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Clinical pathology > Molecular > Flashcards

Molecular Flashcards

0
Q

Nucleotides: Position of phosphodiester bond.

A

Links a 5’ triphosphate with a 3’ hydroxyl group.

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1
Q

Nucleotides: Components.

A

Pentose sugar.

Phosphate group.

Nitrogenous base.

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2
Q

Direction of polymerization of nucleic acids.

A

5’ to 3’.

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3
Q

Nucleotides:

A. Which are purines? Pyrimidines?
B. Which have one ring? Two rings?

A

Purines are adenine and guanine (2 rings); pyrimidines are cytosine and thymine (1 ring).

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4
Q

Nucleotides: Numbers of hydrogen bonds in pairings.

A

Cytosine-guanine: 3 bonds.

Adenine-thymine: 2 bonds.

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5
Q

How hydrogen-bonding between nucleotides affects the melting temperature of DNA.

A

Segments of DNA that are rich in C-G pairs melt at a higher temperature than those with mostly A-G.

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6
Q

Dimensions of a typical molecule of DNA:

A. Diameter.
B. Length of turn.
C. Number of nucleotides per turn.

A

A. 2 nm.

B. 3.4 nm.

C. 10.

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7
Q

Micro-RNAs.

A

Short segments of RNA that regulate levels of messenger RNA.

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8
Q

Heterogenous nuclear RNAs (hnRNAs).

A

Include micro-RNAs and messenger RNAs.

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9
Q

Structural difference between

A. Adenine and guanine.
B. Cytosine and thymine.
C. Thymine and uracil.

A

A. Adenine has no carbonyl group.

B. Thymine has two carbonyl groups.

C. Thymine has an extra methyl group.

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10
Q

RNA polymerases: Direction of action.

A

5’ to 3’.

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11
Q

RNA polymerases: Products.

A

RNA polymerase I: Ribosomal RNA.

RNA polymerase II: Messenger RNA.

RNA polymerase III: Transfer RNA.

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12
Q

Nucleases:

A. Function.

B. Types.

A

A. To cleave phosphodiester bonds.

B. Exonucleases require a free end; endonucleases do not.

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13
Q

Mitochondrial genome:

A. Number of copies per mitochondrion.
B. Number of genes.
C. Products of genes.

A

A. One or more.

B. 37.

C. Oxidative proteins, tRNAs, rRNAs.

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14
Q

Heteroplasmy: Definition.

A

Heterogeneity of mitochondrial genomes within one cell (antonym: homoplasmy).

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15
Q

Epigenetic regulation: Types (2).

A

Methylation.

Acetylation.

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16
Q

CpG islands:

A. Definition.
B. Significance.

A

A. Regions of cytosine-phosphate-guanine sequences.

B. Methylation of the cytosine molecules turns off transcription of adjacent genes.

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17
Q

Effect of acetylation on DNA transcription.

A

Acetylation of histones increases transcription of DNA; deacetylation decreases it.

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18
Q

Splicing of mRNA:

A. Mediators.
B. Causes of alternative splicing.

A

A. Small nuclear ribonucleoproteins (snRNP).

B. Mutation in site of splice acceptor, splice donor, or branching.

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19
Q

Protein structure:

A. Primary.
B. Secondary.
C. Tertiary.
D. Quaternary.

A

A. The sequence of amino acids.

B. The coiling of the polypeptide (e.g. α helix).

C. The 3-dimensional structure of a polypeptide.

D. The combining of polypeptides to make a protein.

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20
Q

DNA replication:

A. Stage of cell cycle.
B. Place in the DNA molecule where it begins.

A

A. S phase.

B. At AT-rich “origins”.

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21
Q

DNA polymerase: Direction of action.

A

5’ to 3’.

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22
Q

Parts of the cell cycle.

A

G1 phase: Diploid.

S phase: Duplication of chromosomes.

G2 phase: Tetraploid.

M phase: Mitosis.

