Primary Immunodeficiencies Flashcards
(146 cards)
1
Q
What is the gene mutated in Ataxia Telengiectasia
A
ATM
2
Q
What is the gene product mutated in AT? What is its role?
A
Ataxia telengiectasia mutated gene (ATM gene) encodes a PI3K-like serine/threonine protein kinase
Central role in activting apoptosis and cell responses to ds DNA breaks (facilitates cell cycle arrest and DNA repair)—> e.g. in response to radiation OR recomibination in lymphocytes, meiosis, telomere maintenance
3
Q
What is the complex that sense ds DNA breaks and recruits ATM gene?
A
MRN complex
-mutations in this complex can have AT-like disorder
4
Q
What are the cutaneous features of Ataxia telengiectasia?
A
-telengiectasias on lateral and medial bulbar conjuctivae as red symmetric horiontal streaks (around 3-6 years)
-telenegiectasias on ears, eyelids, malar prominences, antecubital/popliteal fossa and presternal area
(Less commmonly on dorsal hands, feet, jhard and soft palate)
(Non facial telengiectasias often are subtle, resembling fine petechiae)
- atrophic and sclerotic face (loss of subcutaneous fat)
- gray hairs in children and diffuse graying in adolescence
- persistent cutaneous granulomas, can ulcerate
- pigmentary mosaicism—>hyper or hypopigemnted macules, nevoid hyper or hypopigementation (likely due to chromosomal instability)
- facial papulosquamous rash
- poikiloderma
- hypertrichosis on arms
- warts
- acanthosis nigricans
5
Q
What is the first manifestation of AT?
A
Ataxia-appearing when they start to walk, but often not diagnosed until skin findigns around age 6
6
Q
Name 5 non cutaneous features of ataxia-telengiectasia syndrome
A
- Ataxia
- swaying of head and trunk - Immune deficiency/ frequent sinopulmonary infections
- Chromsomal instability with persistent dna damage after radiation
- Premature aging
- Progressive neurological deterioration
- choreoathetosis, dysarthria, oculomotor abnormalities, myoclonic jerks - Mask-like facies (progeric change)
- Glucose intolerance/insulin resistance
- Growth retardation
- Intellectual disabilit
- Hypogonadism
- Lymphoid neoplasia
- leukemia, lymphoma especially
7
Q
What is most common cause deathin AT?
A
Respiratory failure and bronchiectasis
8
Q
What do carriers of AT have an increase risk of?
A
Breast cancer and likelihood of death from cancer (stomach, cololon, lung, breast)
9
Q
Name 6 laboratory findings in AT
A
- DEcreased IgE, IgA, IgG (Ig2 and 4 esp),
- Low molecular weight IgM and increased IgM in some
- Elevated AFP and CEA
- Elevated liver enzymes
- Lymphopenia
- Decreased CD4+ T-cells, increased gamma-delta T cells
- Increased IL-8
10
Q
Name 4 differential diagnoses of AT?
A
- FRiedrichs ataxia-no telengiectasis
- Bloom-no neuro abnormalities but can present with CALMS, telengiectasias (facial, sometimes conjuctival), decreased IG levels, recurrent resp infections, heme maligancies
- FILS syndrome (facial dysmorphism, immunodeficiency,livedo, short stature, due to POLE-1 mutations —> can have telengiectasias or poikiloderma
- RIDDLE syndrome-radiosensitivity, immune deficiency, facial Dysmorphism, difficulty learning, abnormal motor control and short stature (also has to do with site of dsDNA break repair)
11
Q
What is the mode of transmission in AT?
A
AR
12
Q
What is the median lifespan of patients with AT?
A
25 years +
13
Q
Name 5 treatments for AT (not directed, supportive)
A
Abx, prophylaxis and IVIG
Sun protection
Physical therapy
Screening for malignancy
Chest physio. +- steroids for lungs
Antioxidants (alpha lipoic acid)
14
Q
Which interleuken response deficiency plays a role in chronic mucocutaneous candidiasis
A
IL-17
15
Q
Name 9 variants/subtypes of CMC?
A
- Non syndromic CMC
- APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome)
- CMC due to increased STAT-1 signalling
- CMC + suscpeibility to mycobacterial infections
- CARD9-associated CMC
- Decin-1 deficiency
- Candidal granuloma
8,. Late onset CMC - Familial chronic nail candidiasis
- CMC associated with other immune deficiency disorders (multipl
- CMC associated with metabolic disorders
16
Q
Which biologics through what mechanism can also cause recurrent candidiasis?
