Pediatric Immunodeficiency Disorders

Question 1

In general, B-cells are responsible for making Ig’s (antibodies), and provide immunity against ______; on the other hand, T-cells are responsible for providing immunity against ______.

Answer 1

B-cells provide immunity against extra-cellular bacteria.

T-cells provide immunity against viruses, fungi, and intra-cellular bacteria.

Question 2

_____ -cell deficiencies are commonly associated with infections with encapsulated bacteria.

Answer 2

B-cell deficiencies.

Question 3

Encapsulated bacteria are covered with a ____ capsule, and include (examples) _______.

Answer 3

polysaccharide capsule;

MN: Yes, Some Killer Bacteria Have Pretty Nice Capsule!

-Yersinia
-Strep. Pneumoniae
-Klebsiella
-Bacillus Anthracis
-Hemophilus Influenzae
-Pseudomonas
-Neisseria Meningitidis
-Cryptococcus Neoformans (fungus).

Question 4

Major pediatric B-cell deficiency disorders include ______ (list most).

Answer 4

1. Bruton Agammaglobulinemia
   (No B cells; All Ig’s ↓↓; Tonsils & lymph. tissue absent; T cells high).
2. CVID
   (B cells normal; plasma cells ↓↓; All Ig’s ↓↓)
3. IgA deficiency
4. Hyper-IgM syndrome
   (absent/↓↓ class-switching memory B-cells absent).**

Question 5

Memory AID:
B in Bruton Agammaglobulinemia for ____, and _____.

Answer 5

B in Bruton Agammaglobulinemia
for
-B-cell deficiency
-Boys only (X-linked recessive).

Question 6

Onset of life-threatening infections with *encapsulated bacteria in Bruton Agammaglobulinemia typically begin around ____ age d/t _____.

*Yes, Some Killer Bacteria Have Pretty Nice Capsules! (Yersinia, Strep. Pneumoniae, Klebsiella, B. Anthracis, H. Influenzae, Pseudomonas, Neisseria, Cryptococcus).

Answer 6

onset ~ 6 months of age d/t depletion of transplacental maternal antibodies (IgG).

Question 7

The diagnosis of Bruton Agammaglobulinemia is based on ____ tests with ___ results.

Answer 7

Quantitative Ig levels with T-/B- cell subset study if Ig low;

results: Low Ig levels with
-absent B-cells, and
-high numbers of T-cells.

Question 8

Absent tonsils and other lymphoid tissue may provide a clue for presence of ____.

Answer 8

Bruton Agammaglobulinemia.

Question 9

The mainstay m/m in Bruton Agammaglobulinemia include t/t with ______ (list all).

Answer 9

-prophylactic antibiotics, and
-IVIG

Question 10

______, a primary humoral immunodeficiency disorder, however, characterized by a combined intrinsic B- and T-cell defect leading to low IgG, IgA, and IgM, adequate number of B cells, and decreased plasma cells (antibody producing activated B-cells) .

Answer 10

Combined variable immune deficiency (CVID)

*primary humoral immunodeficiency disorder characterized by
-low IgG, IgA, and IgM,
-adequate number of B cells, and
-decreased plasma cells.
-recurrent sino-pulmonary infections,
-autoimmune disorders,
-granulomatous diseases,
-enhanced risk of malignancy.

Question 11

CVID was previously known as ____.

Answer 11

adult-onset hypogammaglobulinemia.

Question 12

CVID patients are at increased risk of ____ disorders.

Answer 12

-↑ r/o pyogenic URTI and LRTI.
-↑ r/o malignancy (lymphoma), and
- ↑ r/o autoimmune diseases.

Question 13

Symptom onset in CVID is typically around ___ age.

Answer 13

15-35 years of age.

*most cases diagnosed after puberty

Question 14

True/False?
Even though the main cause of CVID is unknown, environmental and genetic factors are thought to be involved in the causation.

Answer 14

True.

Question 15

What is the basis of genetic causation theory in CVID ?

Answer 15

-approx. 20% of CVID patients have a first-degree family member with a selective IgA deficiency.
- Possible intrinsic B cell defect (mutation-induced CD19 deficiency),
-an intrinsic T cell defect, and
-mutations in TNF receptors.

Question 16

In CVID, the risk of death is higher with ____ (? infectious, non-infectious) complications such as ___ (list most).

Answer 16

non-infectious complications such as malignancy, and autoimmune diseases.

The prevalence of non-infectious complications in CVID is ~ 60-70% leading to 11 times increased r/o death d/t the same.

Question 17

In CVID, the prevalence of non-infectious complications (malignancy, autoimmune diseases) is around ____% leading to ___ times higher risk of mortality.

Answer 17

60 to 70%;
11 times higher r/o mortality.

Data Source: https://www.ncbi.nlm.nih.gov/books/NBK549787/

Question 18

____,____ and _____ levels are a/w a higher prevalence of autoimmune disease, granuloma formation, recurrent bacterial pneumonia, and lymphoid hyperplasia in CVID patients;
hence, can be used to predict mortality risk in CVID.

Answer 18

Sr. IgG, IgM, and circulating class-switched memory B cells levels;

↓↓ Sr. IgG, ↑ Sr. IgM, & ↓ circulating class-switched memory B cells -> higher prevalence of autoimmune disease, granuloma formation, recurrent bacterial pneumonia, and lymphoid hyperplasia-> higher mortality.

Question 19

Overall mortality in CVID patients, according to age and sex-matched population controls is ____.

Answer 19

around 20%.

Data Source: https://www.ncbi.nlm.nih.gov/books/NBK549787/

Question 20

Bruton agammaglobulinemia can be differentiated from CVID on the basis of _____.

Answer 20

B-cell levels;

B-cells absent in Bruton agammaglobulinemia;

B-cells adequate but plasma cells decreased in CVID.

Question 21

Immunoglobulin A (IgA) deficiency is characterized by _____.

Answer 21

↓↓ sr. IgA (< 7mg/dL),
↓ secretory IgA, and
normal levels of Sr. IgG, IgM, IgE.

Question 22

Secondary IgA deficiency can result from _____ factors (list most).

Answer 22

Drugs:
- Cyclosporine,
- Penicillamine,
- Antiepileptic drugs (carbamazepine, valproate);
- Anti-rheumatic (sulphasalazine, gold), and
- ACE inhibitors
- Rituximab: anti-CD20 monoclonal antibody -> impairs B-cell proliferation.

Viral infections: HCV, EBV, congenital rubella, others.

Question 23

True/False;

Secondary IgA deficiency caused by drugs is often readily reversible with the cessation of the medication.

Answer 23

True.

Question 24

IgA deficient individuals can experience anaphylactic type transfusion reactions due to ___.

Answer 24

d/t the presence of anti-IgA antibodies (IgG or IgE) in their blood.

*administer IgA-poor or washed RBCs.

Question 25

The prevalence of selective IgA deficiency is estimated to be ____-fold higher in first-degree relatives of the patients with the disorder.

Answer 25

38-fold

Question 26

Increased prevalence of atopic disease in IgA deficient individuals may be due to ___.

Answer 26

d/t compensatory increase in IgE in IgA-deficient individuals.

Question 27

Describe the clinical presentation spectrum of IgA deficiency disorder?

Answer 27

-Majority asymptomatic.
-Recurrent sino-pulmonary infections caused by extracellular encapsulated bacteria (S pneumoniae, H influenzae, e.t.c.).
-Allergic conjunctivitis, eczema, rhinitis, urticaria, food allergy, and asthma.
-Autoimmune (20%-30%): through haplotype sharing a/w T1DM, SLE, celiac disease, and Graves disease.
-GI disorders
-Malignancies, and
-other severe complications.

Question 28

All IgA deficient individuals (including asymptomatic) should receive ____vaccines, and must avoid ____ vaccines, and considered contraindicated for ____ vaccines.

