B3-070 Congenital Disorders Flashcards by Felicia Jones

diseases on a newborn screening have

significant morbidity and mortality
improved outcomes with early treatment
available testing that is simple and inexpensive

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newborn screening are [sensitive/specific]

sensitive

confirmatory testing is always necessary

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newborn screenings are obtained at

24 hrs of life

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recurrent bacterial infections means

4 episodes of AOM/year
2 episodes of pneumonia/year
2 episodes of sinusitis requiring antibiotics/year
recurrent abcessess

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if a recurrent infection is only occuring in one anatomic location consider

anatomic abnormality over immunodeficiency

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recurrent ear infections may be caused by

ET dysfunction

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recurrent UTI may be caused by

ureteral abnormalities

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unilobar pneumonia may be caused by

aspiration or anatomical anomaly

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deep seated infections

organ abscesses
sepsis/bacteremia
fungal infections

except mucocutaneous candidiasis

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difficult to treat infections

antibiotic course greater than 2 months without improvement
need for parenteral antibiotics rather than oral

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family history of primary immune deficiency triggers

early workup, usually prior to symptom onset

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first test for possible congenital disorder

CBC w diff

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lymphopenia is suggestive of

T cell disorder

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neutropenia is suggestive of

phagocytic disorder

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follow up tests should be guided by

clinical suspicion and family history

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considerations of genetic testing

follow index of suspicion
sequential
consider cost
aggregate outside evaluation

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identifies monosomy, trisomy, large deletions, translocations, non-disjunction

karyotype

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commonly employed with multiple genetic anomalies

karyotype

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pre natal amniotic fluid, chorionic villus tissue

karotype

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higher resolution than chromosome analysis

FISH

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used fluorescent-tagged sequence/probe

FISH

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steps of FISH

denature DNA –> expose probe –> visualize under microscopy

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detects 50-200kb deletions

FISH

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limited to one disease

FISH

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DiGeorge is diagnosed with

FISH

Williams syndrome is diagnosed with

FISH

trisomy 21 is dx with

karyotype

turner syndrome is diagnosed with

karyotype

detects deletions >5000

karyotype

various mutation of gene coding regions

single gene analysis

Factor V Leiden is diagnosed with

single gene analysis | specific mutation

cystic fibrosis is diagnosed via

single gene analysis | panel of common variants

done by PCR

single gene analysis

evaluates for gains or losses of chromosome segments at much higher resolution

comparative genomic hybridization/microarray

can do targets vs whole genome evaluation

comparative genomic hybridization/microarray

in comparative genomic hybridization/microarray, patient DNA amplification is

green

in comparative genomic hybridization/microarray, absence of patient DNA is

red

in comparative genomic hybridization/microarray, equal patient and reference DNA is

yellow

examine multiple gene and genetic regions simultaneously

comparative genomic hybridization/microarray

for patients who have a likely genetic component to symptoms, but testing has not identified cause

exome sequencing/next gen sequencing

ideally symptom driven

exome sequencing/next gen sequencing

trio analysis is best for interpretation

exome sequencing/next gen sequencing

risks of genetic screening

can reveal non-paternity, consaguinity, unrelated parental diagnosis

only about 1/3 of patients will have an identified diagnosis

exome sequencing/next gen sequencing

the first successful HSCTs were for

SCID and WAS

what has contributed to a higher success rate of HSCTs?

improvements to donor selection, conditioning, and post transplant immunosuppression

HSCTs can serve as a "rescue" following

malignancy

the most important trait to qualify for HSCT

an immunodeficiency where the defect is isolated to hematopoietic cells | **not great for Hyper IgE

HSCT is efficacious and recommended for

SCID WAS

Step 1 of HSCTs

Find HLA match

4 types of donors

matched related donor matched unrelated donor cord blood donor mismatched related donor

most desirable donor

matched related | sibling

efficacy approaches that of matched related donors

matched unrelated donor

less likely to find a match for

patients of racially mixed backgrounds ethnic minorities

more forgiving of HLA mismatches

cord blood donor

requires myeloablative conditioning

cord blood donor | dangerous for patient

less antiviral immunity because cells are naive

cord blood match

takes longer for engraftment to occur

cord blood match | increased risk of infection or complication during this time

takes longer for engraftment to occur

cord blood match | increased risk of infection or complication during this time

usually haploidentical

mismatched related donor | parents

highest risk for graft rejection of GVHD

mismatched related donor

Step 2 of HSCT

Conditioning

may not require conditioning due to lack of immune system

SCID

most aggressive and reduces risk of failure of GVHD, but comes at a cost of toxicity and infections

myeloablative | need for cord blood donor

serves to minimize the immune response only

minimal intensity/immunosuppressive

generally only if you have a matched related donor

minimal intensity/immunosuppressive

middle ground, can be an option if patients have severe infections before transplants that would prevent myeloablative conditioning

reduced intensity

Step 3 HSTCs

prevent GVHD

the less intense conditioning regimen used,

the more immunosuppression needed after transplant to prevent GVHD

if myeloablative conditioning was used, the patient may become

aplastic if fails

donor chimerism

mixed donor and recipient cells

primary graft failure

never engrafted at all

secondary graft failure

engrafted and lost over time

treatment of mild GVHD

get labs and imaging go back to previous level of immunosuppression + topical corticosteroids

treatment of moderate to severe GVHD

labs/imaging if stable go back to previous level of immunosuppression + IV corticosteroids

limited area of involvement and hemodynamically stable

mild GVHD

IRT checks for

cystic fibrosis

best when there is only one specific muations you are looking for (i.e. 22q11)

FISH

when you need to look at very large deletions or chromosomal duplications/deletions (trisomies, monosomies)

karyotype/chromosomal analysis

best when there is one gene of interest, even if there are many possible mutations within that gene | CTFR

single gene analysis/PCR

when you are fishing for a genetic cause you believe to be syndromic

exome sequencing

is bronchiolitis in children reason to suspect immunodeficiency?

recurrent infections in multiple locations is concern for

immunodeficiency

what test should you always start with?

CBC w/ diff

after CBC, what test[s] are next best step in immunodeficiency workup?

**flow cytometry** Ig levels vaccine titers | results from flow cytometry can help determine need for Ig or vaccine ti

what genetic test should start with if uknown disorder of genetic origin is suspected?

karyotype

extrachromosomal DNA byproducts of T cell receptor rearrangement

TRECs

TRECs are only expressed in

T cells of thymic origins

differential for abnormal TRECs

SCID DiGeorge T cell lymphopenia Ataxia telangiectasia Wiskott Aldrich

SCID patients should be placed in

positive pressure rooms

if SCID infant requires blood products they should be

leukoreduced, irradiated, and CV negative

should SCID patients receive live viral vaccines?

SCID patients should receive a ........ ASAP

transplant

usually best match for HSCT

MDR: sibling

donor sources ranked best to least good

MRD>MURD>CBD>MMRD

how is the stem cell graft conditioned?

antibody tagged removal radiation

how is the recipient bone marrow conditioned?

myeloablation immunosuppression total body irradiation

myeloablation facilitates

engraftment

immunosuppression in conditioning limits

rejection

donor immune cells recognize recipient cells as foreign and attack

GVHD

acute GVHD

.<100 days after transplant

chronic GVHD

.>100 days after transplant

GVHD commonly involves what tissues?

liver, GI tract, skin,

short tandem repeat PCR is used to analyze

chimerism

HSCT only treats

immune deficiencies that arise from defects in hematopoeitic cells

even post HSCT, what is a common complication of WAS?

IBD

if GVHD is suspected and patient is stable

labs and endoscopy