Primary Immunodeficencies Flashcards
What is the inheritance of Ataxia-Telangiectasia?
Autosomal recessive
The carrier rate of Ataxia-Telangectasia is 1% of the population
True
What is the prevalenc of Ataxia - Telangectasia?
Occur in 1 in 40 000 to 100 000 live births
with a carrier rate of up to 1% of the population.
What are the key features of Ataxia Telengectasia?
Ataxia–telangiectasia (AT) is characterized by:
1. oculocutaneous telangiectasias
2. progressive cerebellar ataxia beginning in infancy,
3. a variable immunodeficiency with a tendency to develop sinopulmonary infections,
4. chromosomal instability with persistent DNA damage after
exposure to ionizing radiation.
What is the gene invovled in Ataxia Telangectasia?
ataxia–telangiectasia mutated gene
(ATM)
The first manifestation of Ataxia Telangectasia is usually ataxia, which typically appears when the affected child begins to walk.
T
In regard to Ataxia Telangiectasia, oculocutaneous telangiectasias are well developed by age 10
False - median age is 6
70% of patients with ataxia telangectasia get progenic skin changes
F - 90%
What are the progeric changes seen in ataxia telangectasia?
Skin and hair changes.
Subcutaneous fat is lost early
Facial skin tends to become atrophic and sclerotic
Gray hairs frequently appear in young children, and diffuse graying of the hair may occur by adolescence.
Cutaneous granulomas in ataxia telangectasia are caused by persistent rubella virus.
T - Vaccine strain > wildtype
Cutaneous granulomas in ataxia telangectasia are caused by persistent Parvovirus B19
F - rubella
What are the cutaneous findings associated with Ataxia Telangectasia?
- Telangectasias - eye, face, trunk
- Granulomatous plaques - these are persistent and can ulcerate
- Progenic skin changes:
- 90%
- loss of subcut fat
- epidermal atrophy
- scleroderma like changes
- graying of the hair
- Hyper/hypopigmented macules and pigmentary mosaicism, particularly along lines of Blaschko.
- facial papulosquamous rash,
- poikiloderma,
- hypertrichosis favoring the arms,
- warts
- acanthosi nigricans
What are the non-cutaneous features of ataxia telangectasia?
- Cerebellar ataxia
- usually begins during infancy
- characterized by swaying of the head and trunk.
- Choreoathetosis (involventary movements)
- dysarthric speech
- oculomotor abnormalities
- myoclonic jerks
- facies become dull and hypotonic, with mask-like changes
- Recurrent sinopulmonary infections in >80% of AT patients
- most common cause of death being bronchiectasis with respiratory failure
- glucose intolerance, hyperinsulinemia, and insulin resistance
- growth delay (>70%)
- hypogonadism (especially in female patients)
- intellectual disability (~30%)
- High risk of developing malignancy - esp leukemia (70-fold increase compared to unaffected individuals) and lymphoma (200-fold increase). BCC
Patients with Ataxia telangectasia have a high risk of developing malignancy. Especially leukemia (200-fold increase compared to unaffected individuals) and lymphoma (70-fold increase).
F - other way around –> **leukemia = 70-fold increase ** compared to unaffected individuals) and lymphoma (200-fold increase).
Carriers of ATM do not have an increased maligiancy risk
F - Carriers of heterozygous ATM mutations have a **two- to threefold increase in both the risk of developing breast cancer and the likelihood of death from cancer, including malignancies of the stomach, colon, and lung as well as the breast. **
There is greater excess mortality in individuals <50 years of age
Describe
What immunological defects are associated with Ataxia Telangectasia?
Immunologic defects in patients with AT include:
(1) decreased serum levels of IgE, IgA, and IgG (especially IgG2 and IgG4) in ~80%, 70%, and 60% of patients, respectively;
(2) low-molecular-weight IgM (in 80% of patients) and increased serum levels of IgM (in a minority of patients)
(3) defects in cell-mediated immunity such as lymphopenia (in 70% of patients) and deficient in vitro responses to antigens and mitogens
Affected individuals tend to have a relative deficiency of CD4+ T cells and an** excess of γ/δ T cells **as well as **elevated serum levels of interleukin-8 (IL-8), **
Most patients have an absent or abnormal thymus
IL - 6 is a key driver of inflammation in ataxia telangectasia
F - it is IL - 8
Individuals with Ataxia Telangectasia have defects in humoral and cell mediated immunity.