Answer 28

Receive: polyvalent pneumococcal and influenza vaccines;

Avoid: attenuated or live vaccines;

Contraindicated: OPV, BCG, and yellow fever.

Question 29

What are the most common complications associated with IgA deficiency?

Answer 29

1. Obliterative bronchiolitis: “popcorn lung” on CXR.
2. Bronchiectasis d/t recurrent LRTI; colonization by Pseudomonas or non-TB mycobacterium.
3. Pneumonia: daily prophylactic antibiotics for pts. with recurrent sino-pulmonary infections.
4. Malignancies: gastric adenocarcinoma, Nodular Lymphoid Hyperplasia (NLH) -> Lymphoma.
5. Transfusion reactions (anaphylaxis): anti-IgA antibodiesin 20 - 40% cases; give washed RBCs or products from an IgA-deficient donor.
6. Severe COVID: with the lack of IgA lining the GI tract, viruses are thought to be enter through the mucosal border, leading to a cytokine storm syndrome- > ARDS, vaccine failures, prolonged viral shedding.

Question 30

Mainstay of treatment in symptomatic IgA deficient patients is ___.

Answer 30

-prophylactic antibiotics
-IgA-depleted IVIG

Question 31

____ is a disorder of abnormal T- and B-cell function, characterized by low serum levels of IgG, IgA, and IgE with normal or elevated serum levels of IgM.

Answer 31

Hyper IgM syndrome.

Question 32

Hyper-IgM syndrome is caused by an absence of ____ needed for class-switching of IgM to other Ig classes.

Answer 32

absence of CD40 ligand.

Question 33

While the total number of B-cells are normal, ___ type of B-cells are markedly reduced in Hyper-IgM syndrome?

Answer 33

class-switched memory B-cells

Question 34

What is the inheritance pattern in Hyper-IgM syndrome?

Answer 34

X-linked recessive;

hence, males mostly affected.

Question 35

Onset of symptoms in Hyper-IgM syndrome is typically around ___ age.

Answer 35

within first year of life (infancy);

*~ 50% are symptomatic within 1st year of life; > 90% symptomatic by age 4 yrs.

Data Source: https://www.ncbi.nlm.nih.gov/books/NBK1402/

Question 36

What is the spectrum of c/p in hyper-IgM syndrome?

Answer 36

A male infant or child p/w h/of
-recurrent bacterial &/or opportunistic URTI/LRTI including P jirovecii pneumonia, recurrent/protracted diarrhea (infectious/non-infectious)
-with FTT, neutropenia (common) +/- thrombocytopenia and/or anemia (both less common).
+/- s/s of
-autoimmune and/or inflammatory disorders (sclerosing cholangitis), neoplasms, neurologic infections (in 5%-15%), or liver disease secondary to cryptosporidium infection.

Question 37

The diagnosis of X-linked hyper IgM syndrome is based on ___ criteria (list all).

Answer 37

CLINICAL: male infant/child less than age 4 years, with humoral immunodeficiency c/p.

LABORATORY:
-Normal TLC but ↓↓↓ class-switched memory B-cells.
-Neutropenia (common)
-Thrombocytopenia (less common)
-Anemia (less common)

MOLECULAR GENETIC TESTING
-a hemizygous pathogenic variant in CD40 ligand.

Question 38

Management of Hyper-IgM syndrome includes t/t with ____.

Answer 38

-Ig: IVIG or subcutaneous.

-Antimicrobials: acute infections or prophylaxis (P jirovecii).

-Recombinant GCS for neutropenia,

-Immunosuppressants for autoimmune disorders.

-Hematopoietic stem cell transplantation (HSCT): curative.

Question 39

Patients with Hyper-IgM syndrome must avoid _____ activities and vaccines to prevent serious infections overall and esp. by Cryptosporidium species.

Answer 39

• Avoid swimming in pools, lakes, ponds, or certain water sources,
• Avoid drinking unpurified or unfiltered water,
• Avoid live vaccines: rotavirus, MMR, varicella, live attenuated polio, and BCG.

Question 40

Management of patients with Hyper-IgM syndrome includes surveillance for _____ conditions.

Answer 40

Annually:
1. CBC with DLC to monitor for cytopenias,
2. IgG levels and lymphocyte subpopulations,
3. Pulmonary function tests after age seven years.

Regular assessment of
-Liver function (r/o severe disease d/t cryptosporidium).
-Abdominal imaging for neoplasms/lymphomas
-PCR testing for the presence of enteric pathogens including Cryptosporidium.
-Lymph node biopsy: Monitor growth and general health with a LOW THRESHOLD for LN biopsy d/t elevated oncologic risk.

Question 41

Bruton agammaglobulinemia can be confused with transient hypo-gamma-globulinemia of infancy (THI) as both p/with increased susceptibility to infections around 6 months of age when transplacental maternal IgG levels have declined. How can these conditions be differentiated?

Answer 41

B-cell numbers;

B-cells are absent/↓ in Bruton agammaglobulinemia;

B-cell levels are normal in THI.

Question 42

What is/are the differentiating features of Bruton agammaglobulinemia and CVID, both of which p/with similar symptoms?

Answer 42

Bruton agammaglobulinemia:
-boys (XLR),
-onset ~ 6 months of age,
-B-cells are absent/↓↓↓
-severe c/p

CVID:
-~ 15-35 yr-old
-both males and females.
-Total # B-cells normal but plasma cells ↓↓.
-c/p less severe.

Question 43

Transient hypo-gammaglobulinemia of infancy (THI) is a primary immunodeficiency caused by a ______ in an infant beginning between 5 and 24 months of age.

Answer 43

a persistent but transient low state of IgG levels following the transition between maternal transplacental IgG decline and infant IgG catch-up phase such that infant IgG levels do not catch up to normal reference range.

Question 44

In Transient hypo-gamma-globulinemia of infancy (THI), the low IgG levels typically return to reference range by ___ age.

Answer 44

2-6 years of age

Question 45

Because the majority (~45%) of body calcium is bound to albumin, total calcium should always be corrected for albumin level before the diagnosis of hypocalcemia is made. There is an approx. ____ drop in total serum calcium for every 1 g/dL (10 g/L) reduction in the serum albumin levels.

Answer 45

approx. 0.8 mg/dL (0.25 mmol/L) drop in total sr. calcium for every 1 g/dL (10 g/L) reduction in the serum albumin concentration.

Question 46

Changes in pH will affect_____ form of calcium, whereas changes in serum albumin will affect ___ form of calcium.

Answer 46

Changes in pH will affect the ionized form of Ca2+ (biologically active aka free Ca2+) in the serum, whereas

changes in serum albumin will affect total sr. calcium without changing the level of free calcium.

Question 47

Serum calcium levels are rigidly controlled by _____.

Answer 47

PTH, Vit. D, Calcitonin, and FGF23.

Question 48

How do acid-base disturbances affect serum Ca2+ levels?

Answer 48

In acidosis, more free H+ in the blood bind with albumin, reducing albumin availability for Ca2+ binding -> increased free (aka ionized) Ca2+ in the blood (aka HYPERCALCEMIA);
an acidic environment also promotes the exchange of high EC H+ ions for IC Ca2+, increasing ionized calcium levels in the blood.

On the other hand, in alkalosis (less free H+ in blood) more Ca2+ is able to bind with albumin leading to HYPOCALCEMIA. Also, there is exchange of high EC Ca2+ for IC H+.

Thus, overall, acid-base disturbances alter the binding capacity of Ca2+ to albumin, and also affect the exchange of ca2+ and H+ ions between the IC and EC space.

Question 49

The major T-cell deficiency disorders in pediatric patients include _____ conditions (list all).

Answer 49

1. Thymic Hypoplasia/ Aplasia (DiGeorge Syndrome)
2. SCID
3. Ataxia Telangiectasia
4. Wiskott-Aldrich syndrome

Question 50

Inappropriate development of the pharyngeal pouches predominantly d/t microdeletion of chr. 22 at a location q11.2 results in a broad range of phenotypic manifestations of _____ syndrome.

