Primary Immunodeficiency Disorders

Question 1

Defect in Severe Combined Immunodeficiency (SCID)

Answer 1

Fully or mostly absent T cells that do not function

->functionally deficient B cells given lack of T cells

Question 2

Diagnosis of SCID

Answer 2

T cell count <300 microL
AND
absence of T-cell responses to mitogens (<10% response compared to control)

Question 3

Hypomorphic SCID

Answer 3

Reduced number of T cells for age (or normal number with reduced diversity)
AND
<30% T-cell function compared to control

Question 4

SCID Newborn screening

Answer 4

T-cell receptor excision circles - marker of T cell receptor development (>99% sensitive for classic and hypomorphic SCID)

Question 5

Wiskott-Aldrich Syndrome Defect

Answer 5

Mutation in WAS protein (WASP) expressed in all hematopoetic cells, which is important for cell mobility, cell-cell interactions and platelet function
-> Leads to poor T cell function

Question 6

WAS Triad

Answer 6

Thrombocytopenia (with decreased MPV)
Eczema
Recurrent infections
(also with predisposition to malignancy, autoimmunity and childhood mortality)

Question 7

Most common etiology for Hyperimmunoglobulin (Ig) M Syndrome

Answer 7

CD40 Ligand deficency

Question 8

CD40 Ligand Deficiency genetics

Answer 8

X-linked

Question 9

HyperIgM Syndrome (NOT CD40 Ligand deficiency) genetics

Answer 9

Autosomal recessive

Question 10

CD40 Ligand Function

Answer 10

Expressed on all B cells - Pivotal for B-cell growth, survival and differentiation

Question 11

CD40 Ligand Deficiency Labs

Answer 11

High IgM (or normal)
Low or absent IgG, IgA, IgE due to inability to class switch
Lack of specific IgG production
CD4 count is normal, but non-functioning

Question 12

CD40 Ligand Deficiency Presentation

Answer 12

Present like CD4 deficient (AIDS) patients - PJP, cryptosporidum, cryptococcus

No lymphadenopathy (unlike AR-HyperIgM, which can have excessive LAD since production defect is downstream)

GI disease (diarrhea, liver dysfunction) is common

High risk for malignancy (especially lymphomas and liver cancer)

Question 13

GATA2 Deficiency age of onset

Answer 13

Teens to late adulthood (median 20 years)

Question 14

GATA2 Deficiency Lab findings

Answer 14

Decreased B and NK cells
Monocytopenia (>80%)
Occasional CD4 lymphopenia and neutropenia (50%)

Question 15

GATA2 Deficiency Infections (4)

Answer 15

Recalcitrant, severe HPV
Disseminated NTM
EBV viremia
HSV outbreaks

Question 16

GATA2 Deficiency Non-infectious presentation (4)

Answer 16

Antibody-negative pulmonary alveolar proteinosis
Hematologic malignancies (MDS/AML)
Sensorineural hearing loss
Lymphedema

Question 17

Familial Hemophagocytic Lymphohistiocytosis etiology

Answer 17

Prolonged, excessive activation of antigen-presenting and cytotoxic cells due to inability to clear inciting pathogen

Cytokine storm from APCs

Question 18

Diagnostic Criteria for FHLH:

Answer 18

5 of 8:

• Fever
• Splenomegaly
• Cytopenias (Hgb <9, PLT <100, ANC <1000)
• Hypertriglyceridemia (>265)
• Low fibrinogen (<150)
• High ferritin (>500)
• High soluble IL-2 receptor (>2400) - marker of T-cell activation
• Low or absent NK-cell activity
• Hemophagocytosis on pathology

(Also transaminitis and HSM, but not part of criteria)

Question 19

IgA Deficiency diagnosis

Answer 19

Undetectable IgA in blood and secretions without other immunoglobulin deficiencies

Question 20

IgA deficiency presentation

Answer 20

Most have on illness
25-50% have recurrent infections, especially involving mucosal surfaces (ear infections, sinusitis, bronchitis, pneumonia)
May also have GI manifestations and chronic diarrhea
Autoimmune diseases and allergies may be more common

Question 21

T-cell defects (5)

Answer 21

1. SCID - most common severe PID
2. Wiksot-Aldrich Syndrome
3. CD40 Ligand Deficiency - most common etiology for hyperIgM syndrome
4. GATA2 Deficiency - later onset
5. Familial HLH

Question 22

B Cell defects (3)

Answer 22

1. IgA deficiency - most commonly found primary immune deficiency, especially among caucasians (?1/500)
2. X-linked agammaglobulinemia
3. CVID - very common, mainly in adults

Question 23

X-linked agammaglobulinemia defect

Answer 23

Deficiencies in Bruton’s Tyrosine Kinase leading to severely decreased B-cell numbers and absence of serum Ig

Question 24

X-linked agammaglboulinemia infections

Answer 24

Bacterial respiratory and GI infections: H flu, S aureus, S pneumonia

Chronic enteroviral infections, can cause meningoencephalitis

Monoarticular arthritis, usually aseptic and responds to high-dose gammaglobulin treatment