T - They have
(1) decreased serum levels of IgE, IgA, and IgG (especially IgG2 and IgG4) in ~80%, 70%, and 60% of patients, respectively;
(2) low-molecular-weight IgM (in 80% of patients) and increased serum levels of IgM (in a minority of patients)
(3) defects in cell-mediated immunity such as lymphopenia (in 70% of patients) and deficient in vitro responses to antigens and mitogens
Radiotherapy is the treatment of choice for patients with lymphoma and ataxia telangectaisa
F - these patients are highly sensitive to ionising radiation. Radiotherapy should be avoided, and when necessary limited to 20 grays
What chromosomal abnormalities occur in ataxia telangectasia?
- Spontaneous chromosomal fragments, breaks, gaps, and translocations 2–18 times more frequent than in unaffected individuals
* Increased telomeric shortening
* Common chromosome 7 and 14 rearrangements, may predict lymphoma development
What investigations should you do for someone with suspected Ataxia Telangectasia? And expected findings
FBC - lymphopaenia
UEC
LFTs - Mildly elevated hepatic transaminases in approximately half of patients
Immunoglobulins - low IgG, IgA and Ige (possibly incrased IgM)
Lymphocyte subsets - Relative deficiency of CD4+ T cells and excess of γ/δ T cells
Alpha-feto protein - elevated
carcinoembryonic antigen - elevated
MRI - cerebellar atrophy
Genetic testing
- targeted gene panel for ATM
- karotype to detect translocations
? Radiosensitivity testing with colony survival assay, abnormal S phase checkpoint
DDx of Ataxia Telangectasia?
- Friedreich ataxia: May be confused with AT until ocular telangiectasias become apparent.
- Conjunctivitis: Telangiectasias may be misdiagnosed as conjunctivitis, but the chronicity and size of the vessels distinguish AT.
- Bloom syndrome: Shares facial and conjunctival telangiectasias, café-au-lait macules, immunoglobulin deficiencies, respiratory infections, and hematologic malignancies but lacks neurological abnormalities.
- FILS syndrome: Features facial dysmorphism, immunodeficiency, short stature, and telangiectasias or poikiloderma, caused by POLE1 mutations.
- RIDDLE syndrome: Includes radiosensitivity, immunodeficiency, facial dysmorphism, motor difficulties, and short stature, caused by mutations in RNF168.
What is the prognosis for Ataxia Telengactasia? What is the management?
Median lifespan: >25 years, with chronic sinopulmonary disease or malignancy being the most common causes of death.
Rx:
- MDT care; General paeds, Neurologist, geneticist, physio, OT, oncologist, immunologist
Supportive therapies:
○ Infections: Antibiotics, prophylactic antibiotics, and IVIg replacement for severe immunodeficiency.
○ Sun protection: Avoidance of sun exposure and use of sunscreens.
○ Lung care: Early physiotherapy for bronchiectasis, consider corticosteroids for interstitial lung disease.
○ Neurologic care: Physical therapy to prevent contractures due to neurologic dysfunction.
○ Cancer screening: Regular monitoring for malignancies.
What are the clinical features of chronic mucocutaneous candidiasis
Range of severities
- from mild, treatment-resistant thrush to severe, generalized granulomatous plaques.
Common Infections:
○ Oral Thrush: Persistent, hyperkeratotic plaques on the tongue.
○ Scalp Infections: Can lead to scarring alopecia.
○ Nail Involvement: Thickened, brittle, discoloured nails with paronychia.
○ Cutaneous Plaques: Most often occur on the scalp, periorificial, and intertriginous areas.
○ Esophageal, Genital, and Laryngeal Involvement: Chronic lesions may lead to strictures.
Dermatophyte Infections:
Common, presenting as tinea corporis (annular and polycyclic plaques) and tinea faciei (pustules and scaling).
Systemic Candidiasis: Rare, but recurrent infections with other organisms, including bacterial septicemia, can occur.
What is the overarching cause of chronic mucocutanoues candidiasis?
primarily associated with impaired responses from T helper 17 (Th17) cells,
What genes are associated with chronic mucocutaneous candidiasis?