A
Ixekizumab
Secukinumab
(IL-17A=free floating cytokine)
Brodalumab (IL-17 RA=receptor A)
17
Q
What is the role of STAT-1 and STAT-3 in candida immunioty
A
JAK-STAT3 responds to Il-12/23 receptor activation —> upregulated retinoic acid receptor related orphan recptor (RORC) —> leads to IL-17A, IL-17F and Il-22 production and thus activated IL-17 receptor = somehow internally causes candidal death?
STAT-1 actually repressesIL-17 production
18
Q
What is the mode of transmission of APECED?
A
AR
19
Q
What is the gene mutated in APECED
A
AIRE gene
20
Q
What is APECED
A
Autoimmune polyendocrinop[athy-candidiasis-ectodermal dystrophy syndrome
21
Q
What are 6 clinical featuers of APECED
A
Mucocutaneous candidal-mean onset age 3
Candidal granulomas-face and scalp
Autoimmune endocrinopathies (can be teen or adult)
- hyperpara MC
- hyperadrenocorticisms
- hypogonadism
- thyroid
- t1DM
- hypopit
Cutaneous autoimmune d/o
- AA
- vitiligo
- urticarial eurption
- lupus like panniculitis
Other autoimmune:
- low B12 from pernicious anemia
- hepatitis
- pneumonitis
- sjogren like
Dental enamel hypoplasia, chronic diarrhea, keratoconjuctivitis, hyposplenism, htn, oral/esophageal SCC
Anti-type I interferon antibodies (antithyroglobulin, anitmicrosomal, antiparietal, antiadrenal antibodies, RF)
22
Q
What gene (s) is mutated in CMC disease? Transmission pattern?
A
IL17F= AD mutation (cytokine)
IL17RA or RC = AR mutation in receptor
TRAF3IP2 and ACT-2 = TRAF3 interacting protein 2 —> adaptor protein ACT1 intracellularly attached to IL17 receptor
23
Q
What are 4 clinical features CMC disease
A
ORal candidiasis 6 mo-2 years
Cutaneous and ungual candidiasis common
NO endocrinopathies
Cutaneous staph infections (IL17RA or TRAF3IP2)
24
Q
Name 10 clinical features CMC due to increased STAT1 signalling (including gene and transmission)
A
AD-gain of function STAT-1 (Stat 1 inhibits IL-17 production)
Mucocutaneous cndida around 1 year-oropharynx>nails > skin (50%)
Dermtophyte infections skin and or nails
Cutaneous AI d/o vitiligo, AA
Autoimmunity:
- thyroid
- t1dM
- cytopenias
- celiac
- SLE
Other infections variable-staph, bacterial PNA, viral, mycobacterial
Aneurysms
Mucocutaneous SCC
25
What mutation results in CMC + mycobacterial infection susceptibility
RORC (retinoic acid receptor related orhpahnr eceptor C gene)
-this protein product responds to STAT3 and results in Il-17 production
Functionally, similar to STAT 1 activating mutations
End result decreased IL-17 and interferon-gamma production
AR
26
What is 2 manfiestaitons CARD-9 mutation
- chronic oral and vulvovaginal canadidias
- dermatophytosis
- invasive funcal infections esp brain in 2nd year of life
27
Name 5 immunodeficiencies that can present with chronic candidiasis
HyperIGE syndromes-STAT3 or DOCK8 deficiencies
SCID
DiGeorge
KID-syndrome (keratosis, ichtyosis, deafness)
AD hypohidrotic ectoderal dysplasia with immunodeficiency
28
NAme 3 metabolic syndromes with chronic candidiasis
Multiple carboxylase deficiency
Acrodermatitis enteropathica
Ectodermal dysplasia-ectrodacyly clefintgsybdrome
29
What is the AIRE gene and what is it responsible for
Autoimmune regulator gene
- TF responsible for expression self antigens in thymus allowing for peripheral tolerance to be developed
- mutation causes failure to delete autoreactive T-cells
- 17-pathwayinvolved due to neutralizing antibodies targetting TH17 cytokines
30
What is the MC causes of CMC?