Answer 50

DiGeorge syndrome (DGS)

pharyngeal pouch anomalies: CATCH-22
-Conotruncal cardiac anomalies (TOF, VSD).
-Abnormal facies: retrognathia or micrognathia, long face, short philtrum, low-set ears.
-Thymic Hypoplasia/aplasia -> T-cell deficiency.
-Cleft palate.
-Hypocalcemia.

Question 51

The various syndromes under the bigger umbrella of 22q11 deletion syndromes include ______ (list all).

Answer 51

-DGS
-Shprintzen-Goldberg syndrome
-Velocardiofacial syndrome
-Cayler cardiofacial syndrome
-Sedlackova syndrome
-Conotruncal anomaly face syndrome.

Question 52

True/False?
Most of the 22q11 deletion mutations arise de novo with no genetic abnormalities noted in the genome of the parents of children with DGS.

Answer 52

true

Question 53

Thymic aplasia (complete absence) in DGS is very rare, affecting ____% of patients with DGS, and is usually a/w ____.

Answer 53

less than 1% of patients with DGS; usually a/w a form of severe combined immunodeficiency (SCID).

Question 54

Individuals affected by DGS have a ____- fold increased risk of developing schizophrenia.

DGS: DiGeorge Syndrome

Answer 54

30-fold

Data Source: https://www.ncbi.nlm.nih.gov/books/NBK549798/

Question 55

Patients with 22q11.2 deletion syndrome usually have characteristic facial features such as ____ (list most).

Answer 55

-Retrognathia or micrognathia
-Long face
-High and broad nasal bridge
-Narrow palpebral fissures
-Small teeth
-Asymmetrical crying face
-Downturned mouth
-Short philtrum
-Low-set, malformed ears
-Hypertelorism
-Dimple on the tip of the nose

Question 56

True/False?
The majority of patients with DGS have minor immunodeficiency, with preservation of T cell function despite decreased T cell production;
hence, immunization, boosters, IVIG, and antibiotic prophylaxis regimens should revolve around the individual patient’s laboratory values.

Answer 56

True.

Question 57

Mainstay management of immunodeficiency in neonates with complete DGS (cDGS) requires ____ treatments/strategies.

Answer 57

-ISOLATION,
-IVIG,
-antibiotic prophylaxis, and
-thymic or hematopoietic cell transplant (HSCT).

Question 58

In patients with DGS, antibody titer in response to administered vaccines should be re-evaluated every ____ months/years to determine the necessity of re-vaccination.

Answer 58

every 6-12 months

Question 59

Rotavirus vaccine has been a/w diarrheal illness in patients with ___ type of immunodeficiency.

Answer 59

reduced T-cell function (SCID, DGS etc.).

Question 60

True/False?
Cardiac anomalies a/w DiGeorge syndrome, if not diagnosed during the fetal ultrasound, may present shortly after birth as life-threatening cyanotic heart disease.

Answer 60

True.

Question 61

Why must blood/blood products be irradiated, and rendered CMV-negative and leukocyte-reduced before transfusion in DGS patients?

Answer 61

-to prevent transfusion-associated GVHD, and

-to reduce lung injury, especially in surgical cases that may require cardiopulmonary bypass.

Question 62

Hypocalcemia in DGS is manageable with ____ treatment agents.

Answer 62

calcium and vitamin D supplementation.

Question 63

____ is used to t/t hypocalcemia in DGS patients refractory to standard therapy with calcium and vit. D.

Answer 63

Recombinant human PTH.

Question 64

Ataxia telangiectasia aka Louis-Bar Syndrome is a rare autosomal ____ condition characterized by ___ (list characteristic findings).

Answer 64

autosomal recessive; characterized by a TRIAD of

1. Progressive cerebellar atrophy
2. Oculo-cutaneous telangiectasias,
3. Immune (IgA, IgG, CD4) deficiency.

-↑ incidence of malignancy,
-radiosensitivity, and
-↑ sr. AFP levels.

Question 65

What is the pathogenic mechanism in Ataxia telangiectasia?

Answer 65

loss-of-function mutation of the *ATM gene -> aberrant repairing of ds DNA breaks caused by pathogenic triggers such as oxidative damage, ionizing radiation, alkylating agents etc. -> cell death in susceptible tissues (cerebellum, others), and malignant proliferation.

*Ataxia Telangiectasia Mutated gene

Question 66

What are the three different C/P phenotypic variants of Ataxia telangiectasia (A-T)?

Answer 66

1. Classic AT: onset in childhood within the 1st decade; severe form.
2. Intermediate: Onset in 1st/2nd decade but milder than classic form.
3. Adult-onset: milder and slowly progressive.

Question 67

Neuro-cognitive manifestations in Ataxia telangiectasia include ____ s/s.

Answer 67

-Progressive Ataxia
-Dysarthria,
-oculomotor apraxia, nystagmus, saccadic intrusions, & hypo-metric saccades.
-Basal ganglia involvement: tremor, parkinsonism, chorea, dystonia, and myoclonus.
-Axonal neuropathy: orthopedic abnormalities
-Mild to moderate cognitive impairment: language, memory, and executive functions.

https://pubmed.ncbi.nlm.nih.gov/29436738/

Question 68

Define oculomotor apraxia?

Answer 68

Impaired vision and reading skills d/t deficiency in the voluntary, horizontal, lateral, and fast eye movements (saccades) with retention of slow pursuit movements;
the inability to follow objects visually is often compensated by head movements.

Question 69

The initial movement disorder manifestations in Ataxia-telangiectasia include _____ findings (list most).

Answer 69

-cerebellar symptoms (67%),
-dystonia (18%),
-choreoathetosis (10%), and
-tremors (4%),

*parkinsonism and myoclonus are not reported as initial features.

DataSource: https://pubmed.ncbi.nlm.nih.gov/29436738/

Question 70

What are the most prevalent movement disorders during the disease course in patients with Ataxia-telangiectasia?

Answer 70

-cerebellar symptoms (96%),
-myoclonus (92%) (not an initial symptom),
-dystonia (89%),
-choreoathetosis (89%),
-tremor (74%), and
-parkinsonism (41%) (not an initial symptom).

Question 71

Ataxia telangiectasia is a/w a higher incidence of ____ malignancies.

Answer 71

lymphoid malignancies.

Question 72

Ataxia telangiectasia is the ____ most common autosomal recessive ataxia in children, after ____ ataxia, but it is the most common genetic ataxia with onset in ____ age.

Answer 72

2nd most common autosomal recessive ataxia after Friedreich’s ataxia;

most common genetic ataxia with onset in the first decade of life.

Question 73

___ is usually the first noticeable sign in the classic form of Ataxia telangiectasia.

Answer 73

ataxia;
instability of the trunk in toddlers or an unstable gait in a child who can walk.

AT is the 2nd most common cause of ataxia in children after Friedrich’s ataxia, and the most common ataxia with onset in the first decade of life.

Question 74

Patients with Ataxia telangiectasia often need a wheelchair-accessible vehicle by the age of _____.

Answer 74

10 years

Question 75

Telangiectasias, which are present in almost all cases of A-T, usually become evident at ___ age.

Answer 75

after the age of 6.

Question 76

Telangiectasias in A-T develop in ____ locations.

Answer 76

-Eyes (most frequently) esp. conjunctiva, and/or
-sun-exposed areas (face, nasal ala, ears).

Other areas include the brain and bladder.

Question 77

True/False?

Bleeding is a common complication of telangiectasias in A-T patients.

Answer 77

False;

Telangiectasias do not evolve and do not tend to bleed.

Question 78

What are some skin manifestations other than telangiectasias in A-T patients?

Answer 78

premature aging and cutaneous graying.

Question 79

Immunological impairment is common in patients with Ataxia telangiectasis, affecting about _____ % of cases.

Answer 79

about two-thirds of cases (~67%).