- STAT 1 (most common)
- Gain of function
- Autosomal dominant
- AIRE gene
- Causes Autoimmune polyendocrinopathy– candidiasis–ectodermal dystrophy syndrome (APECED)
- Usually Autosomal Recessive
- IL-17F (IL17F), Jun N-terminal kinase 1 (JNK1; MAPK8);
- Autosomal dominant
- IL-17 receptor A or C (IL17RA or IL17RC) and TRAF3-interacting protein 2 (TRAF3IP2; ACT1)
- Autosomal recessive
- CARD9
- AR
- Dectin -1 Deficency
others…
What is the phenotype of CMC due to incrased STAT1 signalling?
Onset of mucocutaneous candidal infections at a mean age of 1 year – oropharynx (>95%), nails (60%), skin (50%)
Dermatophyte infections of skin and/or nails (15%)
**
Cutaneous autoimmune disorders, e.g. vitiligo, alopecia areata (10%)**
Autoimmunity (40%)
* thyroid disease (25%)
* type 1 diabetes mellitus (5%)
* cytopenias (5%)
* colitis or celiac disease (5%), hepatitis (2%)
* systemic lupus erythematosus (2%)
Other infections (variable)
* cutaneous staphylococcal
* demodicosis
* bacterial pneumonia (e.g. pneumococcal, Pseudomonas; 50%), otitis, sinusitis
* recurrent/severe viral (e.g. HSV, VZV, EBV, CMV, orf; 40%)
* invasive fungal (e.g. Candida, Aspergillus, Cryptococcus, endemic dimorphic, mucormycosis, Fusarium; 10%)
* mycobacterial (tuberculosis, non-tuberculous; 5%)
Aneurysms (e.g. cerebral, aortic; 5%),
mucocutaneous SCC (5%),
Dental enamel defects
What is the phenotype of Autoimmune polyendocrinopathy–
candidiasis–ectodermal dystrophy syndrome?
Mucocutaneous candidal infections with mean onset at age 3 years
Candidal granulomas, especially of the face and scalp
Autoimmune endocrinopathies, which may not be apparent until teenage or even adult years
* hypoparathyroidism† (90%)
* hypoadrenocorticism† (80%)
* hypogonadism (30%–50%)
* thyroid disease (20%)
* type 1 diabetes mellitus (20%)
* hypopituitarism (e.g. growth hormone deficiency; 15%)
Cutaneous autoimmune disorders
* alopecia areata (30%)
* vitiligo (20%)
* urticarial eruption‡ (up to 60%)
* lupus-like panniculitis
Other autoimmune disorders
*pernicious anemia (15%)
*hepatitis (15%–40%)
*pneumonitis (15%–40%)
*Sjögren-like syndrome (20%–40%)
Dental enamel hypoplasia (70%),
Chronic diarrhea (20%–80%),
Keratoconjunctivitis (20%),
Hyposplenism (15%),
Hypertension (15%),
Oral/esophageal SCC
Anti-type I interferon antibodies (nearly 100%); anti-thyroglobulin, anti-microsomal, anti-parietal cell, and anti-adrenal antibodies; rheumatoid factor
Autoantibodies against type I interferons are a sensitive and specific marker for autoimmune polyendocrinopathy–
candidiasis–ectodermal dystrophy syndrome
T
DDx of chronic mucocutaneous candidiasis
Abx disrupting normal flora
HIV
IPEX syndrome (mmune dysregulation, polyendocrinopathy, enter-
opathy, X-linked) syndrome - normally bacterial > candidal
How do you treat chronic mucocutanoeus cadidiasis?
MDT care, referral to immunology, general paediatrician, geneticist, endocrinologist depending on sx and ix
Topical Medications: Often ineffective for CMC, particularly for cutaneous granulomas.
** Systemic Antifungals: **
- itraconazole or fluconazole, with alternatives like posaconazole, voriconazole, and echinocandins for fluconazole-resistant cases.
Adjunctive Therapy:
- **Granulocyte colony-stimulating factor (G-CSF) **to increase IL-17 production;
- nail avulsion, drainage, and debridement of abscesses and plaques.
- ** JAK Inhibitors: **In patients with gain-of-function STAT1 mutations, drugs like ruxolitinib may help with infections and autoimmune disease.
Endocrinopathy Screening: Annual evaluation for endocrinopathies, especially in those with APECED diagnosis or family history.
Mutations in the lysosomal trafficking regulator gene (LYST) are responsible for Chédiak–Higashi Syndrome (CHS).
T
85% of Chédiak–Higashi Syndrome patients develop a fatal lymphoproliferative “accelerated phase” by age 10 without hematopoietic stem cell transplantation (HSCT).