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23
Q

Phase of mitosis in which

A. The centrioles move to opposite poles of the cell.
B. The nuclear envelope disappears.
C. The chromosomes are aligned in the middle of the cell.

A

A. Prophase.

B. Metaphase.

C. Metaphase.

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24
Q

Period of meiosis in which

A. Recombination occurs.
B. Nondisjunction occurs.

A

A. Prophase I.

B. Meiosis I (mostly) or meiosis II.

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25
Q

Periods of meiosis in which the oocyte pauses, and how long these pauses last.

A

Dictyotene stage (after prophase I): Until puberty.

Metaphase II: Until fertilization.

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26
Q

Definition of polymorphism.

A

A genetic change that causes no harm and occurs in at least 1% of the population.

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27
Q

Point mutation: Types (5) and their consequences.

A

Nonsense: Termination codon.
Missense: Different amino acid.
Silent: Same amino acid.

Splice mutation: Different donor or acceptor site.
Frameshift: Different reading frame.

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28
Q

Histones: Charge.

A

Positive.

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29
Q

Nucleosome: Structure.

A

A sequence of 146 base pairs of DNA wrapped around an octamer of histone proteins (two each of H2A, H2B, H3, H4).

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30
Q

Nucleosome: What connects one to the next.

A

20-50 bases and a linking histone, H1.

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31
Q

Packing of DNA into chromosomes.

A

The chain of nucleosomes is coiled into the 30-nm chromatin fiber, which then forms loops; the loops are formed into minibands, the minibands into chromosomes.

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32
Q

Shortest chromosome.

A

21 (not 22).

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33
Q

Classification of chromosomes by location of centromere.

A

Metacentric: p ≈ q.

Submetacentric: p < q.

Acrocentric: p ≈ 0 and is frequently involved in translocation.

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34
Q

Meaning of “22q12.3”.

A

Chromosome 22, long arm, region 1 (nearest to the centromere), band 2, subband 3.

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35
Q

Techniques of staining of chromosomes for karyotypes.

A

G (Giemsa) banding.

Q (quinacrine) banding.

R (reverse-Giemsa) banding.

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36
Q

G banding: Areas that take up the stain.

A

AT-rich areas > GC-rich areas.

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37
Q

How to assess the purity of extracted DNA.

A

Calculate the ratio of absorbance at 260 nm (DNA) to that at 280 nm (protein).

A value <1.8 corresponds with relative purity.

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38
Q

PCR: Components (6).

A 
Heat-stable polymerase.
Template DNA.
Primers.
Deoxynucleotides.
Divalent cation.
pH buffer.
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39
Q

PCR: Steps.

A

Denaturation of DNA at 95 degrees.

Annealing at about 65 degrees.

Extension (polymerization) at 72 degrees.

Return to 95 degrees.

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40
Q

PCR: Formula for estimating the number of copies at a particular cycle.

A

Number of copies = 2^n.

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41
Q

Methylation-specific PCR: Purpose.

A

To detect methylated sequences for amplification.

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42
Q

Methylation-specific PCR: Procedure.

A

Sodium metabisulfate converts methylated cytosine bases to uracil.

Uracil-specific PCR primers are used to amplify the methylated sequence.

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43
Q

Reverse-transcription PCR: Purpose.

A

To detect specific sequences of RNA.

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44
Q

Reverse-transcriptase PCR: Procedure.

A

Reverse transcriptase is used to make a cDNA copy of the RNA; the DNA can then be amplified by PCR.

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45
Q

Real-time PCR.

A

Use of a fluorescent dye to measure the quantity of DNA as it forms.

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46
Q

Melting point of DNA: How to measure it.

A

Incorporate non-hydrolyzable probes or dyes into the DNA.

Measure the fluorescence while incrementally increasing the temperature.

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47
Q

Melting point of DNA: Definition (2).

A

The point at which half the DNA is single stranded.

The point of maximal change in the rate of melting (on a plot of fluorescence vs. temperature).

