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MyDermatology-Bolognia > Primary Immunodeficiencies > Flashcards

Primary Immunodeficiencies Flashcards

1
Q

What is the gene mutated in Ataxia Telengiectasia

A

ATM

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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

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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

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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
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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

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6
Q

Name 5 non cutaneous features of ataxia-telengiectasia syndrome

A
  1. Ataxia
    - swaying of head and trunk
  2. Immune deficiency/ frequent sinopulmonary infections
  3. Chromsomal instability with persistent dna damage after radiation
  4. Premature aging
  5. Progressive neurological deterioration
    - choreoathetosis, dysarthria, oculomotor abnormalities, myoclonic jerks
  6. Mask-like facies (progeric change)
  7. Glucose intolerance/insulin resistance
  8. Growth retardation
  9. Intellectual disabilit
  10. Hypogonadism
  11. Lymphoid neoplasia
    - leukemia, lymphoma especially
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7
Q

What is most common cause deathin AT?

A

Respiratory failure and bronchiectasis

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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)

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9
Q

Name 6 laboratory findings in AT

A
  1. DEcreased IgE, IgA, IgG (Ig2 and 4 esp),
  2. Low molecular weight IgM and increased IgM in some
  3. Elevated AFP and CEA
  4. Elevated liver enzymes
  5. Lymphopenia
  6. Decreased CD4+ T-cells, increased gamma-delta T cells
  7. Increased IL-8
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10
Q

Name 4 differential diagnoses of AT?

A
  1. FRiedrichs ataxia-no telengiectasis
  2. Bloom-no neuro abnormalities but can present with CALMS, telengiectasias (facial, sometimes conjuctival), decreased IG levels, recurrent resp infections, heme maligancies
  3. FILS syndrome (facial dysmorphism, immunodeficiency,livedo, short stature, due to POLE-1 mutations —> can have telengiectasias or poikiloderma
  4. 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)
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11
Q

What is the mode of transmission in AT?

A

AR

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12
Q

What is the median lifespan of patients with AT?

A

25 years +

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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)

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14
Q

Which interleuken response deficiency plays a role in chronic mucocutaneous candidiasis

A

IL-17

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15
Q

Name 9 variants/subtypes of CMC?

A
  1. Non syndromic CMC
  2. APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome)
  3. CMC due to increased STAT-1 signalling
  4. CMC + suscpeibility to mycobacterial infections
  5. CARD9-associated CMC
  6. Decin-1 deficiency
  7. Candidal granuloma
    8,. Late onset CMC
  8. Familial chronic nail candidiasis
  9. CMC associated with other immune deficiency disorders (multipl
  10. CMC associated with metabolic disorders
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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)

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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

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18
Q

What is the mode of transmission of APECED?

A

AR

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19
Q

What is the gene mutated in APECED

A

AIRE gene

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20
Q

What is APECED

A

Autoimmune polyendocrinop[athy-candidiasis-ectodermal dystrophy syndrome

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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)

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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

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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)

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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

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25
Q

What mutation results in CMC + mycobacterial infection susceptibility

A

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

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26
Q

What is 2 manfiestaitons CARD-9 mutation

A
  • chronic oral and vulvovaginal canadidias
  • dermatophytosis
  • invasive funcal infections esp brain in 2nd year of life
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27
Q

Name 5 immunodeficiencies that can present with chronic candidiasis

A

HyperIGE syndromes-STAT3 or DOCK8 deficiencies

SCID

DiGeorge

KID-syndrome (keratosis, ichtyosis, deafness)

AD hypohidrotic ectoderal dysplasia with immunodeficiency

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28
Q

NAme 3 metabolic syndromes with chronic candidiasis

A

Multiple carboxylase deficiency

Acrodermatitis enteropathica

Ectodermal dysplasia-ectrodacyly clefintgsybdrome

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29
Q

What is the AIRE gene and what is it responsible for

A

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
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30
Q

What is the MC causes of CMC?

A

STAT-1 heterozygous gain of function mutations

-increasedINF and decreased IL-17

=infections, autoimmunity, aneutrysms

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31
Q

What is mechanism of dectin-1 deficiency in CMC

A

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

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32
Q

DDX of CMC

A

HIV

Normal young children

*other immune deficiency or metabolic d/o

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33
Q

What is clinical features of CMC

A

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

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34
Q

What is 1 systemic medication that can be used in gain of function sTAT-1 mutations?

A

STAT-1 inhibitors such as ruxolibtinib

-can help withAI and infections

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35
Q

What is the gene mutationin Cartilage-Hair-HYpoplasia syndrome?

A

RMRP

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36
Q

What are 4 clinical manifestations, other than impaired immune sytem, of cHH?