TRUE
10%-15% of Chédiak–Higashi Syndrome patients with missense mutations experience a severe phenotype and do not survive into adulthood.
False (They have a milder phenotype and can survive into adulthood.)
Patients with Chédiak–Higashi Syndrome commonly experience photophobia, nystagmus, and strabismus, with normal visual acuity.
True
Hematopoietic stem cell transplantation (HSCT) can reverse the immunodeficiency of Chédiak–Higashi Syndrome (CHS) but does not affect pigmentary changes or halt neurologic degeneration.
True
Chédiak–Higashi Syndrome presents with severe pigmentary changes in the skin, hair, and eyes, including silvery metallic hair and hyperpigmentation in sun-exposed areas.
True
What type of inheritance pattern does Chédiak–Higashi Syndrome (CHS) follow?
Autosomal recessive.
What gene mutation causes Chédiak–Higashi Syndrome?
Mutations in the lysosomal trafficking regulator gene (LYST).
What types of infections are common in Chédiak–Higashi Syndrome?
Skin and respiratory tract infections caused by Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae.
What are the cutaneous findings in Chédiak–Higashi Syndrome?
Pigmentary changes:
- Mild pigmentary dilution in skin, hair, and eyes, with
- silvery metallic hair
- hyperpigmentation in sun-exposed areas
Superficial pyodermas, gingivitis, and ulceration of oral mucosa.
Mild bleeding diathesis: easy bruising, petechiae, epistaxis.
What immunological features are seen in Chédiak–Higashi Syndrome?
Neutropenia, reduced leukocyte chemotaxis, impaired antibody-dependent cell-mediated cytotoxicity, decreased NK cell function, and diminished T cell act
Complement deficency increases the risk of infection with encapsulated bacteria
T
Defiency of early complement factor (C1 - 4) results in increase risk of infection secondary to encapsultated bacteria and high propsensity to AI conditions (particularly SLE)
T
Deficency of late complement components leads to increased risk of neisserial infections
True
Heterozygous complement deficiencies are typically assymptomatic.
T - functional allels able to produce enough protein to mask effects
Individuals with homozygous deficiencies in C2 have a >90% risk of SLE
False - individuals with homozygous C1q deficencies have >90 % risk. Individuals with homozygous c2 have a 10 - 20 % risk
When / who does C2 deficency related SLE present?
Among those with C2 deficiency, features of lupus erythematosus (especially photosensitivity and subacute cutaneous lupus erythematosus) are:
- most common in women,
- with the age at onset ranging from early childhood to adulthood (median 30 years)
SLE in the setting of C1q/r/s or C4 deficiency usually afffects who and at what age?
- usually develops during childhood,
- affects boys and girls equally,
- often associated with renal disease and palmoplantar keratoses as well as photosensitivity.
Clinical features of MBL deficency?
- increased risk of acute respiratory infections in children aged 6–18 months, who no longer have maternal
antibodies but are not yet able to mount an efficient antibody response to the carbohydrate antigens of encapsulated bacteria56. - increased risk of developing SLE or dermatomyositis and - higher incidence of infections in the setting of immunosuppressive therapy.
Individuals with C5 to C9 (membrane attack complex; MAC), properdin, and factor D deficiencies develop recurrent neisserial infections in their teenage years.
T
the mortality of meningococcal infections in patients
with MAC deficiency is higher than that in immunocompetent
individuals.
F - lower due to a lack of lytic activity which limits release of
bacterial products (e.g. lipopolysaccharide) that stimulate a damaging cytokine response
patients with a properdin or factor D deficiency are unable to eradicate Neisseria spp. via opsonophagocytosis and have severe disease that is often fatal.
T
C1q deficiency is the most common hereditary complement disorder.
False - C2
What is Chronic Granulomatous Disease (CGD)?
CGD is a group of disorders characterized by severe, recurrent infections due to the inability of leukocytes to kill phagocytosed bacteria and fungi by generating reactive oxygen species (ROS), caused by reduced NADPH oxidase complex activity.
What is the incidence and gender prevalence of Chronic Granulomatous disease?
1 in 200,000 live births.
90% of patients are male.
What are the inheritance patterns of Chronic Granulomatous Diseases?
Around 75% of cases are X-linked recessive,
while the remainder are autosomal recessive.
What additional syndrome may occur in some male patients with X-linked Chronic Granulomatous Disease?