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48
Q

Multiplex PCR: Purpose.

A

To permit simultaneous identification of multiple PCR products.

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49
Q

Multiplex PCR:

A. Procedure.
B. Limitation.

A

A. Many templates and primers are added to one tube and allowed to react at the same time.

B. Reactions may be affected by competition for limited resources within the system.

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50
Q

Transcription-mediated amplification:

A. Purpose.
B. Application.

A

A. Isothermal amplification of RNA.

B. Mainly in the study of infectious agents.

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51
Q

Types of blotting (3).

A

Southern: DNA.

Northern: RNA.

Western: Protein.

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52
Q

Sanger sequencing: Principle.

A

Incorporation of dideoxy-bases to cause termination of strand elongation.

The different strands can be analyzed by electrophoresis.

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53
Q

Sanger sequencing: Modern adaptation.

A

The dideoxy-bases are labeled with different fluorochromes and incorporated in one reaction. The products are analyzed by capillary electrophoresis and detection of fluorescence.

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54
Q

Pyrosequencing: Principle.

A

A molecule of pyrophosphate is released upon the formation of a phosphodiester bond. The amount of pyrophosphate can be used to determine the sequence of DNA.

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55
Q

Chromosome-enumeration probes: Target.

A

Conserved, highly repetitive sequences of satellite DNA, often near the centromeres.

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56
Q

Locus-specific probes: Types (2).

A

Fusion probes: Used for well-defined translocations with conserved breakpoints or fusion points.

Breakapart probes: Used when a gene may have various translocation partners.

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57
Q

Comparative genomic hybridization: Procedure.

A

Various probes are applied in metaphase in order to count copies of chromosomes or regions thereof.

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58
Q

Comparative genomic hybridization:

A. Application.
B. Limitation.

A

A. To characterize inherited and acquired (neoplastic) chromosomal abnormalities.

B. Cannot detect unbalanced translocations.

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59
Q

Array comparative genomic hybridization:

A. Advantage over conventional CGH.
B. Application.

A

A. Array CGH has higher resolution.

B. Investigation of a developmentally delayed child with an apparently normal karyotype.

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60
Q

Short tandem repeats:

A. Definition.
B. Applications (3).

A

A. Normally occurring sequences of 2-5 repeated oligonucleotides.

B. Determination of parentage, identification of remains, assessment of chimerism in transplant recipients.

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61
Q

Short tandem repeats: Disorders (2).

A

Unstably inherited: Trinucleotide repeats.

Unstable within an individual: Disorders of mismatch repair.

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62
Q

Single-nucleotide polymorphisms:

A. Definition.
B. Frequency in genome.
C. SNP haplotype.

A

A. Polymorphism of single base-pairs.

B. 1 in 1000 bases.

C. Total of an individual’s polymorphisms.

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63
Q

Single-nucleotide polymorphisms: Applications (3).

A

DNA fingerprinting for forensics.

Forming a genetic family tree.

Determining predisposition to diseases, responses to medications, and other traits.

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64
Q

Sequencing of whole genomes:

A. Methods (2).
B. Variation.

A

A. Next-generation sequencing, high-throughput sequencing.

B. Sequencing of whole exomes (exons).

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65
Q

Cytochrome P450: Nomenclature.

A

Example: CYP2D6*1.

Superfamily: CYP.
Family: 2.
Subfamily: D.
Isoenzyme: 6.
Allele: 1.
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66
Q

Drugs whose metabolism is affected by:

A. CYP2D6 (2).
B. CYP2C9 (4).

A

A. Codeine, tricyclic antidepressants.

B. Warfarin, phenytoin, omeprazole, diazepam.

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67
Q

VKORC1.

A

Vitamin K epoxide reductase: Involved in the metabolism of vitamin K and inhibited by warfarin.

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68
Q

Enzymes in which polymorphisms can alter the effect of isoniazid.

A

N-acetyltransferase.

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69
Q

Some genetic disorders are not inherited: How so?

