. Nitroblue tetrazolium (NBT) test is negative.
Which of the following is the most appropriate next step in management?
A) Initiate trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis and itraconazole
B) Begin intravenous immunoglobulin (IVIG) therapy
C) Administer interferon-gamma therapy
D) Perform a bone marrow transplant
E) Administer live-attenuated BCG vaccine
Correct Answer:
A) Initiate trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis and itraconazole
Explanation: This child has Chronic Granulomatous Disease (CGD), a disorder of neutrophil function caused by defective NADPH oxidase, leading to impaired respiratory burst and inability to kill catalase-positive organisms. Key features include recurrent infections with catalase-positive organisms (e.g., Staphylococcus aureus, Aspergillus, Serratia marcescens),
Recurrent abscess formation in the skin, lymph nodes, and internal organs (e.g., liver), and
diagnosis confirmed by DHR test showing decreased fluorescence and negative NBT test. TMP-SMX and itraconazole prophylaxis is the first-line management for CGD to prevent bacterial (catalase-positive) and fungal infections. Long-term prophylaxis improves survival and reduces the frequency of infections.
Incorrect answers:
B) IVIG therapy: IVIG is indicated for humoral immunodeficiencies (e.g., X-linked agammaglobulinemia, CVID) but not for CGD, which is a phagocytic defect.
C) Interferon-gamma therapy: Interferon-gamma is used adjunctively in CGD to enhance macrophage and neutrophil activity but is not the first step in management. Prophylaxis must be started first.
D) Bone marrow transplant: Bone marrow transplant can cure CGD but is reserved for severe cases with recurrent, life-threatening infections or when medical therapy fails.
E) Live-attenuated BCG vaccine: Live vaccines are contraindicated in CGD and other immunodeficiencies due to the risk of disseminated infections.
176
What is the primary defect in Chronic Granulomatous Disease (CGD)?
A deficiency of superoxide production by neutrophils and macrophages due to defective NADPH oxidase, leading to impaired killing of phagocytosed pathogens.
177
What is the inheritance pattern of CGD?
X-linked recessive (most common, 2:1).
Autosomal recessive (less common).
178
What is the pathophysiology of CGD?
Defective NADPH oxidase leads to impaired production of reactive oxygen species (ROS), including superoxide.
Results in a decreased respiratory burst in neutrophils, impairing the ability to kill catalase-positive organisms.
179
What types of pathogens are patients with CGD most susceptible to?
Catalase-positive organisms, including:
Bacteria:
Staphylococcus aureus.
Nocardia spp..
Escherichia coli.
Klebsiella pneumoniae.
Serratia marcescens.
Fungi:
Aspergillus spp..
Candida spp..
180
Why are catalase-positive organisms problematic in CGD?
Catalase degrades hydrogen peroxide that would otherwise be used by neutrophils to kill pathogens, making these organisms more resistant in CGD.
181
What are the hallmark infections of CGD that are frequently tested?
Aspergillus pneumonia (often fatal without treatment).
Serratia marcescens infections (neonatal sepsis).
Suppurative lymphadenitis caused by Staphylococcus aureus.
182
What are the common clinical features of CGD?
Recurrent severe infections involving:
Respiratory tract (most common manifestation is pneumonia).
GI and GU tract.
Granulomas in the skin, GI tract and urinary tract (leading to obstructions).
Apthous ulcers and inflammation of the nares with purulent material.
Lymphadenopathy.
Chronic inflammatory symptoms.
Skin, Lymph nodes (e.g., suppurative lymphadenitis), and Bones (osteomyelitis).
183
What imaging findings might be seen in CGD?
Chronic pulmonary infections can lead to bronchiectasis.
Granulomas in the GI or GU tract might cause obstruction.
184
How does CGD present in infancy or childhood?
Delayed wound healing.
Recurrent abscesses (skin and organ-specific).
Failure to thrive due to chronic infections.
185
How is CGD diagnosed?