Data Source: https://www.ncbi.nlm.nih.gov/books/NBK519542/

Question 80

Immunological impairment in Ataxia telangiectasia is marked by _____.

Answer 80

-Low IgA & IgG levels, with
-variable IgM, and
-low total CD4 cell count.

Question 81

The immunodeficiency in Ataxia telangiectasia predisposes to _____.

Answer 81

1. recurrent sinopulmonary infections-> bronchiectasis, restrictive lung disease.
2. Autoimmune diseases.
3. Chronic inflammatory diseases.

Question 82

About ____% of patients with A-T will develop a tumor.

Answer 82

25% to 30%

Data Source: https://www.ncbi.nlm.nih.gov/books/NBK519542/

Question 83

The most common malignancy (ies) in patients with Ataxia Telangiectasia is/are ____.

Answer 83

-leukemia and lymphoma (arise early in life).
-Solid tumors: breast, melanomas, gastric, or liver tumors.

Overall, 25-30% of patients with AT will develop a tumor.

Question 84

Exposure to _______ and _____ (? x-rays, gamma rays, UV rays) must be avoided in patients with Ataxia Telangiectasia due to an extreme detrimental radiosensitivity overall as well as of the tumors.

Answer 84

x-rays and gamma-rays

*not ultraviolet (UV) rays

Question 85

Which metabolic derangements may be seen in patients with Ataxia Telangiectasia?

Answer 85

-Insulin resistance/diabetes,
-hypercholesterolemia,
-hepatic steatosis.

Question 86

Endocrine system involvement in Ataxia Telangiectasia can present with _____ s/s.

Answer 86

-Growth hormone deficiency (short stature)
-Gonadal failure -> infertility.

Question 87

Laboratory tests used as aids to clinical and neuro-imaging studies in the diagnosis of Ataxia Telangiectasia include ___ tests.

Answer 87

-↑↑ AFP: characteristic feature.
-↓ total IgG & IgA with
-variable levels of IgM.

Question 88

Live vaccines are contra-indicated in patients with Ataxia Telangiectasia due to ___.

Answer 88

low T-cell (CD4) count.

Question 89

Other than the mainstay management in the form of support for neurologic manifestations and IVIG with antibiotics for immuno-deficiency, patients with Ataxia Telangiectasia must undergo diligent surveillance for early diagnosis and/or prevention of sequelae/complications such as ______.

Answer 89

-malignancies (early diagnosis).

-pulmonary, restrictive lung disease (for anesthesia or surgery requirements in the future).

Question 90

What is the characteristic etiologic difference between DGS and SCID?

Answer 90

DGS is primarily a T-cell and PTH deficiency disorder;

SCID is a combined T- & B-cell (+/- NK cell) deficiency disorder a/w severe early c/p and early death d/t severe and opportunistic bacterial, viral, fungal and protozoal infections.

Question 91

What is the inheritance pattern of SCID?

Answer 91

-Autosomal
-Sporadic
-X-linked (most common).

Question 92

What are the different etiopathological types of SCID?

Answer 92

1. T- B- NK- caused by
   -Reticular dysgenesis -> lack of stem cells, or
   -ADA deficiency/defect -> toxic metabolites in T, B, and NK cells.
2. T- B- NK+ caused by
   -RAG1/RAG2 defect-> RAG enzymes snip DNA for VDJ rearrangement for TCR and BCR, or
   -Artemis deficiency -> failure to repair DNA after RAG1/2 snips.
3. T- B+ NK- (can be X-linked) c/by
   -lack of common gamma chain -> absent IL receptor for cytokines, or
   -Jak 3 deficiency (Jak 3 cannot follow signal via IL-R binding).
4. T- B+ NK+ c/by
   -IL-7 deficiency d/t lack of IL-7 alpha chains -> failed T cell differentiation, or
   -CD3 activation failure -> defective signal transduction.
5. T+ B+ NK+ c/by
   -MHC class I deficiency (bare lymphocyte syndrome) d/t defect in TAP-2 transcription,
   MHC class II deficiency d/t defect in transcription of MHC class II proteins.

Question 93

The majority (~ 89%) of the patients with SCID p/w the first symptoms of the disease within ___ months of age.

Answer 93

within 6 months of age.

Question 94

The clinical manifestations observed at presentation in SCID include ____ s/s.

Answer 94

-recurrent pneumonia (66%),

-failure to thrive (60%), and

-chronic diarrhea (35%).

Question 95

____ cells develop separately from T and B cells and can provide a degree of protection in individuals with T and B cell dysfunction.

Answer 95

Natural killer (NK) cells.

NK cells are members of a specialized cohort of leukocytes collectively referred to as innate lymphoid cells (ILC) derived from a common ILC precursor.
ILCs are distinguished from B- & T cells by their lack of somatic rearrangement of Ig and TCR genes.
NK cells belong to ILC1(of total 3 ILC subsets), and their characteristics include the production of cytokines esp. IFNγ, a variety of chemokines, and the mediation of MHC-independent and antibody-dependent cellular cytotoxicity.
In addition to direct killing of pathogen-infested and malignant cells, recent evidence suggests that NK cells are also capable of immunological memory.

Question 96

The most severe form of SCID seen with reticular dysgenesis causing lack of stem cells, or with ADA deficiency/defect leading to accumulation of toxic metabolites in T, B, and NK cells, is due to ____.

Answer 96

complete lack of physical or function of T, B, and NK cells.

Question 97

Assessing for the presence of ____ cells helps determine the severity and prognosis of the SCID.

Answer 97

NK cells.

Question 98

On HP exam of the GIT in SCID patients, numerous _____ can be found especially over the mucosa of the jejunum d/t complete lack of protective immunity.

Answer 98

Giardia lamblia.

Question 99

In SCID, microscopic examination of the thymic stroma reveals a fetal appearance with ___ findings.

Thymus stromal cells located in different areas of the thymus are subsets of specialized cells that include all non-T-lineage cells, such as thymic epithelial cells (TECs), endothelial cells, mesenchymal cells, dendritic cells, and B lymphocytes; they provide signals essential for thymocyte development and the homeostasis of the thymic stroma.

Answer 99

absence of lymphoid cells and the Hassall’s corpuscles.

*Hassall’s corpuscles are groups of epithelial cells within the thymic medullary stroma. Human Hassall’s corpuscles express thymic stromal lymphopoietin (TSLP) which activates thymic CD11c +ve Dendritic cells to express high levels of CD80 & CD86; the TSLP-conditioned Dendritic cells are then able to induce the proliferation and differentiation of CD4(+)CD8(-)CD25(-) thymic T cells into CD4(+)CD25(+)FOXP3(+) Regulatory T cells; thus Hassall’s corpuscles have a critical role in Dendritic-cell mediated secondary positive selection of medium-to-high affinity self-reactive T cells, leading to the generation of CD4(+)CD25(+) regulatory T cells within the thymus. *

Question 100

Biopsy of lymph nodes (if detectable) shows ____ findings in SCID patients.

Answer 100

-severe cellular depletion with lack of cortico-medullary differentiation or follicle formation.

Question 101

Mainstay m/m in SCID patients include ____ treatments.

Answer 101

-IVIG
-Antibiotic prophylaxis for esp. PCP.
-BMT or SCT.

Question 102

A male newborn baby/infant who presents with petechiae, bruises, and congenital or early-onset thrombocytopenia a/w small platelet size must be evaluated for _____ immunodeficiency disorder.

Answer 102

Wiskott- Aldrich syndrome (WAS).

MN: Wiskott-All-Drink (WATER) syndrome!

W: WASp gene defect
A: Impaired interaction between APCs and T-cells.
T: Thrombocytopenia
E: Eczema
R: Recurrent infections

Question 103

____ is a rare X-linked disorder with a characteristic triad of immunodeficiency, thrombo-cytopenia, and eczema.

Answer 103

Wiskott- Aldrich syndrome (WAS).