A

Some are acquired during gametogenesis or early in embryogenesis (germline).

Some are acquired in differentiated cells (somatic).

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70
Q

Autosomal-dominant inheritance:

A. Appearance of pedigree.
B. Probability of transmitting the trait.

A

A. Disease is present in every generation.

B. 50% for each offspring.

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71
Q

Autosomal-dominant inheritance: Typical products of affected genes.

A

Structural proteins, receptor proteins, transmembrane channels.

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72
Q

Autosomal-recessive disorders:

A. Appearance of pedigree.
B. Probability of transmitting the trait.

A

A. Disease may skip generations.

B. 25% per offspring (if both parents are carriers).

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73
Q

Autosomal-recessive disorders: Typical product of affected genes.

A

Enzymes.

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74
Q

For which type of Mendelian inheritance are penetrance and expressivity most relevant?

A

Autosomal-dominant inheritance.

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75
Q

How X-linked-recessive disorders may be expressed in females (3).

A

Homozygosity.

Asymmetric lyonization.

Turner’s syndrome.

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76
Q

Types of inherited nephritic syndrome (3).

A

Mild: Benign familial hematuria, thin-basement-membrane disease.

Severe: Alport’s syndrome.

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77
Q

Penetrance vs. expressivity:

A

Penetrance: How many who have the mutation express the disease.

Expressivity: Degree to which they express it.

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78
Q

Alport’s syndrome:

A. Clinical triad.
B. Course.

A

A. Glomerulonephritis, sensorineural hearing loss, ocular lesions.

B. Hematuria initially; progression to end-stage renal disease.

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79
Q

Alport’s syndrome:

A. Inheritance.
B. Effect on carriers.

A

A. X-linked recessive.

B. Asymptomatic hematuria in some.

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80
Q

Alport’s syndrome:

A. Diagnosis.
B. Appearance on electron microscopy.

A

A. IHC of biopsy of skin or kidney shows lack of α₅ chain of type IV collagen.

B. Thin or disrupted lamina densa.

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81
Q

Congenital nephrotic syndrome: Definition.

A

Nephrotic syndrome before 3 months of age.

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82
Q

Congenital nephrotic syndrome: Differential diagnosis (2).

A

TORCH infection.

Inherited nephrotic syndrome.

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83
Q

Congenital nephrotic syndrome of the Finnish type: Clinical features (3).

A

Markedly enlarged placenta.

Massive proteinuria in utero.

Nephrotic syndrome by 1 month of age.

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84
Q

Congenital nephrotic syndrome of the Finnish type: Electron microscopy.

A

Abnormal variation in size of slit pores.

Rarefaction of slit diaphragms.

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85
Q

Congenital nephrotic syndrome of the Finnish type: Gene, location, and product.

A

NPHS1 on 19q13.1 encodes nephrin, a key component of the glomerular slit diaphragm.

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86
Q

Pierson’s syndrome: Clinical associations (2).

A

Microcoria, death within several months.

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87
Q

Pierson’s syndrome: Renal biopsy.

A

Mesangial sclerosis and crescents.

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88
Q

Pierson’s syndrome: Gene, location, and product.

A

LAMB2 on 3p21 encodes β₂-laminin, a component of the glomerular basement membrane.

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89
Q

Alport’s syndrome: Gene and its location.

A

COL4A5 on Xp22.3.

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90
Q

Nail-patella syndrome: Clinical manifestations.

A

Abnormalities of nails, skeleton, and eyes.

Variable renal disease.

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91
Q

Nail-patella syndrome: Renal biopsy.

A

Basement membrane expanded by fibrillary collagen deposits.

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92
Q

Nail-patella syndrome: Inheritance.

A

Autosomal dominant.

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93
Q

Nail-patella syndrome: Gene, location, and product.

A

LMX1B on 9q34.1 encodes a factor that regulates the transcription of COL4A3.

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94
Q

Denys-Drash syndrome: Clinical manifestations (3).