Dihydrorhodamine (DHR) test is the preferred method to diagnose and is a flow cytometry test showing abnormal NADPH oxidase activity by the failure to reduce dihydrorhodamine to rhodamine (decreased green fluorescence).
Nitroblue tetrazolium (NBT) test will be negative and indicates failure of leukocytes to reduce NBT to formazan (fails to produce the blue byproduct).
Genetic testing confirms the diagnosis.
186
How is the DHR test superior to the NBT test in diagnosing CGD?
The DHR test is more sensitive and quantifies NADPH oxidase activity using flow cytometry.
The NBT test is qualitative and more prone to errors.
187
What hematologic abnormalities are commonly associated with CGD?
Hypergammaglobulinemia.
Anemia (chronic inflammation-related).
188
What is the standard treatment approach for CGD?
Infection treatment: Antibiotics and antifungals.
Lifelong prophylactic antibiotics:
TMP-SMX for catalase-positive bacterial infections.
Antifungals (e.g., itraconazole, voriconazole, posaconazole).
Glucocorticoids for inflammatory complications.
IFN-γ therapy: Boosts macrophage activation and bacterial killing.
Bone marrow transplantation (curative in severe cases).
189
What is the prognosis for CGD with proper treatment?
With lifelong prophylaxis and infection management, many patients survive into adulthood.
Bone marrow transplant offers a potential cure.
190
This is observed on a peripheral blood smear in a patient with delayed reflexes and albinism.
What is the likely diagnosis?
Chédiak-Higashi neutrophil.
Chediak-Higashi Syndrome (CHS), an autosomal recessive disorder caused by a mutation in the LYST gene, leading to defective lysosomal trafficking and impaired phagosome-lysosome fusion in neutrophils and other cells.
191
A 6-year-old boy is brought to the clinic by his parents due to recurrent infections and progressive weakness. Over the past year, he has had multiple episodes of otitis media, pneumonia, and skin abscesses. On examination, the child has partial albinism with silvery hair, hepatosplenomegaly, and generalized lymphadenopathy. Neurologic examination reveals decreased deep tendon reflexes and muscle weakness in the lower extremities.
The peripheral blood smear demonstrates neutrophils with large cytoplasmic granules. Laboratory tests show normal total leukocyte and platelet counts.
Which of the following is the most likely underlying cause of this child’s condition?
A) Deficiency in NADPH oxidase
B) Impaired phagosome-lysosome fusion
C) Mutation in STAT3 affecting Th17 cells
D) Impaired respiratory burst
E) Mutation in FOXP3 leading to loss of regulatory T cells
This child presents with the classic features of Chediak-Higashi Syndrome (CHS), an autosomal recessive disorder caused by a mutation in the LYST gene, leading to defective lysosomal trafficking and impaired phagosome-lysosome fusion in neutrophils and other cells.
Key features include:
- Progressive neurodegeneration: Manifesting as peripheral neuropathy and neurologic decline (e.g., weakness, decreased reflexes).
- Lymphohistiocytosis: Can lead to hepatosplenomegaly and lymphadenopathy due to an overactive inflammatory response.
- Albinism: Partial albinism (silvery hair, light skin) due to defective melanosome trafficking.
- Recurrent pyogenic infections: Particularly with Staphylococcus aureus and Streptococcus pyogenes, due to impaired neutrophil function.
- Peripheral neuropathy: Seen in advanced disease stages.
192
What is the genetic defect in Chediak-Higashi Syndrome (CHS)?
Autosomal recessive mutation in the LYST gene.
Microtubule polymerization dysfunction.
Leads to defective:
- Lysosomal trafficking
- Impaired phagosome-lysosome fusion
- Chemotaxis (neutropenia)
- serotinin and platelet defects
193
What is the hallmark pathophysiology of CHS?
Defective phagosome-lysosome fusion, causing impaired killing of ingested pathogens and the formation of giant granules in neutrophils and other cells.
Pancytopenia
Mild coagulation defects
194
What does the ALPINe mnemonic for CHS stand for?
ALPINe:
Albinism (partial, light-colored skin, silvery hair).