MN:
Wiskott-All-Drink (WATER) syndrome!
W: WASp gene defect
A: Impaired interaction between APCs and T-cells.
T: Thrombocytopenia
E: Eczema
R: Recurrent infections

Question 104

Wiskott-Aldrich syndrome (WAS) results from a mutation in the ____ gene.

Answer 104

WAS gene mutation -> impairs encoding of the WAS protein (WASp) -> impaired cellular signaling and immunological synapse formation.

WASp is expressed in non-erythroid hematopoietic cells; it functions as a bridge between signaling and movement of actin filaments in the cytoskeleton facilitating the interaction between T-cells and APCs such as dendritic cells as well as other immunological response cells.

Question 105

How does the “loss of function” mutation in the WASp gene affect immunological response?

Answer 105

“Loss of function” mutation -> WAS, or *XLT via the following mechanisms:
1. ↓↓ phagocytosis and chemotaxis in WASp-deficient myeloid lineage cells.
2. impaired chemotaxis of monocytes, macrophages, and dendritic cells.
3. increased clearance of platelets, ineffective thrombocytopoiesis, reduced platelet survival -> XLT.

*X-linked Thrombocytopenia

Question 106

How does the “gain of function” mutation in the WASp gene affect immunological response?

Answer 106

“gain-of-function” missense mutations impair the autoinhibitory conformation of the WASp molecule -> increased actin polymerization and hyperactive migration of neutrophils into tissues-> congenital neutropenia.

Question 107

Describe the spectrum of clinical presentation in Wiskott-Aldrich syndrome (WAS).

Answer 107

variable presentation ranging from

-classic WAS: severe c/p (loss of function mutation).
-X-linked thrombocytopenia (milder); (loss of function mutation).
-X-linked neutropenia (milder); (gain of function mutation). .

mutation in the actin regulator WASp.

Question 108

____ is the most common finding present at the time of diagnosis of WAS usually around ____ age.

Answer 108

*Bleeding and thrombocytopenia, usually present at birth;

bleeding in the form of
-petechiae (common)
-prolonged bleeding from the umbilical stump or after circumcision (common).
-Other: purpura, hematemesis, melena, epistaxis, hematuria, and such life-threatening symptoms as oral, gastrointestinal, and intracranial bleeding.

Question 109

_____ is some cases of WAS is a/w a poor prognosis.

Answer 109

-severe refractory thrombocytopenia.

Question 110

Eczema of varying severity develops in approx. ___ % of WAS patients during the first year of life and resembles classical atopic dermatitis.

Answer 110

approx. 50% of WAS patients

Data Source: https://www.ncbi.nlm.nih.gov/books/NBK539838

Question 111

The classic presentation of WAS include s/s such as ___ (list all).

Answer 111

A male newborn baby presenting at birth with bleeding and low platelets, and eventually with
-eczema, and
-recurrent otitis media.

Question 112

WAS patients are at increased risk of developing ___ complications.

Answer 112

-autoimmune diseases
-malignancies (lymphoma/leukemia, others)

Question 113

____ is necessary for diagnostic confirmation of WAS.

Answer 113

presence of a deleterious mutation in the WAS gene.

Question 114

Immunology assessment reveals ___ findings in WAS patients.

Answer 114

-↓↓ number and function of T cells and regulatory T cells,

-↑↑ IgE/IgA, normal IgG,↓ IgM.

-ALC is usually normal during infancy, but T and B cell numbers decrease later in life in classic WAS.

-defective antigen-antibody response,

-impaired cytotoxicity of NK cells with normal to increased cell numbers,

-impaired chemotaxis of neutrophils and phagocytic cells.

Question 115

____ is most frequently the cause of death in patients with classic WAS.

Answer 115

Bleeding.

Question 116

The prognosis of ____ type of WAS is good with life expectancy as close to the normal population.

Answer 116

X-linked thrombocytopenia subtype of WAS.

Question 117

What is the common ground between immunological disorders such as Chronic granulomatous disease (CGD), Leukocyte adhesion deficiency (LAD), Chediak-Higashi Syndrome, and Job syndrome (aka Hyper-IgE syndrome)?

Answer 117

all are phagocytic cell disorders.

Question 118

Hyper-IgM syndrome is a ____ cell disorder, whereas Hyper-IgE syndrome (Job syndrome) is ___ cell disorder.

Answer 118

Hyper-IgM syndrome is a B-cell disorder (CD40 ligand deficiency) such that IgM cannot class switch to form other Ig’s.

Hyper-IgE (Job) syndrome is a phagocytic cell disorder (neutrophil chemotaxis defect).

Question 119

What is the underlying defect in CGD?

Answer 119

Defective production of ROS (e.g. superoxide O-) d/t loss of function mutations of the NADPH oxidase complex subunits within phagocytic cells such as neutrophils, monocytes, macrophages -> they cannot kill the engulfed microorganisms -> recurrent infections esp. with *catalase-positive organisms.

MN: CATs Need PLACES to Belch their Hairballs! Catalase +ve: Nocardia, Pseudomonas, Listeria, Aspergillus, Candida, E. coli, Staph, Serratia, B. Cepacia, H. Pylori.

Question 120

What is the inheritance pattern of CGD?

Answer 120

2/3rd are X-linked (1/3 de novo).

1/3rd are autosomal recessive.

Question 121

True/False?
Children with the X-linked variant of CGD (2/3rd) tend to have an earlier onset and severe disease as compared to the ones with autosomal recessive form.

Answer 121

True

Source: https://www.ncbi.nlm.nih.gov/books/NBK493171/

Question 122

How are patients with CGD able to maintain their capacity to kill catalase-negative organisms?

Answer 122

Patients with CGD can use the hydrogen peroxide (H2O2) produced by catalase -ve microbes to form ROS, and thus, consequentially, bypass the intrinsic CGD defect in forming ROS via the NADPH pathway.

On the other hand, catalase produced by *catalase +ve organisms can inactivate the H2O2 produced by some bacteria and fungi. hence, CGD patients are highly susceptible to infections with catalase +ve organisms d/t the loss of the bypass pathway to form ROS.

*MN: CATs Need PLACES to Belch their Hairballs! Catalase +ve: Nocardia, Pseudomonas, Listeria, Aspergillus, Candida, E. coli, Staph, Serratia, B. Cepacia, H. Pylori.

Question 123

Symptoms in CGD typically begin within _____ years of life; however, some experience symptoms later in life. The median age at diagnosis is _____ age.

Answer 123

begin within the first 2 years of life;

The median age at diagnosis is 2.5 to 3 years of age.

Question 124

True/False.

CGD infections often begin in tissues/organs exposed to the outside environment such as gingiva, lungs, GIT, and skin including the draining lymph nodes followed by contiguous or hematogenous spread to internal organ systems such as the liver, bones, kidney, and brain.

Answer 124

True.

Question 125

Describe the spectrum of clinical illness in patients with CGD.

Answer 125

-C/P: highly variable (based on the gene mutated, mutation type, and position of the mutation).

-Onset: recurrent bacterial and fungal infections typically within the first 2 years of life (median 2.5-3 yrs);
milder phenotypes may present in late childhood/adulthood.

-Initial c/p: FTT along with h/o recurrent infections esp. with catalase +ve organisms.

-Infections begin in exposed systems causing gingivitis, periodontinitis, skin abscesses, cellulitis, impetigo, URTI/LRTI, and GI infections, along with regional adenitis -> contiguous or hematogenous spread -> osteomyelitis, bacteremia, liver, kidney, and brain infections.

-Granulomas: skin, GIT, GU tract are hallmark features of the disease.

Question 126

NADPH oxidase assays used to measure _____ in the diagnosis of CGD include ____ and ____ tests.

Answer 126

measure superoxide;

include
-cytochrome c reduction assay, and
-nitroblue tetrazolium (NBT) slide assay.