Some male patients with X-linked CGD may also have McLeod neuroacanthocytosis syndrome, which includes neurological, neuromuscular, cardiovascular, and hematological manifestations.
What causes the defective immune response in Chronic Granulomatous disease?
The defects involve subunits of NADPH oxidase in phagocytes. This results in the inability to generate ROS and effectively kill phagocytosed microbes.
How does the failure to generate ROS impact immune function in Chronic Granulomatous disease?
Without ROS, microbial killing is impaired, leading to excessive inflammation, disrupted immune regulation, and increased susceptibility to infections.
What is the clinical presentation of Chronic Granulmatous Disease?
Common infections occur in the skin, lymph nodes, lungs, and gastrointestinal tract.
It presents with staphylococcal abscesses, cutaneous granulomas, and systemic infections,
often caused by S. aureus, Serratia marcescens, and fungi.
What are common skin manifestations of Chronic Granulmatous Disease?
staphylococcal abscesses,
cutaneous granulomas,
lupus erythematosus-like lesions,
Sweet syndrome-like lesions, and
ulcers in the oral and perioral areas.
What are the common organisms that cause infection in chronic granulomatous disease?
What are the features of SLE in C2 Deficency?
Photosensitivity
SCLE, ACLE, DLE
Cicatricial alopecia
Oral ulcerations (50%)
Fever (>50%)
Arthralgia / arthritis
Leukopaenia (50%)
Anti-SSA/ Ra antibody (75%)
Rheumatoid factor (40%)
Features that are more suggestive of C2 deficency than classic SLE
- childhood onset
- extensive, treatment-resistant skin lesions
- Mild or absent renal disease
- Absent or low titre ANA and dsDNA abs
- Negative lupus band test
- Less severe disease overall
- pyogenic infections
- increased risk of atherosclerosis
What do you expect to see on biopsy for a patient with Chronic Granulmatous Disease?
**Skin biopsy specimens from granulomas in CGD show **
- histiocytic infiltrates (a collection of macrophages and other immune cells),
- foreign body giant cells (multinucleated cells),
- accumulation of neutrophils
- Necrosis is often observed within the granuloma due to the ineffective immune response in CGD.
Lupus Erythematosus-Like Skin Lesions:
Some CGD patients and carriers develop skin lesions resembling discoid lupus erythematosus.
These lesions may share histologic features with classic lupus lesions but typically lack vacuolar degeneration of basal keratinocytes.
Immunofluorescence examination of the skin lesions in CGD is negative
What pathology results are you likely to see in CGD?
Common Nonspecific Abnormalities:
* Leukocytosis: Elevated WBC count due to persistent infections and inflammation.
* Anemia: Often normocytic or microcytic, resulting from chronic infections and inflammation.
* Elevated ESR: An indicator of systemic inflammation.
* Hypergammaglobulinemia: Elevated immunoglobulins, mainly IgG, due to chronic immune activation.
* Decreased T Cell Count: Reduced T cell numbers due to impaired immune modulation in CGD.
* Abnormal Chest Radiograph: Imaging may show granulomatous changes or pulmonary pathology.
Immune Function Testing:
* Delayed-Type Hypersensitivity (DTH) Testing: Normal in CGD, as it does not assess the phagocytic function directly.
- Phagocytosis and Chemotaxis: Normal in CGD, as the defect lies in the microbial killing, not in pathogen engulfment or migration.
Diagnostic Assays for CGD:
1/ NBT (Nitroblue Tetrazolium) Reduction Assay:
- NBT dye reduction is abnormal in CGD, with only 5-10% of leukocytes from CGD patients reducing NBT, compared to 80-90% in healthy controls.
- Carriers show partial reduction (20-70%).
2/ DHR (Dihydrorhodamine) Flow Cytometry:
- More accurate and quantitative compared to NBT.
- Measures neutrophil respiratory burst and is commercially available for CGD diagnosis.
- Not sensitive for detecting p40phox-related CGD.
Immunoblot Analysis:
- Used to detect the absence of specific NADPH oxidase subunits: gp91phox, p22phox (membrane-bound subunits) absence suggests the defect in the oxidase complex.
- p47phox, p67phox, p40phox absence indicates defects in cytoplasmic subunits.
- EROS deficiency results in the absence of membrane-bound subunits.
Genetic Testing:
Gene Sequencing: Performed to identify mutations in the specific genes encoding NADPH oxidase subunits.