Lymphohistiocytosis (hepatosplenomegaly, lymphadenopathy).
Infections (recurrent pyogenic).
Neuropathy (progressive peripheral neuropathy and decreased reflexes).
Progressive neurodegeneration.
Neutropenia.
195
What is the primary cause of lymphohistiocytosis in CHS?
Uncontrolled activation of the immune system, leading to hepatosplenomegaly, lymphadenopathy, and systemic inflammation.
This is rapid and fatal.
196
What are the neurologic symptoms are associated with CHS?
Peripheral neuropathy (progressive weakness, decreased reflexes).
Cerebellar dysfunction in advanced disease.
197
What infections are common in CHS?
Recurrent pyogenic infections caused by:
Staphylococcus aureus.
Streptococcus pyogenes.
Pseudomonas spp.
198
What hematologic findings are seen in CHS?
Pancytopenia in advanced stages (neurtropenia is a common feature).
Prolonged bleeding due to abnormal platelet granules.
199
What is the pathognomonic finding on a peripheral blood smear in CHS?
Giant cytoplasmic granules in neutrophils and other white blood cells.
Diagnostic.
200
How is CHS diagnosed?
Peripheral smear: Shows giant granules in neutrophils.
Genetic testing: Confirms mutation in the LYST gene.
Immune function testing shows impaired intracellular pathogen killing.
201
How are infections managed in CHS?
Prophylactic antibiotics to prevent bacterial infections.
Antifungals for fungal infections.
202
What supportive care is provided for CHS patients?
Management of infections.
Nutritional support.
Immunosuppressive therapy (e.g., corticosteroids) for lymphohistiocytosis.
203
What is the definitive treatment for CHS?
Bone marrow transplant (BMT) is curative for the immune defect.
204
What is the prognosis of CHS without treatment?
Death in early childhood, typically from severe infections or complications of lymphohistiocytosis (can occur in the accelerated phase and is potentially fatal).
205
What are the complications of untreated lymphohistiocytosis in CHS?
Multiorgan failure due to excessive immune activation and tissue damage.
206
What distinguishes CHS from Chronic Granulomatous Disease (CGD)?
CHS: Partial albinism, peripheral neuropathy, and giant granules in neutrophils.
CGD: Susceptibility to catalase-positive organisms, no albinism or neuropathy.
207
Why are catalase-positive organisms not uniquely problematic in CHS compared to CGD?
CHS affects lysosomal trafficking and phagocytosis, not ROS production, so its defect is broader.
208
A 7-year-old boy is brought to the pediatrician for evaluation of poor coordination and frequent infections. His parents note that he started walking later than expected and has progressively developed an unsteady gait. Physical examination reveals conjunctival telangiectasias, difficulty with tandem walking, and multiple scars from frequent respiratory infections. Laboratory studies show elevated alpha-fetoprotein (AFP) and decreased levels of IgA, IgG, and IgE.
Which of the following is the most likely underlying cause of this patient's condition?
A) Defective phagosome-lysosome fusion
B) Mutation in STAT3 affecting Th17 cells
C) Impaired DNA repair due to an ATM gene defect
D) Defective respiratory burst in neutrophils
E) FOXP3 mutation causing loss of regulatory T cells
Impaired DNA repair due to an ATM gene defect.
This child has Ataxia-Telangiectasia (AT), a rare autosomal recessive disorder caused by mutations in the ATM gene. The ATM protein is crucial for detecting DNA damage and halting the cell cycle for repair. Mutations result in: DNA instability, Increased risk of malignancies (e.g., lymphoma, leukemia), Immunodeficiency due to lymphopenia and reduced immunoglobulins.
Clinical features include:
- Cerebellar ataxia (progressive unsteady gait).
- Telangiectasias (spider-like blood vessels on the skin and conjunctiva).
- Immunodeficiency (frequent infections, low IgA, IgG, IgE).
- Increased alpha-fetoprotein (AFP).
- Hypersensitivity to ionizing radiation.
209
What is the genetic defect in Ataxia-Telangiectasia?