STAT-1 heterozygous gain of function mutations
-increasedINF and decreased IL-17
=infections, autoimmunity, aneutrysms
31
What is mechanism of dectin-1 deficiency in CMC
AR form
Truncated dectin 1
Chronic recurrent vulvovaginal candida and onychomycosis
DEctin 1 is pattern-recognition recptor binding to B-glucan in candida cell wall —> activated TH17 response
32
DDX of CMC
HIV
Normal young children
*other immune deficiency or metabolic d/o
33
What is clinical features of CMC
Ranges from recurrent treatment resistant thrush
Few erythematous scaly plaques and dystrophic nails to severe, genrezied,c rusted eurhtmeatous plaques
NMails can be thickened with brittle discoloration and paronychia
34
What is 1 systemic medication that can be used in gain of function sTAT-1 mutations?
STAT-1 inhibitors such as ruxolibtinib
-can help withAI and infections
35
What is the gene mutationin Cartilage-Hair-HYpoplasia syndrome?
RMRP
36
What are 4 clinical manifestations, other than impaired immune sytem, of cHH?
Fine, spare, hypopigmented hair
Soft doughy skin
Short limbed dwarfism due to metaphyseal dysotsotsis
Ligamgental laxity
Others:
- Cytopenias from bone marrow hypoplasia or autoimmunity
- Hirschprungs
- some can present as SCID -erythroderma, eos, diarrhea, HPS, lymphadonpathy
- hodkgkins and BCC
37
What type of immune deficiency is seen in CHH
Impaired T-cell mediated
1/3 have abnormal humoral iwth IgA or IgG deficiency too
38
What type of infections seen in CHH
Viral-HSV and varicella severely
Resp tract/bronchiecasis with humoral impoairment
39
Mode transmission Chediak-Higashi
AR
40
What is gene affected inChediak Higashi?
LYST=lysosomal trafficking regulator gene —> disorder of vesicle trafficking
41
What is the characteristic feature seenonCBC in Chediak Higashi
Giant organelles-melanosomes, leukocyte granules, platelet dense granules
-result of dysregulateed fission/fusion of lysosome related organelles (mealonosomes, platelet dense granukels, leukocytes cytolytic granules)-these granules cant migrate or expel their cell-killing granules
42
What are the cutaneous features of Chediak Higashi?
Diffuse pigmentary dilutionof skin, hairs, eyes
-if dark constitutive pigemnts—> bronze to slate-gray hyperpigmentation in sun exposed yes with guttate hypopigmented macules
Characteristics silvery metallic sheenof the hair can.be seen
Eyes—> ocular pigment may be disrupted-photophobia, nystagmus, strabismus but acuit is normal
Think of as OCA!
43
What are the non cutaneous manifestations of Chediak Higashi
Infections- SKIN and Resp infections -staph, strep pyo and strep pneumo
Skin= often superficial pyodermas (but often PG, gingiviate and ulceration can occur)
Bleeding diathesis-bruising,petechiae, epistaxis
Lymphoprolfierative accelerated phase —> pancytopenia and lymphohistiocytic infiltrated liver,spleen, lymph nodes, mucodsa= HLH essentially (can be from EBV)—> often leads to death by age 10 due to infectionor hemmorhage unless stem cell
IF they survive—> neurological deterioration(abnormal gait, paresthesias, developmental dely, parkinsonism, dementia, neuropathies)—> can occur in adult patients post stem cell transplant
44
What can you see on hair of chediak higashi microscopically
Clumps of melanin (giant melanosomes in melanocytes on bx)
45
What is on ddx of CHS
Griscelli-defective attachment of organelles to actin cytoskeleton —> doesnt affect leukocytes though (but still get plts and melanocyte affected with bleeding and dilution. Get silver hair and pigment dilution. LOOK AT NEUTROPHILS! Alot milder.
Gene= MYO5A, RAB27A or MLPH
Hermansky Pudlak-can have infections, bleeding, neuro and pigment dilution but NOT silvery hai
Tricho-hepato-enteric syndrome=diarreha in infancy, pigment dilution, plt abnormalities but also brittel hair, trichrrheix nodosa, diarrea, facial dysmorpghism, liver disease, cardaic defects
46
Treatment for Chediak-Higashi syndrome
HSCT
-often followign chemotherapy to abrogate the lymphoproliferative accelerted phase
DOES NOT HALT NEUROLOGICAL DEGENRATION!
Abx
47
What is the most common hereditary complement d/o?
Deficiency C2
48
What pathogens are those with complement deficiencies particularly suscpetible to?