Question 127

____, and ____ assays used to diagnose CGD measure hydrogen peroxide.

Answer 127

-Dihydrorhodamine-123 (DHR) assay, and
-Amplex Red assay.

Question 128

What are the three main principles of management of CGD?

Answer 128

1) lifelong antibacterial and antifungal prophylaxis,

2) early diagnosis of infection, and

3) aggressive management of infectious complications.

Question 129

Globally accepted prophylactic therapy in CGD includes t/t with ____ and ___.

Answer 129

TMP-SMX and Itraconazole

+/-
IFN-gamma (reduces the incidence of serious infections).

Question 130

____is the only established curative treatment for CGD, and ____ is a promising potential curative t/t for CGD.

Answer 130

Hematopoietic cell transplantation (HCT) is an established curative t/t;

gene therapy is promising curative t/t.

Question 131

____ is a combined B- & T-cell immunological disorder of chemotaxis, and decreased phagocytosis, characterized by an inability to form pus with recurrent infections.

Answer 131

Leukocyte adhesion deficiency (LAD).

Question 132

What is the primary immunological issue in leukocyte adhesion deficiency (LAD)?

Answer 132

decreased phagocytic activityd/t impaired chemotaxis of leukocytes.

THINK:leukocytes cannot extravasate to infected tissues to phagocytose the bacterial pathogen! -> recurrent skin, mucosal, and pulmonary bacterial infections.

MN: LAD! (Late separation of UC, Absent pus, dysfunctional neutrophils).

Question 133

____ may be the earliest sign of LAD in a newborn baby.

Answer 133

Omphalitis with delayed separation of the umbilical cord (> 14 days post-birth).

Question 134

True/False?
LAD is primarily a T-cell immunodeficiency disorder.

Answer 134

False;
LAD is a chemotaxis disorder of leukocytes (phagocytic cells);

hence, maybe considered a combined B- and T-cell immunodeficiency disorder.

Question 135

What are the hallmark features of infections a/w LAD?

Answer 135

-No pus with minimal inflammation in wounds (as neutrophils cannot enter infected tissues d/t chemotaxis defect).

-Leukocytosis esp. neutrophilia (as neutrophils cannot extravasate from blood).

Question 136

In LAD, leukocytes are unable to emigrate to the infected tissues to phagocytose the offending microorganisms due to _____ (? pathophysiology).

Answer 136

defect in the common β-chain of Integrins: LFA-1/Mac-1, p150, and p95 -> decreased expression of adhesion proteins on the surface of phagocytic leukocytes (lymphocytes, granulocytes, monocytes, and large granular lymphocytes) -> phagocytic cells unable to emigrate to infected/inflammed tissue.

β2 integrins are heterodimeric surface receptors composed of a variable α (CD11a-CD11d) and a constant β (CD18) subunit and are specifically expressed by leukocytes.

Question 137

____ cell activity is not affected in LAD.

Answer 137

NK cell activity.

Question 138

Which genetic mutations are responsible for the deficiency of the adhesion proteins (integrins) on phagocytic leukocytes leading to the pathophysiology of LAD?

Answer 138

-CD18 gene mutations (LAD type I) -> deficient beta-2 integrin.

-Absence of *Sialyl Lewis X of E-selectin (CD 15a) (LAD type II).

-beta integrins 1, 2, and 3 defects (esp. kindlin-3 gene defect) (LAD Type III) -> impairment of the integrin activation cascade.

β2 integrins are heterodimeric surface receptors composed of a variable α (CD11a-CD11d) and a constant β (CD18) subunit and are specifically expressed by leukocytes.
Sialyl LewisX (sLeX) is a necessary partner for the three selectins (L, P and E) that allow the circulating leukocytes to stick and roll along the endothelial cells to accumulate at a site of inflammation. sLeX is a tetra-saccharide carbohydrate usually attached to the O-glycans on cell surfaces. It plays a vital role in cell-to-cell recognition, attraction of sperm by the egg and eventual sticking, bonding, and zygote formation. sLeX is also one of the most important blood group antigens and is displayed on the glycolipids present on the cell surface; sLeX determinant is also expressed preferentially on activated Th1 cells (not Th2 cells).

Question 139

LAD has ____ mode of inheritance.

Answer 139

an autosomal recessive

Question 140

_____and _____ are the most prevalent clinical findings in patients with LAD.

Answer 140

recurrent bacterial infections with lack of pus (93.3%), and
poor wound healing (86%).

Question 141

Beginning in the neonatal period., individuals with LAD commonly suffer from bacterial infections such as ______ (list most).

Answer 141

-omphalitis,
-pneumonia,
-gingivitis, and
-peritonitis.

*Individuals with LAD do not form abscesses because granulocytes cannot migrate to the sites of infection.

Question 142

Severe LAD (LAD-I) without HSCT is fatal by the age of ______years.

Answer 142

1-2 years.

Question 143

LAD patients with moderate disease characterized by _____ may survive childhood with appropriate antibiotic therapy; eventually, however, multiple infections affecting the skin and mucosal surfaces may lead to a documented mortality rate that exceeds 50% by the age of 40 years.

Answer 143

the presence of 2% - 30% CD18-expressing neutrophils.

Question 144

____on HPE with ____ finding in lab test are hallmark features of LAD?

Answer 144

complete lack of neutrophils in inflammatory infiltrate study of infected tissue or umbilical cord remnant (evident with lack of pus on gross exam), and markedly elevated TLC (> 29000/μL) esp. NEUTROPHILIA d/t an impaired mobilization of leukocytes to extravascular sites of inflammation.

Question 145

Infections in LAD type ___ are less severe and fewer as compared to LAD type ____.

Answer 145

LAD II infections are less severe and fewer as compared to infections in LAD I.

Question 146

The most common complications in LAD are ______ (list all/most).

Answer 146

-infectious diseases affecting the skin, respiratory system, GIT, oral cavity, and some internal organs with high mortality rate.

Question 147

The treatment of LAD-I is _____.

Answer 147

allogeneic HSCT.

Question 148

The clinical spectrum of ____ immunological syndrome occurs d/t defective neutrophil chemotaxis caused by microtubule dysfunction leading to recurrent overwhelming pyogenic infections, neurological s/s, pancytopenia, and lympho-histiocytosis.

Answer 148

Chediak-Higashi syndrome

MN: Sir Chediak-Higashi’s LYST of demands are LMNOP!

-LYST (lysosomal traffiking) gene mutation.

-L: lymphohistiocytosis
-M: microtubule dysfunction
-N: neuropathy (peripheral)
-O: Oculocutaneous albinism (partial)
-P: Phagolysosome formation issues; Pancytopenia.

Question 149

What is the inheritance pattern in Chediak-Higashi syndrome?

Answer 149

autosomal recessive

Question 150

What is the underlying defect in Chediak-Higashi syndrome?

Answer 150

Mutation in the LYST (aka CHS1) gene -> impaired lysosomal trafficking -> Disorganized synthesis, fusion and transport of cytoplasmic granules esp. within leukocytes, fibroblasts, dense bodies of platelets, azurophilic granules of neutrophils, and melanosomes -> non-functional lysosomes and accumulation of abnormally large fused azurophilic intracytoplasmic granules within the affected cells -> **impaired neutrophil chemotaxis/mictotubule polymerization **-> c/p of partial oculo-cutaneous albinism, recurrent infections, peripheral neuropathy, neutropenia.

Question 151

The onset of the disease in Chediak-Higashi syndrome is typically ____ age.

Answer 151

typically after birth and under the age of 5 years.

Question 152

The immunodeficiency in Chediak-Higashi syndrome typically begins at ____ age and presents as _____.

Answer 152

Immunodeficiency typically begin in infancy, and presents as severe bacterial and fungal infections commonly of the skin and URT including periodontitis, with staphylococcal, streptococcal, pneumococcal, and beta-hemolytic species being the most predominant.