A

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
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37
Q

What type of immune deficiency is seen in CHH

A

Impaired T-cell mediated

1/3 have abnormal humoral iwth IgA or IgG deficiency too

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38
Q

What type of infections seen in CHH

A

Viral-HSV and varicella severely

Resp tract/bronchiecasis with humoral impoairment

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39
Q

Mode transmission Chediak-Higashi

A

AR

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40
Q

What is gene affected inChediak Higashi?

A

LYST=lysosomal trafficking regulator gene —> disorder of vesicle trafficking

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41
Q

What is the characteristic feature seenonCBC in Chediak Higashi

A

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

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42
Q

What are the cutaneous features of Chediak Higashi?

A

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!

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43
Q

What are the non cutaneous manifestations of Chediak Higashi

A

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

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44
Q

What can you see on hair of chediak higashi microscopically

A

Clumps of melanin (giant melanosomes in melanocytes on bx)

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45
Q

What is on ddx of CHS

A

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

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46
Q

Treatment for Chediak-Higashi syndrome

A

HSCT

-often followign chemotherapy to abrogate the lymphoproliferative accelerted phase

DOES NOT HALT NEUROLOGICAL DEGENRATION!

Abx

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47
Q

What is the most common hereditary complement d/o?

A

Deficiency C2

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48
Q

What pathogens are those with complement deficiencies particularly suscpetible to?

A

Encapsulated bacteria

  • Step pneumoa
  • haemophilus influenzae
  • strep pyogenes

If membrane attack component missing, high risk neisseria gonaorrhea

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49
Q

What is the trigger for each of the 3 complement pathways?

A

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

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50
Q

In general what are the 2 outcomes/disease types from complement deficiency

A

Immune deficiency

Autoimmunity-SLE, DM, HUS, HAE

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51
Q

Which complements are highest risk for SLE?

A

C1, C4, C2= classical pathway

C1q is highest risk >90%

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52
Q

Which complements lead to increased risk neisseruia?

A

MAC comlpex C5-9 -lower risk death

Properidin and dactor D of alternative pathway -higher risk death

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53
Q

What are the featuers of a C2-deficiency related SLE vs. Classical SLE

A

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

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54
Q

What blood test to screen for complement deficiencies

A

CH50-total complement -low or undetectable (other than HAE)

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55
Q

What diseases are associated with anti-c1q ab’s?

A

SLE

Urticarial vasculitis -hypocomplementemic

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56
Q

What is the Leiner phenotype?

A

Exfoliative dermatitis (Erythroderma dequamativum)
FTT
Diarrhea
REcurrent infections

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57
Q

What is the Leiner phenotype seen in?

A

C3 or C5 deficiency
X-linked agammaglobulinemia
Hyper IgE syndrome
SCID

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58
Q

Which complement deficiencies need meningococcal vaccination

A

C3, C5-9, properdin, factor D, factor H

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59
Q

What is the inheritance mechanism of CGD (Chronic Granulomatous Disease)

A

X-linked recessive 75%

AR 25%

60
Q

What is the problem in CGD?

A

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
Q

What is the most common cause cutaneous infections, abscesses and suppurative adenitis in cGD?

A

Staph aureus

62
Q

NAme5 common organisms cause disease in cGD

A

Staph aureus
Nocardia

Burkholderia cepacia
Klebsiella
Serratia marcescens

Candida
Aspergills

Incommonly mycobacteria

63
Q

Name the cutaneous manifestations of CGD

A
  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
Q

What can female carriers of X-linked CGD sometimes present with?

A 
Discoid lesions
Lymphocytic infiltrate of jessner
Photosenstiviity
Raynauds
Severe apthougs stomatitis
Granulomatous cheilitis
65
Q

What are the most common sites affected in CGD

A

Skin
Perinala
Lymph nodes
Lungs

66
Q

Name 10 non cutaneous features of CGD

A

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
Q

What are the 4 main features CGD

A

Skin abscesses
PNA
LAD
Hepatosplenomegaly

68
Q

What do biopsies show of granulomas in cGD?

A

Histiocytic infiltrate with foreign body giant cells, neutrophils and ncerosis

69
Q

What is the screeing test for CGD

A

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
Q

Name 7 treatments (other than acute abx for infection) for CGD

A
  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
Q

NAme the 4 main characteristics of hyperigE/Job syndrome

A

Skin infection
Sinopulmonary infection
Early onset eczematous dermatitis
Elevated IgE

72
Q

What is Job syndrome?

A

Subgroup of AD HIE with females, fair skin red hair and hyperextensible joints + typical HIES features

73
Q

What is mode of inheritance HIES?

A

AD-HIES- classive form with vaiarbale expressivity

AR-HIES-broader spectrum infectious complications

74
Q

What is gene mutated in HIE-AD?