Encapsulated bacteria
- Step pneumoa
- haemophilus influenzae
- strep pyogenes
If membrane attack component missing, high risk neisseria gonaorrhea
49
What is the trigger for each of the 3 complement pathways?
Classical-Ab-Ag complexes
(C1, C4, C2)
Mannose binding lectin (MBL) binds to mannan on pathogen cell surface
(C4, C2)
Alternative=binds direct to pathogen surface
(C3, B, D)n
50
In general what are the 2 outcomes/disease types from complement deficiency
Immune deficiency
| Autoimmunity-SLE, DM, HUS, HAE
51
Which complements are highest risk for SLE?
C1, C4, C2= classical pathway
C1q is highest risk >90%
52
Which complements lead to increased risk neisseruia?
MAC comlpex C5-9 -lower risk death
| Properidin and dactor D of alternative pathway -higher risk death
53
What are the featuers of a C2-deficiency related SLE vs. Classical SLE
Childhood onset
PPK
Mild or absent renal disease
LEss severe disease overall
Absent or low titre ANA and anti dsDNA
Extensive treatment resistant skin lesions
Pyogenic infections with encapsulated bacteria
54
What blood test to screen for complement deficiencies
CH50-total complement -low or undetectable (other than HAE)
55
What diseases are associated with anti-c1q ab’s?
SLE
| Urticarial vasculitis -hypocomplementemic
56
What is the Leiner phenotype?
Exfoliative dermatitis (Erythroderma dequamativum)
FTT
Diarrhea
REcurrent infections
57
What is the Leiner phenotype seen in?
C3 or C5 deficiency
X-linked agammaglobulinemia
Hyper IgE syndrome
SCID
58
Which complement deficiencies need meningococcal vaccination
C3, C5-9, properdin, factor D, factor H
59
What is the inheritance mechanism of CGD (Chronic Granulomatous Disease)
X-linked recessive 75%
| AR 25%
60
What is the problem in CGD?
NADPH oxidase can’t generate ROS to cause the respiratory burst after phagocytosis. NADPH oxidase also regulates neutrphil apoptosis and prevents tissue damage
= unable to kill intracellular organisms
= excess inflammation
61
What is the most common cause cutaneous infections, abscesses and suppurative adenitis in cGD?
Staph aureus
62
NAme5 common organisms cause disease in cGD
Staph aureus
Nocardia
Burkholderia cepacia
Klebsiella
Serratia marcescens
Candida
Aspergills
Incommonly mycobacteria
63
Name the cutaneous manifestations of CGD
1. Staph infections skin and nose
- start neonatal
- progress to purulent dermatitis with regional LN
2. Ecthyma gangrenosum
3. Cutaneous abscesses-staph and serratia
4. Non infectious purulent inflammaotry reactions at minor trauma or regional lymph node drainage
5. Sterile cutaneous granuloma
6. Acute or chonic cutanoues lupus-like lesions, often discoid
7. Sweets-like
8. , oral, perianal ulcers
9. Seb derm scalp
64
What can female carriers of X-linked CGD sometimes present with?
```
Discoid lesions
Lymphocytic infiltrate of jessner
Photosenstiviity
Raynauds
Severe apthougs stomatitis
Granulomatous cheilitis
```
65
What are the most common sites affected in CGD
Skin
Perinala
Lymph nodes
Lungs
66
Name 10 non cutaneous features of CGD
Lymphadenopathy and suppurative lymphadenitis (often leads to abscess and fistula
Granulomas of lungs, liver, spleen , GI and GU more common than SKIN!
```
Hepatosplenomegaly
Pneumonia
Underweight
Short stature
PErsistent diarrhea/abdo pain
Hepatic/perihepatic abscess
Pleuritis/empyeme
Osteomyelitis
{Perianal abscess)
Septicemia/meningitis
Onset by age 1
Ulcerative stomatitic
Facial orficial dermatitis
```
67
What are the 4 main features CGD
Skin abscesses
PNA
LAD
Hepatosplenomegaly
68
What do biopsies show of granulomas in cGD?