Question 25

Common variable immune deficiency (CVID) lab findings

Answer 25

Low levels of serum Ig with decreased specific antibody responses Small subset also have minor T-cell defects

Question 26

CVID presentation

Answer 26

Mostly adults, very common (1/25,000) Recurrent respiratory and GI tract infections Subset present with autoimmunity, including IBD, granulomas, endocrinopathies May be at higher risk of developing cancer (esp. lymphoma)

Question 27

Chronic granulomatous disease (CGD) defect

Answer 27

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase defects leading to inability to produce superoxide anions Inflamed tissue around uncleared pathogens creates granulomas

Question 28

CGD Diagnosis

Answer 28

Dihydrorhodamine testing (DHR)

Question 29

Most common (and most severe) genetic defect for CGD

Answer 29

CYBB - X-linked

Question 30

CGD prognosis

Answer 30

Without diagnosis - fatal within 1st year With diagnosis and adequate prophylaxis: -X-linked median life-expectancy: 20-25 years -AR: 30-40 years

Question 31

CGD infections

Answer 31

Most common is GI disease (can mimic colitis, IBD) Fungal - mostly aspergillus - ubiquitous and most common cause of death Sepsis from uncommon catalase-positive organisms: -Granulibacter bethesdensis -Chromobacterium violaceum -Francisella philomiragia -Burkholderia cepacia -Nocardia (not 2/2 steroids)

Question 32

Phagocytic defects (5)

Answer 32

1. CGD 2. Severe congenital neutropenia 3. X-linked neutropenia 4. Shwachman-Diamond Syndrome 5. Leukocyte adhesion deficiency (LAD)

Question 33

Severe congenital neutropenia: 1. Inheritance 2. age of onset 3. Presentatoin

Answer 33

1. AD 2. Variable, typically childhood 3. Severe neutropenia, cyclic neutropenia, neutropenic infections (bacterial, fungal), MDS/leukemia

Question 34

X-linked neutropenia: 1. Age of onset 2. Presentation

Answer 34

1. Childhood | 2. Gain-of-function mutation in Wiskott gene -> myeloid maturation arrest

Question 35

Schwachman-Diamond syndrome 1. Inheritance 2. Age of onset 3. Presentation

Answer 35

1. AR 2. 0-18y 3. Neutropenia, pancytopenia, exocrine pancreatic insufficiency, skeletal abnormalities

Question 36

Leukocyte adhesion deficiency (LAD) 1. Inheritance 2. Age of onset 3. Presentation

Answer 36

1. AR 2. Infancy 3. Delayed umbilical cord separation, omphalitis, gingivitis, periodontitis, bacterial and fungal mucous membrane infections without pus

Question 37

Complement defect infections

Answer 37

Recurrent sinopulmonary infections, bacteremia, and/or meningitis (mild to moderate severity) Encapsulated bacteria - S. pneumoniae, H. influenza type B, N. meningitidis Recurrent pyogenic infections when other components of immune system are normal

Question 38

Complement defect associated syndromes (2):

Answer 38

1. SLE | 2. atypical hemolytic uremic syndrome

Question 39

Folate metabolism Defects (3)

Answer 39

1. Hereditary folate malabsorption 2. Methylenetetrahydrofolate dehydrogenase (MTHFD1) Deficiency 3. Hyper IgE (Job's) Syndrome

Question 40

Hereditary folate malabsorption defect

Answer 40

Defect in proton-coupled folate transporter leading to decreased intestinal absorption of folate and folate intake through blood-brain-barrier

Question 41

Hereditary folate malabsorption presentation

Answer 41

Megaloblastic anemia Pancytopenia -> T-cell lymphocytopenia -> SCID-like infections (PJP most common) Also with hypogammaglobulinemia Other symptoms include diarrhea, oral mucositis, failure to thrive, developmental delay, seizures

Question 42

Hereditary folate malabsorption diagnosis

Answer 42

Serum and CSF folate concentrations | Can have normal serum folate but elevations in total homocysteine

Question 43

Hereditary folate malabsorption treatment

Answer 43

Folinic acid (NOT folic acid, which interferes with active folinic acid transport)

Question 44

Hyper IgE (Job's) Syndrome defect

Answer 44

AD mutation in STAT3

Question 45

Hyper IgE Presentation

Answer 45

Newborn eosinophilic pustulosis followed by eczematoid dermatitis Cold skin abscesses (without inflammatory reaction) Formation of pneumoatceles following lung infections Retained primary teeth, scholiosis, fractures under minimal trauma, joint laxity, increased nasal widgth

Question 46

Adult-onset (or diagnosis) immunodeficiency syndromes (5)