A

STAT3

75
Q

What is the role of STAT-3

A

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
Q

What is the gene mutated in AR-HIES

A

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
Q

There are 2 new variants of HIES, what are the genes mutated and name 1 clinical feature of each

A
  1. TYK2 mutation, AR, atypical mycobacterial infections

2. PGM3 mutation, AR, LCV and neuro abnormalities (low IQ, ataxia

78
Q

NAme 5 cutaneous features AD-HIES

A

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
Q

Name 8 non cutaneous HIE features

A
  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
Q

Describe 6 similarities and 6 differences from AD vs. AR HIE

A

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
Q

What does the infantile papulopustular eruption of HIES show?

A

Eosinophilic folliculitis, eosinophilic spong, superficial and deep perivascular infiltrate with many EOS

82
Q

Name 4 lab features of HIES-AD? AR?

A
  • 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
Q

How do you make a definitive, probable and possible diagnosis AD-HIES

A

Possible: score 30+ and IgE >1000
Probable: Above + lack Th17 OR FDR with it
Definitive: Above + dominant negative heterozygous STAT3 mutation

84
Q

What 5 characteristics are in the scoring system for HIE

A 
Pneumonias
Characteristic facies
High arched palate
Neonatal papulopustular eruption
Pathological bone fractures
85
Q

Name 3 ddx for eczema, staph infections and high IgE

A

HIES
Wiskott Aldrich–> PLT abn
Eczema–> no osteopenia, cold absences, characteristic facies
Prolidase deficiency

86
Q

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

A

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
Q

2 other transmission modes of agammaglobulinemia?

A

AD-even less
AR-10%

X-Linked recessive most common-90%

88
Q

What is the most common immunoglobulin deficiency? How does it present? What is it associated with, name 4?

A

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
Q

What is CVID, generally speaking, a deficiency of>?

A

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
Q

Average age onset of CVID

A

30

91
Q

Name 4 non infectious complications CVID

A
  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
Q

Name.6 cutaneous features CVID

A
  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
Q

How does selective IgM deficiency present?

A
  • recurrent bacterial infections
  • autoimmune disease
  • warts
  • dermatitis
  • SLE
94
Q

How do the hyper-IgM syndromes present in terms of infections

A

Recurrent sinopulmonary and gastrointestinal infections
with pyogenic bacteria and opportunistic organisms

Neutropenia

Small lymph nodes

95
Q

What is most common transmission pattern hyper IgM syndrome

A

XLR mostly

AR exists

96
Q

Name 4 skin findings hyper IgM

A 
Warts
Oral and perianal ulcers
Pyoderma's
Non infectious granulomas
Autoimmune diseases like SLE
97
Q

What is IPEX syndrome

A

Immune deficiency
Polyendocrinopathy
Enteropathy
X-linked

IgE and eosinophilia!
Eczema

98
Q

What is the genetic mutation and mode of transmission of IPEX

A

FOXP3–> abnormal development Tregs

X-linked

99
Q

How does IPEX present

A

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
Q

What is the primary issue in LAD deficiency?

A

Defect in BLANK that prevents lymphocytes, monocytes and neutrophils from being able to adhere to vascular endothelium and migrate to tissue injury

101
Q

What is the most common manifestation of LAD?

A

Gingivitis with periodontitis

102
Q

Name 5 non gingival manifestations of LAD

A

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
Q

Life expectancy of LAD patients

A

<5 years if severe

Moderate-30 years

104
Q

What does LAD show on bloodwork?

A

marked peripheral blood neutrophilia (5–20 times normal levels

105
Q

What does LAD show on bloodwork?

A

marked peripheral blood neutrophilia (5–20 times normal levels

106
Q

Name 3 causes of SCID (there are many)

A

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
Q

Name 5 possible cutaneous features seen in SCID

A
  • morbilliform eruption or widespread seb-derm like eruption representing maternofetal GVHD
  • lichen planus, acrodermatitis enteropathica, Langerhans cell histiocytosis, ichthyosiform erythroderma, and systemic sclerosis.
108
Q

Name the triad of SCID

A

FTT
Diarrhea
Recurrent infections

First 3-6 mo life

109
Q

3 most common causes cutaneous infections in SCID

A

C. albicans, S. aureus , and Str. pyogenes.

110
Q

What is OMENN syndrome and how does it present

A

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
Q

What does CBC show for SCID

A

T- B- NK-

112
Q

What derm malignancy increased risk in SCID

A

DFSP

113
Q

How to tell SCID vs. HIV

A

HIV has normal or elevated immunoglobulins

relative decrease in CD4

114
Q

What is number one treatment for SCID?

A

Stem cell transplant

115
Q

Mode of transmission of Wiskott Aldrich

A

X-linked recessive

116
Q

What is triad of Wiskott Aldrich

A

Eczema
Bleeding diathesis with PLT abnormalities
Recurrent sinopulmonary infections and pyogenic infections

117
Q

What is most common feature in WA?