Histiocytic infiltrate with foreign body giant cells, neutrophils and ncerosis
69
What is the screeing test for CGD
Nitroblue tetrazolium (NBT) reduction assay
-yellow—> blue when reduced
In CGD, only 5-10% leukocytes can reduce from yellow-> blue (vs. 80% in normal people, 50% in carriers)
70
Name 7 treatments (other than acute abx for infection) for CGD
1. PPx with septra*
2. Ppx with itraconazole *
3. Interferon-gamma (augments oxidant independent antimicrobial pathway)
4. Granulocyte transfusions acutely
5. Short courses prednisone if obstructive granulomas (e.g. GI, GU, bronchopulmonary)
6. AZA, HCQ, anakinra, pioglitozone,—> inflammatory manfiestations
7. HSCT-potentially curative
71
NAme the 4 main characteristics of hyperigE/Job syndrome
Skin infection
Sinopulmonary infection
Early onset eczematous dermatitis
Elevated IgE
72
What is Job syndrome?
Subgroup of AD HIE with females, fair skin red hair and hyperextensible joints + typical HIES features
73
What is mode of inheritance HIES?
AD-HIES- classive form with vaiarbale expressivity
AR-HIES-broader spectrum infectious complications
74
What is gene mutated in HIE-AD?
STAT3
75
What is the role of STAT-3
Il-6, 21, 23 are STAT-3 dependent cytokines that upon binding, activate stat-3 and contribute to IL-17 producing CD4+ T cells= infections
Also STAT-3 critical for IL-6 (acute phase reactant) and Il-10 (anti inflammatory cytokine)
—>. Explains “cold” abscesses and destructive inflammation
LAck of IL-10 —> may contribute to atopic derm and high IGE
STAT-3 down regulates osteoclasts—> OSteopenia
76
What is the gene mutated in AR-HIES
DOCK-8–> mutation/deficiency in DOCK8 causes increase in TH2 cells and pruritogen IL-31, but decreased TH1/TH17
DOCK-8 is part of complex that interacts with Wiskott-Aldrich protein (WASp) that links T-cell receptors to actin cytoskeleton
77
There are 2 new variants of HIES, what are the genes mutated and name 1 clinical feature of each
1. TYK2 mutation, AR, atypical mycobacterial infections
| 2. PGM3 mutation, AR, LCV and neuro abnormalities (low IQ, ataxia
78
NAme 5 cutaneous features AD-HIES
Non infectious, folliculocentric papulopustular eruption on fce, neck, scalp, axillae, diaper area
Chronic candidiasis (mucosa, nails, periungal)
Cutaneous staph infections
COLD abscesses (NOT RED OR TENDER), often large, afebrile, typically staph, often on scalp, neck, periorbital, axilla, groin
Eczema-often clears in adolescene, often do not have atopic features otherwise)
Progressive facial coarsening with thickened doughy skin, large follicular ostia, broad nasal bidge, wide fleshy nasal tip, pitted scarring, deep set eyes, primnent forehead, irreglarly proportioned cheeks and jaw
scoliosis, high arched palate
79
Name 8 non cutaneous HIE features
1. Recurrent bronchitits and PNA, can get pneumatocele infected with aspergillus, PJP
2. Sinus infections (other viseral infections unusual)
3. OSteopenia -increased fractures
4. Scoliosis, joint hy[erextensiviility
5. High arched palate, retention primary teeth
6. Brain malgormation, lacunar infarcts, focal hyperintensities
7. Coronary artery aneurysms
8. Non hodgkin B cell lymphoma-higher risk
80
Describe 6 similarities and 6 differences from AD vs. AR HIE
AR also has:
- elevated IgE
- peripheal eos
- eczema
- recurrent staph infections
- resp infections
- mucocutaneous candidiasis
Does not have:
-skeletal or dental abnormalities, facial coarsening, pneumatocels
New features:
- warts, molluscum, HSV and VZV OI’s
- atopy (asthma, food allergy, SCC, cerebral vasculitis, lymohoma
*Most pateints die by 20 from infection, malignancy or CNS disease
81
What does the infantile papulopustular eruption of HIES show?
Eosinophilic folliculitis, eosinophilic spong, superficial and deep perivascular infiltrate with many EOS
82
Name 4 lab features of HIES-AD? AR?
- Elevated IGE >2000 IU/ml
- eosinophilia
- abnormal anergy test/cell mediated immunity
- normal Ig levels otherwise
- hgih anti-staph and anti-candidal IgE
In AR:
- combined immunodeficiency
- lymphopenia with low CD4+ T cells,
- low IgM, variable IGG, elevated IgE,
83
How do you make a definitive, probable and possible diagnosis AD-HIES
Possible: score 30+ and IgE >1000
Probable: Above + lack Th17 OR FDR with it
Definitive: Above + dominant negative heterozygous STAT3 mutation
84
What 5 characteristics are in the scoring system for HIE
```
Pneumonias
Characteristic facies
High arched palate
Neonatal papulopustular eruption
Pathological bone fractures
```
85
Name 3 ddx for eczema, staph infections and high IgE
HIES
Wiskott Aldrich--> PLT abn
Eczema--> no osteopenia, cold absences, characteristic facies
Prolidase deficiency
86
What is the genetic defect?
