random congenital facts

Question 1

For an autosomal dominant disorder, if both parents show no sx, and there are two affected children, what is the likely scenario?

Answer 1

Germline mosaicism.

Question 2

What is penetrance? Variable expressivity?

Answer 2

Penetrance - given the genotype, what is the probability the phenotype manifests? (all or nothing) Variable expressivity - given the genotype, how severe is the phenotype? Pleiotropy - one genotype yields multiple phenotypes.

Question 3

Prader-Willi and Angelman. Inheritance and Sx.

Answer 3

15q11-. Prader-Willi: normally, the maternal copy is silenced, and the paternal copy is functional.

In Prader-Willi, paternal allele is mutated and not expressed. Results in hyperphagia, obesity, low muscle tone, MR.

Angelman: normally, the paternal copy is silenced, and the maternal copy is functional. In Angelman, maternal copy is mutated. Results in hand flapping, happy demeanor, seizures, MR.

Question 4

Autosomal recessive diseases

Answer 4

• ARPKD
• CF
• glycogen storage dz
• hemochromatosis
• Hurler’s (not Hunter’s)
• Phenylketonuria
• Sickle cell
• Sphingolipidoses - (except Fabry’s)
• Thalassemias ** (actually codominant)
• Chediak Higashi

Question 5

X-linked recessive diseases (11)

Answer 5

Be Wise, Fool’s GOLD Heeds HOpe

• (Bruton’s) agammaglobulinemia
  
  • BCR signaling defect - Bruton’s tyrosine kinase - heavy chain can finish VDJ, but light chain cannot
  • recurrent encapsulated infections
• WISkott-Aldrich
  
  • WASp mutation causes small abnormal platelets destroyed in spleen
  • eczema, thrombocytopenia, immune deficiency, bloody diarrhea (secondary to thrombocytopenia)
• Fabry’s
  
  • alpha-galactosidase deficiency
  • Renal and cardiac failure, acroparesthesia, angiokeratoma
• G6PD
• Ocular albinism
• Lesch-Nyhan
• Duchenne’s - frameshift; Becker’s - point; anchors actin to dystroglycans -> ECM
• Hunter’s (Hurler’s is autosomal recessive)
  
  • iduronidate sulfatase, heparan and dermatan sulfate buildup
  • aggressive behavior, MR, no corneal clouding
• Hemophilia A & B
• Ornithine transcarbamoylase

Question 6

Trinucleotide repeat expansion diseases? (4)

Answer 6

Tri Hunting for My Fried Eggs(X)

• Huntington’s - Hunt 4 CAGe; low Ach and GABA
  
  • full penetrance at 40 repeats - atrophy of caudate (& putamen) - chorea & personality changes
  • some tx with amantadine
• Friedrich’s ataxia - GAA - **FGAAAAAA NEIN **- chromosome 9
  
  • spinocerebellar tract demyelination
  • Pes cavus & scoliosis, hypertrophic cardiomyopathy & afib, ataxia
• Myotonic dystrophy - **my cute turkey grows 19 **- CTG, chr 19
  
  • cataracts, heart block, muscle wasting, tiny balls (opposite of fragile X)
• Fragile X syndrome - CGG
  
  • macroorchidism; long face & large jaw, ears; mitral valve prolapse; autism

Question 7

Selective IgA deficiency

Answer 7

Mostly asymptomatic, some have recurrent sinopulmonary and GI infections.

Anaphylaxis to IgA containing blood products.

False-positive bHCG.

Question 8

T-cell dysfunction syndromes (3)

Answer 8

• IL-12R deficiency
  
  • Impaired TH1 response
  • Risk for disseminated mycobacterial infx.
  • Low IFN-gamma.
• Hyper-IgE (Job’s syndrome)
  
  • TH1 fails to produce IFN gamma - neutrophils do not respond to chemotactic stimuli
  • FATED:
    
    • coarse Facies
    • cold (noninflamed) staph Abscesses
    • retained primary Teeth
    • elevated IgE
    • Derm problems (eczema)
• Chronic mucocutaneous candidiasis

Question 9

What is the pathology of Hyper-IgE (Job’s syndrome)?

Answer 9

Th1 fails to make IFN-gamma; no neutrophil chemotaxis

FATED:

• coarse Facies
• cold staph Abscesses
• retained primary Teeth
• hyper-IgE
• Derm problems

Question 10

Types of SCID (2)

Answer 10

• AdA deficiency or IL-2 receptor deficiency (X-linked)
• presents with failure to thrive, thrush, and recurrent infections. No thymus or lymphocytes of any kind.
• Associated with few T-cell recombinant excision circles

Question 11

hyper-IgM syndrome

Answer 11

Defective CD40L on Th cells - no class switch

severe pyogenic infections

Question 12

Leukocyte adhesion deficiency vs chronic granulomatous dz

Answer 12

LAD: defect in adhesion (LFA-1)

• recurrent infections, no pus, failure of umbilical cord to separate

CGD - defect in NADPH oxidase

• recurrent infections with catalase + organisms: (staph, e coli, aspergillus)
• Dx with dihydrorhodamine test (or old nitroblue tetrazolium dye).

Question 13

Chediak Higashi?

Answer 13

• Neurologic abnormalities
• Partial albinism (silver hair)
• immunodeficiency due to impaired neutrophil function due to phagolysosome fusion defect.

Question 14

non-obvious teratogens (3)

Answer 14

• Lithium - ebstein’s
• anticonvulsants
  
  • phenytoin - fetal hydantoin syndrome: microcephaly, craniofacial abnormalities, hypoplastic nails and phalanges, cardiac defects, MR, IUGR
  • valproate - antifolate

Question 15

Bloom syndrome

Answer 15

Defect in RecQL3 DNA Helicase

Photosensitivity, short stature, erythema, telangiectasias.

Malignancies.