Answer 46

``` GATA2 Deficiency Familial HLH IgA deficiency CVID Complement defects? ```

Question 47

Adult-onset/diagnosis immunodeficiency-like syndromes (4)

Answer 47

Good's syndrome Atypical hemolytic uremic syndrome Pulmonary alveolar proteinosis Adult-onset susceptibility to mycobacteria

Question 48

Good's Syndrome: 1. Inheritance 2. Age onset 3. Manifestations

Answer 48

1. Unknown 2. 40-70 3. Hypogammaglobulinemia with thymoma, severe opportunistic infections (CMV, PJP)

Question 49

Atypical hemolytic uremic syndrome 1. Inheritance 2. Age onset 3. Manifestations

Answer 49

1. AD, AR, autoimmune 2. 10-60 3. Fever with hemolytic anemia, thrombocytopenia and renal failure

Question 50

Pulmonary alveolar proteinosis 1. Inheritance 2. Age onset 3. Manifestations

Answer 50

1. Autoimmune 2. 20-40 3. Antibodies to GM-CSF, cryptococcal meningitis, Nocardia, PAP

Question 51

Adult-onset susceptibilty to mycobacteria 1. Etiology 2. Age onset 3. Manifestations

Answer 51

1. Autoimmune, antibodies to IFN-gamma 2. 30-60 3. Infections with mycobacteria, fungi, salmonella, VZV

Question 52

T cell defects 1. Main issue 2. Age at presentation 3. Most common organisms 4. Most commonly affected organs

Answer 52

1. Cellular immunity 2. Infancy (<6 mo if classic) 3. Intracellular, viruses, fungi, protozoa (Herpesviridae, pneumocystis, candida, cryptococcus, histoplasma) 4. Systemic

Question 53

B cell defects 1. Main issue 2. Age at presentation 3. Most common organisms 4. Most commonly affected organs

Answer 53

1. Antibodies 2. 6-12 months (after waning of maternal Ab) 3. Encapsulated bacteria (staph, strep pneumo, H. flu) 4. Respiratory (sinus, pneumonias, GI/diarrhea)

Question 54

Phagocytic defects 1. Main issue 2. Age at presentation 3. Most common organisms 4. Most commonly affected organs

Answer 54

1. Dysfunctional phagocytosis 2. First 2 years of life 3. Catalase positive bacteria (staph, serratia, nocardia) and fungi (aspergillus) 4. Skin, GI, GU, dental

Question 55

Complement defects 1. Main issue 2. Age at presentation 3. Most common organisms 4. Most commonly affected organs

Answer 55

1. Opsonization, cell lysis 2. Childhood (opsonization) to adulthood (terminal complement) 3. Bacteria (Neisseria, streptococcus) 4. Central nervous system (meningitis)

Question 56

Disseminated infections with mycobacteria, TB, salmonella predisposition (3)

Answer 56

IL-12 deficiency (AR) IL-23 deficiency (AR) Interferon-gamma receptor deficiency (AR/AD)

Question 57

Familial candidiasis predisposition (1)

Answer 57

CARD9 deficiency (AR)

Question 58

Chronic mucocutaneous candidiasis (CMC) predisposition (2)

Answer 58

IL-17 deficiency (AR) - affects skin, scalp, mucosa, nails; +/- staph skin infections Autoimmune polyendocrine candidiasis ectodermal dystrophy (APECED) syndrome (AR/AD) - CMC, Addison Disease, hypoparathyroidism, metaphyseal dysplasia

Question 59

Predisposition to chronic cholangitis and hepatic cirrhosis due to cryptosporidium infection (1)

Answer 59

IL-21 receptor deficiency (AR)

Question 60

Predisposition to EBV (chronic viremia, EBV-lymphoproliferative disorder, dysgammaglobulinemia) (5)

Answer 60

``` ITK deficiency (AR) MAGT1 deficiency (XL) STK4 deficiency (AR) CD27 deficiency (AR) Coronin-1A deficiency (AR) ```

Question 61

Predisposition to HPV with disseminated wart-like papules with malignant potential

Answer 61

Epidermodysplasia veruciformis (AR)

Question 62

Predisposition to HPV with myelokathexis (retention of neutrophils in bone marrow), hypogammaglobulinemia and warts

Answer 62

CXCR4 deficiency (AD)

Question 63

DOCK-8 deficiency

Answer 63

``` (AR) Hyperimmunoglobulin E Eosinophilia Severe viral skin infections (HPV) Recurrent staph infections Lack of connective tissue or skeletal involvement ```

Question 64

Predisposition to herpes encephalitis

Answer 64

Toll-like receptor 3 deficiency (AD, incomplete penetrance)

Question 65

Predisposition to mucocutaneous HSV

Answer 65

Caspase 8 (AR)

Question 66

Diagnosis of complement deficiency

Answer 66

CH50

Question 67

PJP prophylaxis

Answer 67

All PID with low CD4 (SCID) or CD4 dysfunction (CD40L deficiency)

Question 68

Anticandidal prophylaxis

Answer 68

Severe T-cell defects (SCID)

Question 69

Anti-aspergillus prophylaxis

Answer 69

CGD | Prolonged, nonbenign neutropenia

Question 70

CGD prophylaxis

Answer 70

Aspergillus TMP-SMX Interferon-gamma