What is the clinical presentation?
What doe labs show (B cell, T-cells, Igs)
Skin manifestations
For: X-linked agammaglobulinemia
BTK gene (Bruton tyrosine kinase)
First few years of life with staph, strep, pseudomonas, pneumonoccus enteroviruses*, hep B, rotavirus --> PNA, rhinitis, sinusitis, otitis, diarrhea, meningitis
Boys!
Low or absent B-cells, absent or severely low in all Ig's
Skin:
- infections (furuncle, carbuncle, ecthyma gangrenosum)
- papular dermatitis
- eczematous dermatitis
- sterile granlomas
- dermatomyositis like disorder with chronic echoviral meningitis
87
2 other transmission modes of agammaglobulinemia?
AD-even less
AR-10%
X-Linked recessive most common-90%
88
What is the most common immunoglobulin deficiency? How does it present? What is it associated with, name 4?
Selective IgA deficiency
-asbent IgA or very low after age 4
Most asymptomatic, some get sinopulmonary and GI
Associated with
1) ATOPY
2) AI diseases-lupus, celiac, IBD, ITP
3) increased risk heme and GI malignancies
4) anaphylaxis to blood products
89
What is CVID, generally speaking, a deficiency of>?
Grab bag immune deficiencies with primarily humoral system impaired
it is COMMON: 1 in 5000
and VARIABLE: wide range phenotypes
```
Diagnostic criteria:
Need at least 2 Ig's low
Exclusion of other PIDs
Diagnosed after 2
Documented inability to respond to antigens eg. vaccines,
```
90
Average age onset of CVID
30
91
Name 4 non infectious complications CVID
1. Granulomas-lymph nodes, lungs, spleen, GI tract
2. AI disease-ITP, hemolytic anemia,
3. Malignancy risk-lymphoma and gastric cancer
4. GI- IBD like presentation, chronic diarrhea, protein losing enteropathy, eight loss
92
Name.6 cutaneous features CVID
1. AI-AA, vitiligo, vasculitis
2. Pyoderma's and cutaneous infections
3. mucocutaneous candidiasis
4. sterile grnaulomas
5. CD8 lymphocytic infiltrate in the skin
6. eczematous dermatitis
7. Clinical manifestations of LRBA deficiency variable; include an IPEX-like presentation (see text) and autoimmune lymphoproliferative syndrome
93
How does selective IgM deficiency present?
- recurrent bacterial infections
- autoimmune disease
- warts
- dermatitis
- SLE
94
How do the hyper-IgM syndromes present in terms of infections
Recurrent sinopulmonary and gastrointestinal infections
with pyogenic bacteria and opportunistic organisms
Neutropenia
Small lymph nodes
95
What is most common transmission pattern hyper IgM syndrome
XLR mostly
| AR exists
96
Name 4 skin findings hyper IgM
```
Warts
Oral and perianal ulcers
Pyoderma's
Non infectious granulomas
Autoimmune diseases like SLE
```
97
What is IPEX syndrome
Immune deficiency
Polyendocrinopathy
Enteropathy
X-linked
IgE and eosinophilia!
Eczema
98
What is the genetic mutation and mode of transmission of IPEX
FOXP3--> abnormal development Tregs
| X-linked
99
How does IPEX present
Enteropathy- autoimmune, diarrhea in early infancy
Polyendocrinopathy- autoimmune endocrinopathies, e.g. early-onset type 1 diabetes mellitus, thyroiditis, cytopenias.
Eczema, staph superinfection, sepsis,
Cutaneous AI: psoriasiform dermatitis, cheilitis, nail dystrophy, alopecia areata, chronic urticaria, and bullous pemphigoid
THINK DIARRHEA, DIABETES, ECZEMA
100
What is the primary issue in LAD deficiency?
Defect in BLANK that prevents lymphocytes, monocytes and neutrophils from being able to adhere to vascular endothelium and migrate to tissue injury
101
What is the most common manifestation of LAD?