Question 153

True/False?
Bleeding symptoms in Chediak-Higashi syndrome are usually mild and include epistaxis, mucosal or gum bleeding, and easy bruising; symptoms are mild and generally do not require any medical intervention.

Answer 153

True.

Question 154

_____, the most common cause of mortality in Chediak-Higashi syndrome is marked by diffuse lymphohistiocytic infiltration of the liver, spleen, bone marrow, lymph nodes, and the CNS presenting with fever, hepatosplenomegaly, lymphadenopathy, neutropenia, anemia, and sometimes thrombocytopenia.

Answer 154

the accelerated phase.

*a/w high mortality.

Question 155

This accelerated phase in Chediak-Higashi syndrome arises in approx. ______% of the individuals affected, occurring around ____age.

Answer 155

85% of affected individuals;

can occur at any age.

Question 156

_____ complications usually arise and manifest by early adulthood in Chediak-Higashi syndrome despite successful allogeneic hematopoietic stem cell transplantation.

Answer 156

Neurological complications

*include stroke, coma, ataxia, tremor, motor, and sensory neuropathies, and absent DTRs.

Question 157

Clinically, the diagnosis of Chediak-Higashi syndrome should be considered in individuals who exhibit _____ s/s.

Answer 157

infants/children (< 5 yr-old) exhibiting signs of
-immunodeficiency with
-pigment dilution of the skin, hair, or eyes,
-congenital/transient neutropenia, and
-signs of unexplained neurologic symptoms or neurodegeneration.

Question 158

____ is the most common cause of death in patients with Chediak Higashi syndrome.

Answer 158

-recurrent infections or
-the development of an accelerated phase characterized by marked lymphoproliferation into major organs.

Question 159

True/False?
~ 80% of deaths in Chediak-Higashi syndrome occur in the first decade of life, and those who survive into adulthood develop progressive neurological symptoms.

Answer 159

True.

Question 160

____ is curative in Chediak-Higashi syndrome.

Answer 160

allogeneic HSCT;

*HSCT, however, only cures the hematological and immune dysfunction; it does not stop the progressive neurological impairment.

Question 161

______ should be suspected in any male infant or child p/w P. jirovecii pneumonia, persistent diarrhea d/t Cryptosporidium, recurrent bacterial URTI &/or LRTI, neutropenia, sclerosing cholangitis, and associated bile duct tumors with absent/low serum IgG & IgA, normal/elevated serum IgM, normal number and distribution of T, B, and NK lymphocyte subsets, normal T-cell proliferation, and decreased expression of CD40L on the surface of activated CD4 cells (not universal).

Answer 161

X-linked hyper IgM syndrome (HIGM1).

Question 162

Ataxia Telangiectasia (AT) can be distinguished from Friedreich’s ataxia based on ______.

Answer 162

Serum AFP levels;
high in AT.

Question 163

Job Syndrome aka _____ is a rare, primary immunodeficiency phagocytic deficiency disorder characterized by the clinical triad of ____, ______, and _______, with elevated IgE levels with early onset in primary childhood.

Answer 163

aka Hyper-IgE syndrome (HIES);

characterized by the clinical triad of
-atopic dermatitis,
-recurrent skin staphylococcal infections, and
-recurrent pulmonary infections, with
-↑↑↑ IgE levels with early onset in primary childhood.

+/- musculoskeletal, CNS, vascular, and ocular involvement.

MN: FATED (Coarse Facies, staph. Abscesses, retained 1o teeth, IgE high, Dermatologic).

Question 164

What are the differentiating features between autosomal dominant HIES (AD-HIES) and autosomal recessive HIEST (AR-HIES), both of which share the characteristic clinical triad of highly elevated serum IgE levels with atopic dermatitis, recurring abscesses of the skin, and recurrent pneumonia?

Answer 164

AD-HIES (aka Type I HIES)
-more frequent than AR-HIES.
-clinical triad + connective tissue, musculoskeletal, & vascular involvement.
-CNS s/s and viral infections LESS frequent than AR-HIES.

AR-HIES (aka Type II HIES)
-rare (less common than AD-HIES.
-clinical triad +
-persistent and mutilating cutaneous viral infections esp. HSV, MCV, HPV,
-Neurological involvement
-NO musculoskeletal alterations as in AD-HIES.

Question 165

The pathophysiology of Job syndrome includes mutation of ____, leading to _____ effects.

Answer 165

STAT3 mutation (AD inheritance) ->
-↑↑↑ production of IgE by B cells,

-loss of the modulation capacity of IL-6, IL-10, and IFN-gamma in the production of B-cells,

-defective chemotaxis of neutrophils.
-IL-10 effect deficiency -> lack of anti-inflammatory effects of IL-10.

-IL-6 effect deficiency -> deficiency of Th17 -> loss of defense against infections mainly bacteria and extracellular fungi.

-disrupted pleiotropic signaling -> long bone fractures and a late rash.

Question 166

The spectrum of clinical illness in Job syndrome include ____ immunological features.

Answer 166

Immunological features: ECZEMA & INFECTIONS.

1. SKIN eczema:
   -onset within few weeks after birth.
   -pruriginous eczematoid rash on scalp & face -> rapid superinfection with S. aureus (weeping, crusty, & follicular lesions).
   -chronic eczematoid eruptions.
2. SKIN Infections:
   -Recurrent staph. abscesses a/w little/no inflammation (cold).
   -Candida infections affecting skin, mucous membranes, and nails.
3. Pulmonary infections:
   -Recurrent pneumonia: d/t S. aureus (predominantly), S. pneumoniae, & Haemophilus -> complicating to
   -recurrent lung abscesses, bronchiectasis, and pneumatoceles.
   -Aspergillus & Pseudomonas colonization of pneumatoceles.
   -Superinfection with PCP.

Other infections:
-extra-pulmonary cryptococcosis and histoplasmosis.
-sinusitis, bronchitis, otitis externa, gingivitis, dental abscess, septic arthritis, and osteomyelitis.

Question 167

Non-immunological features in Job syndrome include ____ s/s.

Answer 167

1. ATYPICAL FACIES:
   -appear in late childhood/early adolescence
   -facial asymmetry, prominent forehead, deep-set eyes, broad nasal bridge, wide fleshy nasal tip, rough facial skin, increased inter-alar distance, prognathism, and high-arched palate.
2. Musculoskeletal:
   -Joint hyperextensibility (68%) -> early onset of degenerative disease.
   -scoliosis (~60%)
   -osteopenia, and decreased bone density -> multiple pathological fractures of long bones & ribs (~50% of patients).
   -Deciduous teeth retention (~70%) -> delayed permanent teeth.
3. Vascular tortuosity or dilatation
   -coronary, cerebral, and aortic aneurysms, and
   -congenital coronary artery abnormalities.
4. Ocular: xanthelasmas, chalazions, strabismus, and retinal detachment.

Question 168

About _____% of the patients with Job syndrome have been reported to retain three or more primary teeth.

Answer 168

About 70%.

Question 169

Diagnostic confirmation of Job syndrome is based on ___ test findings.

Answer 169

-Total Serum IgE > 1000 IU/mL in a patient with a weighted clinical probability score of > 30, indicate an AD-HIES of the defect in STAT3.

Confirmation: heterozygote mutation in STAT3 confirms the diagnosis.

Question 170

Eosinophilia is observed in approx. ____ % of the patients with Job syndrome.

Answer 170

more than 90%.

Question 171

____ may lead to a normal or reduced total WBC count in patients with Job syndrome, most of whom (> 90%) have high eosinophil count.

Answer 171

neutropenia.

Question 172

List some complications seen in patients diagnosed with Job syndrome.

Answer 172

1. Malignancies esp. NHL; others include Hodgkin’s lymphoma, cancers of the vulva, and the lung.
2. Autoimmune: SLE, MPGN, vasculitis, and dermatomyositis.
3. Hypertension d/t vascular abnormalities.
4. Rupture of aneurysms: myocardial or lacunar infarcts.

