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.