Gingivitis with periodontitis
102
Name 5 non gingival manifestations of LAD
1- recurrent otitis media, pneumonia,
2- cutaneous infections caused by pyogenic bacteria, presenting as cellulitis and necrotic abscesses with relatively little production of purulent material, typically located in the perianal area or on the face.
3-poor wound healing, large ulcer formation at site of injury often--> burnt out PG
4-paper thin atrophic scars
5- delayed separation of umbilical stump
103
Life expectancy of LAD patients
<5 years if severe
| Moderate-30 years
104
What does LAD show on bloodwork?
marked peripheral blood neutrophilia (5–20 times normal levels
105
What does LAD show on bloodwork?
marked peripheral blood neutrophilia (5–20 times normal levels
106
Name 3 causes of SCID (there are many)
1- γ (γ c ) chain of the IL-2 receptor (x-linked)--> 40% SCID is boys
2- adenosine deaminase deficiency-5-15%
3- IL-7 receptor or JAK3-5-15%
107
Name 5 possible cutaneous features seen in SCID
- morbilliform eruption or widespread seb-derm like eruption representing maternofetal GVHD
- lichen planus, acrodermatitis enteropathica, Langerhans cell histiocytosis, ichthyosiform erythroderma, and systemic sclerosis.
108
Name the triad of SCID
FTT
Diarrhea
Recurrent infections
First 3-6 mo life
109
3 most common causes cutaneous infections in SCID
C. albicans, S. aureus , and Str. pyogenes.
110
What is OMENN syndrome and how does it present
RAG1 and RAG2 deficiency --> defect in pre T cell receptors +- Cell receptors
Absent T and B cells, + NK cells
SCID plus:
- exfoliative erythroderma
- elevated igE
- eosinophilia
- leukocytosis
- diffuse alopecia
- LAN and HPS
- chronic diarrhea
111
What does CBC show for SCID
T- B- NK-
112
What derm malignancy increased risk in SCID
DFSP
113
How to tell SCID vs. HIV
HIV has normal or elevated immunoglobulins
relative decrease in CD4
114
What is number one treatment for SCID?
Stem cell transplant
115
Mode of transmission of Wiskott Aldrich
X-linked recessive
116
What is triad of Wiskott Aldrich
Eczema
Bleeding diathesis with PLT abnormalities
Recurrent sinopulmonary infections and pyogenic infections
117
What is most common feature in WA?
Platelet abnormalities
118
What is the genetic cause of Wiskott Aldrich? What is the pathophys
Loss of function mutation in WAS gene--> codes for WAS protein which is pro-platelet formation as well as T-cell activation, including Tregs
Both T and B cells are affected
119
What are 3 treatments for ADA-deficiency SCID
Stem cell transplant
Enzyme replacement with ADA
Gene therapy--> via retroviral-mediated ex vivo gene transfer into CD34 + cells
120
Most common form SCID and gene mutated? What cells are affected?
X-linked SCID
Common gamma receptor of IL-2
No T or NK cells, B cells unaffected
121
Name 5 clinical features of WA
1. Early onset platelet problems--> petechiae ecchymoses of the skin and oral mucosa, spontaneous bleeding from the oral cavity, epistaxis, hematemesis, melena, and hematuria
2. Eczema- secondary infection common
3. Infections after 3-6 mo life--> otitis externa and media, pneumonia, sinusitis, conjunctivitis, furunculosis, meningitis, and septicemia. Encapsulated bacteria such as Str. pneumoniae, H. influenza , and Neisseria meningitides are the predominant organisms.
4. Ai diseases--> CSVV, arthritis, autoimmune cytopenias, IBD
5. Increased risk lymphoma-non Hodgkins most common, only if no HSCT
6. IgE mediated (urticaria, atopy, food allergy, etc.) increased frequency
122
Name 5 lab findings in WA
1. Persistent thrombocytopenia (<70) and low PLT volume
2. Eosinophilia
3. Lymphopenia
4. Low IgG and IgM, with elevated IgA, D and E
5. Delayed-type hypersensitivity skin test reactions are usually absent
6. Antibody responses to polysaccharide antigen diminished or depressed
123
Name 9 conditions that are primary immunodeficiencies that can present with dermatitis
```
Hyper IgE ++
Ataxia-Telengiectasia
Wiskott Aldirch ++
CVID
SCID
CGD
X-linked agammoglobulinemia
DiGeorge
IgA or IgM deficiency
WHIM syndrome
IPEX
```
124
What is the gene encoding IgA deficiency?