Question 173

____ are the most common (~ 50%) immunodeficiencies that typically present around/after 6 months of age with recurrent sino-pulmonary and GI infections with/without encapsulated organisms.

Answer 173

B-cell deficiencies

Question 174

2. ____-cell deficiencies tend to present earlier after birth (1-3 months of age), whereas ___-cell deficiencies typically present around/after 6 months.

Answer 174

T-cell;

B-cell

Question 175

Complement deficiencies are characterized by _____.

Answer 175

recurrent bacterial infections with encapsulated organisms.

MN: Yes! Some Killers Have Pretty Nice Capsules. (Yersinia, S. pneumoniae, Klebsiella, H. Influenzae, Pseudomonas, Neisseria, Cryptococcus).

Question 176

Mucus membrane infections, abscesses, and poor wound healing are characteristic features of ____-cell deficiency.

Answer 176

phagocytic cell deficiency.

Question 177

_____ is an autosomal dominant disorder p/w recurrent episodes of angioedema, often provoked by stress or trauma.

Answer 177

Hereditary angioedema.

Question 178

The episodes of angioedema last for about _____ duration in patients with Hereditary angioedema.

Answer 178

2-72 hours.

Question 179

Hereditary angioedema is caused by a deficiency of _____.

Answer 179

C1 esterase inhibitor deficiency -> uncontrolled complement activation during periods of stress or trauma.

C1 esterase inhibitor (C1-INH) in human plasma, belongs to the group of serine protease inhibitors (serpins); plays a major role in inhibiting the complement system, the intrinsic coagulation system, the fibrinolytic system, and the coagulation cascade.

Question 180

____ and ___ are indicated in patients with Hereditary angioedema before surgery.

Answer 180

C1-INH concentrate and FFP.

Question 181

The inability to form the membrane-attack complex (MAC), thus predisposing to recurrent infections with encapsulated organisms such as Neisseria species is characteristic of deficiency of ___ complement factors.

Answer 181

terminal complement factors C5-C9.

Question 182

Patients with terminal complement factors deficiency may rarely, get afflicted with autoimmune diseases such as ____ and ____.

Answer 182

Lupus or GN.

Question 183

Kawasaki disease is an acute, multisystem vasculitis of ____-sized blood vessels.

Answer 183

medium-sized blood vessels.

Question 184

Approx. 25% of children with untreated Kawasaki disease may develop the most common and feared complication of ____.

Answer 184

coronary a. aneurysm.

*baseline echocardiogram is indicated for longitudinal F/up of coronary a. morphology.

Question 185

Kawasaki disease primarily affects ___ age groups, and people of ___ descent.

Answer 185

young children usually < 5 years old;

Japanese and Korean descent.

Question 186

Children in the acute phase of Kawasaki disease present with ____ s/s (list most).

Answer 186

MN: 5 days of CRASH and BURN!

-Conjunctivitis: no discharge, painless
-Rash: truncal, erythematous, polymorphous.
-Adenopathy: unilateral, painful, >1.5 cm.
-Strawberry tongue &/or cracked lips; erythematous mouth/pharynx.
-Hands & feet swollen, red, flaky,

BURN: Fever > 40C x ≥ 5 days.

Question 187

How can Kawasaki disease be clinically differentiated from scarlet fever, both of which present in young children with strawberry tongue, rash, desquamation on hands and feet including erythema of mucus membranes?

Answer 187

children with Scarlet fever have normal lips and no conjunctivitis.

Question 188

Lab workup in Kawasaki disease reveals ____ results.

Answer 188

-Leukocytosis with left-shift
-Elevated ESR
-Elevated CRP
-Normochromic anemia
-Thrombocytosis

+/- hyponatremia
+/- hypoalbuminemia (albumin extravasating from inflamed vessels).

Question 189

Follow-up of uncomplicated cases of Kawasaki disease for coronary a. morphology is indicated at ____ weeks after diagnosis.

Answer 189

2 weeks, and 6-8 weeks after diagnosis.

Question 190

Use of ____ as the best initial therapy in children with Kawasaki disease reduces the risk of coronary a. aneurysm from 25% to ____%.

Answer 190

High-dose ASA plus IVIG;

reduces the risk of coronary a. aneurysm from 25% to 5%.

Question 191

Following the initial best t/t with high-dose ASA (& IVIG) in Kawasaki disease, low-dose ASA is continued until ____ criteria is met.

Answer 191

normalization of laboratory inflammatory markers.

Question 192

Under what condition is ASA indicated to be continued as therapy in patients with Kawasaki Disease?

Answer 192

if coronary a. aneurysm develops.

Question 193

____ therapeutic agents are indicated in IVIG-refractory cases of Kawasaki Disease.

Answer 193

Corticosteroids.

Question 194

Encephalopathy a/w Reyes syndrome in children treated with ASA is due to _____ mechanisms.

Answer 194

hyper-ammonemia secondary to mitochondrial injury and fatty degenerative liver failure.

Question 195

Juvenile idiopathic arthritis (JIA) is an autoimmune disorder defined by morning stiffness and gradual loss of motion that is present for at least _____ (duration) in a patient of ____ age.

Answer 195

present for at least 6 weeks in a patient < 16 years old.

Question 196

Approx. ___ % of cases of Juvenile idiopathic arthritis resolve by puberty.

Answer 196

~95%

Question 197

Juvenile idiopathic arthritis is more common in ____ gender.

Answer 197

girls

Question 198

ANA positivity is seen in ___ types (list all) of Juvenile idiopathic arthritis.

Answer 198

1. Oligoarthritis JIA
2. milder polyarthritis JIA;
   *RF +vity seen in severe disease.
3. Psoriatic arthritis

Question 199

____ is the most common type of JIA.

Answer 199

Oligoarthritis JIA

Question 200

Oligoarthritis JIA involves ____ or fewer joints, whereas polyarthritis JIA involves ____ number of joints.

Answer 200

Oligoarthritis JIA: 4 or less

Polyarthritis JIA: 5 or more joints (usually symmetric).

Question 201

Uveitis may be seen in ___ type (s) of JIA.

Answer 201

-Oligoarthritis JIA (commonly seen).
-ANA +ve polyarthritis JIA
-Psoriatic arthritis.

Question 202

Macrophage activation syndrome (MAS) is a life-threatening complication seen commonly in patients with ____ type of JIA.

Answer 202

systemic juvenile idiopathic arthritis (SJIA), and
-Enthesitis-related arthritis.

*also seen in patients with adult-onset Still disease

Question 203

Macrophage activation syndrome (MAS) seen in systemic JIA characterized by widespread hemophagocytosis and cytokine overproduction develops due to ______.

Answer 203

uncontrolled activations and proliferation of T lymphocytes and well-differentiated macrophages.

Question 204

Macrophage activation syndrome (MAS) caused by uncontrolled activation/proliferation of T-lymphocytes and macrophages is characterized by the sudden onset of ____ s/s.

Answer 204

characterized by the sudden onset of
1. Pancytopenia (Plt. < 262 Giga/L, WBC <4 Giga/L): purpura, easy bruising, mucosal bleeding.

2. Liver insufficiency (AST >59 U/L; hepatomegaly ≥3 cm below costal margin),
3. Coagulopathy (fibrinogen ≤2.5 g/L),
4. Neurologic symptoms (irritability, disorientation, lethargy, headache, seizures, coma).

-high levels of triglycerides, LDH,
-low sodium levels.

Question 205

Because serum levels of all classes of immunoglobulins are below the normal range and because he has no evidence of lymphatic tissue on physical exam (absence of tonsils and lymph nodes), the patient likely has Bruton (X-linked) agammaglobulinemia.

Question 206

Treatment of Bruton (X-linked) agammaglobulinemia consists of regular intravenous immunoglobulin administration with the goal of maintaining IgG trough levels between 500 and 800 mg/dL. Prophylactic antibiotics are also administered to combat recurrent bacterial infections.