Mutation in the ATM gene (autosomal recessive), leading to failure to detect DNA damage and halt cell cycle progression. This causes low IgA, low IgM, low IgA, impaired T cells, increased infections of the ears, sinuses, and lungs.
There is a significant increase in risk for the development of malignancy such as lymphona and leukemia.
210
What is the primary function of the ATM gene?
The ATM gene encodes a protein that detects DNA damage, halts the cell cycle, and activates repair pathways.
Defects in ATM gene leads to a failure to detect DNA damage, thus leading to a failure to halt progression of cell cycle causing an accumulation of mutations within various cells.
211
What are the hallmark features of Ataxia-Telangiectasia?
Cerebellar defects (Ataxia).
Telangiectasias (spider angiomas).
Immunodeficiency (especially low IgA).
212
What portion of the cerebellum deteriorates with Ataxia-Telangiectasia?
Vermis
213
Why are patients with Ataxia-Telangiectasia sensitive to radiation?
Mutations in the ATM gene result in defective DNA repair, making cells hypersensitive to ionizing radiation.
214
What laboratory findings are characteristic of Ataxia-Telangiectasia?
Cerebellar atrophy.
↑ Alpha-fetoprotein (AFP).
↓ IgA, IgG, and IgE.
Lymphopenia.
215
How is the diagnosis of Ataxia-Telangiectasia confirmed?
Genetic testing showing the mutation of ATM gene
216
What cancers are patients with Ataxia-Telangiectasia at increased risk for?
Lymphoma and leukemia due to accumulated mutations and DNA instability.
217
What physical examination findings are typical in Ataxia-Telangiectasia?
Cerebellar ataxia (unsteady gait, difficulty with coordination).
Telangiectasias (visible on conjunctiva and skin).
Spider Angiomas.
218
How does immunodeficiency manifest in Ataxia-Telangiectasia?
Frequent sinopulmonary infections (due to low IgA, IgG, and lymphopenia).
Susceptibility to bacterial and viral infections.
219
What immunoglobulin is low in Ataxia-telangiectasia?
Notably IgA is low.
But also IgG and IgE.
220
What is the recommended precaution for medical imaging in Ataxia-Telangiectasia?
Minimize exposure to ionizing radiation (e.g., avoid unnecessary X-rays and CT scans).
221
What is the prognosis of Ataxia-Telangiectasia?
Poor, with most patients dying in early adulthood due to infections or malignancies (e.g., lymphoma).
222
How is Ataxia-Telangiectasia managed?
Supportive care for infections (e.g., antibiotics).
Immunoglobulin replacement therapy for immunodeficiency.
Screening for malignancies.
Radiation avoidance.
223
What differentiates Ataxia-Telangiectasia from other immunodeficiencies?
The combination of neurologic symptoms (ataxia), telangiectasias, and elevated AFP is unique to AT.
224
What is the prognosis of Ataxia-Telangiectasia?
Variable rate of progression.
Affected individuals typically require a wheelchair by adolescence.
Average life expectancy: 25 years of age.
Malignancy is the most common cause of death.
225
A immunological disease leading to T cell deficiency will lead to ...
Bacterial sepsis.
Increased predilection for viral infections (CMV, EBV, JC Virus, VZV) in the respiratory and GI systems.
Fungal infections (local Candida), PCP, and Cryptococcus.
226
A immunological disease leading to B cell deficiency will lead to ...
Increased disease from encapsulated bacteria (Pseudomonas aeruginosa, Streptococcus pneumoniae, Haemophilus Influenzae type b, Neisseria meningitidis, Escherichia coli, Salmonella, Klebsiella pneumoniae, group B Streptococcus).
Enteroviral encephalitis, poliovirus (live vaccine contraindicated).
GI giardiasis (no IgA).
227
Neutropenia and low granulocytes will increzsae the risk for what pathogens?
Staphylococcus, Burkholderia cepacia, Pseudomonas aeruginosa, Nocardia, Serratia.
Candida (systemic), Aspergillus, Mucor.