TNFRSF13B encodes -> TACI
DEfect în converting B-cell to IgA producing plasma cells
125
What is the most common primary immunodeficiency? Second most common
IgA
| then CVID
126
What is the syndrome?
- low immunoglobulins
- warts
- recurrent sinopulmonary infections
- autoimmune diseases like AA, vitiligo
- granulomas
CVID
127
What is the syndrome?
- Oral and perianal ulcerations
- therapy resistant warts
- diarrhea, respiratory infections, otitis
- abnormal CD40 ligand on T cells
HyperIgM syndrome
128
What is the syndrome?
- unusual susceptibility to enteroviruses that can result in death from encephalitis
- boys with atopic derm, urticaria, vasculitis
X-linked hypogammaglobulinemia
129
What is the syndrome?
- eczema
- warts
- increased susceptibility to meningococcemia, H flu, pneumococci
Isolated IgM deficiecny
130
What is the syndrome?
- young infant
- candida, diarrhea, pneumonia
SCID
131
What is the syndrome?
- alopecia
- erythroderma
- diarrhea, FTT, pneumonia
OMENN syndrome
| -RAG1 or 2
132
Melena
Eczema
Recurrent infections
Wiskott Aldrich
133
```
Eczema herpeticum
Molluscum
Warts
SCC
Autoimmune disease
```
AR HIES
134
Eczematous dermatitis
Cold abscesses
Double row of teeth
Candidiasis
AD-HIES
Also:
- itchyosis, urticaria, asthma
- ppk sometimes
- hands and feet resemble ACD
- coarse facies, high arched palate, scoliosis
135
Genodermatoses with extensive warts-name 10
```
EDV
SCID
CVID
HyperIgM
IgM deficiency
WHIM
Wiskott Aldrich
HIES, AR specifically
Netheron
Costello
GATA-2
```
136
NAme 6 genoderms with elevated IgE
```
Wiskott Aldrich
Hyper IgE
Omenn
DiGeorge
Netherton
IRAK-4 deficiency
```
137
Name the organisms seen in CGD?
SPACE in the SKY
All catalase +--> need NADPH oxidase in order to generate ROS to cause respiratory burst to kill catalase + organisms intracellular after phagocytosis
```
Staph, Serratia
Pseudomonas
Aspergillus
Candida
Enterobacter
```
Shigella, Salmonella
Klebsiella
Yersinia
138
```
Osteomyelitis with serratia marcescens
Hepatosplenomegaly with granulomas
PNA
Recurrent pyoderma
Diarrhea
```
CGD
139
What 2 types bugs seen in CGD?
BACTERIA
and
FUNGUS
Do to these being killed intracellularly by respiratory burst
140
Gingivitis and periodontotitis
| Delayed separation of umbilical cord and stump
LAD
Also: pyoderma like necrotic ulcers
Peripheral leukocytosis
141
What is Leiner's disease
C5 gene mutation- C5 complement deficiency
```
DISC:
Diarrhea
Infections
Seb derm
Complement 5 deficiency
```
Severe seb derm, often erythrodermic
Recurrent infections, FTT, diarrhea
Hereditary deficiency of any of the terminal complement components C5-C9 results in susceptibility to meningococcal meningitis
142
What is GATA2 deficiency
AD
```
5 conditions overlapping:
MonoMAC
DCML Deficiency
Emberger Syndrome
( have skin findings)
```
Familial Myelodysplastic Syndrome has few skin manifestations
WILD Syndrome
143
What is WILD syndrome
Warts (disseminated)
Immune deficiency
Lymphedema
anogenital DYPSPLASIA
144
Name 4 features of GATA 2 deficiency
- cytopenias low dendrititi cells, monocytes, B cellsNK cells
- atypical mycobacterial
- dissemeninated HPV, also molluscum
- Pulm arterialn hypertension
- erythema nodosum in 1/3
- lymphedema
- myelodysplasia or AML in 70%
145
What is WHIM syndrome
Autosomal dominant gain of function mutation inf CXCR4
Warts
HYpogammaglobulinemia
Infections-cellulitis, pyoderma,
Myelokathesis =inability PNM to leave bone marrow=neutropenia
146
Diabetes
Diarrhea
eczema
Candida
IPEX syndrome--> immune dysregulation polyendocrinopathy enteropathy, X-linked