A

Platelet abnormalities

118
Q

What is the genetic cause of Wiskott Aldrich? What is the pathophys

A

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
Q

What are 3 treatments for ADA-deficiency SCID

A

Stem cell transplant
Enzyme replacement with ADA
Gene therapy–> via retroviral-mediated ex vivo gene transfer into CD34 + cells

120
Q

Most common form SCID and gene mutated? What cells are affected?

A

X-linked SCID
Common gamma receptor of IL-2

No T or NK cells, B cells unaffected

121
Q

Name 5 clinical features of WA

A
  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
Q

Name 5 lab findings in WA

A
  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
Q

Name 9 conditions that are primary immunodeficiencies that can present with dermatitis

A 
Hyper IgE ++
Ataxia-Telengiectasia
Wiskott Aldirch ++
CVID
SCID
CGD
X-linked agammoglobulinemia 
DiGeorge
IgA or IgM deficiency
WHIM syndrome
IPEX
124
Q

What is the gene encoding IgA deficiency?

A

TNFRSF13B encodes -> TACI

DEfect în converting B-cell to IgA producing plasma cells

125
Q

What is the most common primary immunodeficiency? Second most common

A

IgA

then CVID

126
Q

What is the syndrome?

  • low immunoglobulins
  • warts
  • recurrent sinopulmonary infections
  • autoimmune diseases like AA, vitiligo
  • granulomas
A

CVID

127
Q

What is the syndrome?

  • Oral and perianal ulcerations
  • therapy resistant warts
  • diarrhea, respiratory infections, otitis
  • abnormal CD40 ligand on T cells
A

HyperIgM syndrome

128
Q

What is the syndrome?

  • unusual susceptibility to enteroviruses that can result in death from encephalitis
  • boys with atopic derm, urticaria, vasculitis
A

X-linked hypogammaglobulinemia

129
Q

What is the syndrome?

  • eczema
  • warts
  • increased susceptibility to meningococcemia, H flu, pneumococci
A

Isolated IgM deficiecny

130
Q

What is the syndrome?

  • young infant
  • candida, diarrhea, pneumonia
A

SCID

131
Q

What is the syndrome?

  • alopecia
  • erythroderma
  • diarrhea, FTT, pneumonia
A

OMENN syndrome

-RAG1 or 2

132
Q

Melena
Eczema
Recurrent infections

A

Wiskott Aldrich

133
Q 
Eczema herpeticum
Molluscum
Warts 
SCC
Autoimmune disease
A

AR HIES

134
Q

Eczematous dermatitis
Cold abscesses
Double row of teeth
Candidiasis

A

AD-HIES

Also:

  • itchyosis, urticaria, asthma
  • ppk sometimes
  • hands and feet resemble ACD
  • coarse facies, high arched palate, scoliosis
135
Q

Genodermatoses with extensive warts-name 10

A 
EDV
SCID
CVID
HyperIgM
IgM deficiency 
WHIM
Wiskott Aldrich
HIES, AR specifically
Netheron
Costello
GATA-2
136
Q

NAme 6 genoderms with elevated IgE

A 
Wiskott Aldrich 
Hyper IgE
Omenn
DiGeorge
Netherton
IRAK-4 deficiency
137
Q

Name the organisms seen in CGD?

A

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
Q 
Osteomyelitis with serratia marcescens
Hepatosplenomegaly with granulomas
PNA
Recurrent pyoderma 
Diarrhea
A

CGD

139
Q

What 2 types bugs seen in CGD?

A

BACTERIA
and
FUNGUS

Do to these being killed intracellularly by respiratory burst

140
Q

Gingivitis and periodontotitis

Delayed separation of umbilical cord and stump

A

LAD

Also: pyoderma like necrotic ulcers
Peripheral leukocytosis

141
Q

What is Leiner’s disease

A

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
Q

What is GATA2 deficiency

A

AD

5 conditions overlapping:
MonoMAC
DCML Deficiency
Emberger Syndrome
( have skin findings)

Familial Myelodysplastic Syndrome has few skin manifestations

WILD Syndrome

143
Q

What is WILD syndrome

A

Warts (disseminated)
Immune deficiency
Lymphedema
anogenital DYPSPLASIA

144
Q

Name 4 features of GATA 2 deficiency

A
  • 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
Q

What is WHIM syndrome

A

Autosomal dominant gain of function mutation inf CXCR4

Warts
HYpogammaglobulinemia
Infections-cellulitis, pyoderma,
Myelokathesis =inability PNM to leave bone marrow=neutropenia

146
Q

Diabetes
Diarrhea
eczema
Candida

A

IPEX syndrome–> immune dysregulation polyendocrinopathy enteropathy, X-linked

MyDermatology-Bolognia (31 decks)

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