A

Wilms’ tumor, male pseudohermaphroditism, rapidly progressive renal failure.

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95
Q

Denys-Drash syndrome: Renal biopsy.

A

Mesangial sclerosis.

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96
Q

Denys-Drash syndrome: Gene and its location.

A

WT1 on 11p13.

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97
Q

Denys-Drash syndrome: Variant.

A

Frasier’s syndrome: Less severe; associated with gonadoblastoma.

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98
Q

Familial autosomal-dominant focal-segmental glomerulosclerosis: Clinical presentation.

A

Onset of the nephrotic syndrome in adolescence or young adulthood.

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99
Q

Familial autosomal-dominant focal-segmental glomerulosclerosis: Genes and their products.

A

ACTN4: α-Actinin.

TRPC6: Transient receptor potential cation channel 6.

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100
Q

Familial autosomal-recessive corticosteroid-resistant nephrotic syndrome: Clinical presentation.

A

Onset of proteinuria in early childhood.

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101
Q

Familial autosomal-recessive corticosteroid-resistant nephrotic syndrome: Renal biopsy.

A

Initially resembles minimal-change disease but transforms to FSGS.

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102
Q

Familial autosomal-recessive corticosteroid-resistant nephrotic syndrome: Gene and its product.

A

NPHS2: Podicin.

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103
Q

Renal Fanconi’s syndrome: Definition.

A

Proximal-tubular dysfunction with various causes.

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104
Q

Renal Fanconi’s syndrome: Chemical abnormalities.

A

Glycosuria, aminoaciduria, phosphaturia, hypokalemia, bicarbonate wasting with subsequent metabolic acidosis.

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105
Q

Renal Fanconi’s syndrome: Inherited metabolic causes (6).

A

Cystinosis, tyrosinemia, galactosemia, hereditary fructose intolerance, glycogen-storage diseases, Wilson’s disease.

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106
Q

Renal Fanconi’s syndrome: Acquired causes.

A

Myeloma kidney, amyloidosis, urate nephropathy, heavy metals, others.

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107
Q

Renal Fanconi’s syndrome: Other inherited causes (2).

A

Idiopathic.

Dent’s disease: X-linked recessive mutation in CLCN5, which encodes a chloride channel.

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108
Q

Autosomal-recessive polycystic-kidney disease: Clinical presentation.

A

Oligohydramnios with pulmonary hypoplasia.

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109
Q

Autosomal-recessive polycystic-kidney disease: Gross pathology.

A

Kidneys remain reniform but have radially oriented cysts that consist of ectatic, elongated collecting ducts.

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110
Q

Autosomal-recessive polycystic-kidney disease: Extrarenal manifestation.

A

Malformations of biliary plates.

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111
Q

Autosomal-recessive polycystic-kidney disease: Gene and its location.

A

PKHD1 on 6p.

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112
Q

Autosomal-dominant polycystic-kidney disease:

A. Incidence.
B. Time of presentation.
C. Penetrance.

A

A. 1 in 500 live births.

B. Adulthood.

C. 100% by the 5th decade.

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113
Q

Autosomal-dominant polycystic-kidney disease:

A. Initial presentation.
B. Gross pathology.

A

A. Isosthenuria and hypertension.

B. Cortical and medullary cysts.

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114
Q

Autosomal-dominant polycystic-kidney disease: Extrarenal manifestations (4).

A

Cysts in pancreas and liver.

Mitral-valve prolapse.

Intracranial berry aneurysms.

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115
Q

Autosomal-dominant polycystic-kidney disease: Gene and its location.

A

PKD1 on 16p13 in 85% of cases.

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116
Q

Cystic renal dysplasia:

A. Inheritance.
B. Gross pathology.

A

A. Not inherited; may result from ureteral obstruction in utero.

B. Kidneys are not reniform; mixture of cysts and loose mesenchyme; usually unilateral.

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117
Q

Cystic renal dysplasia: Associated syndrome.

A

Meckel-Gruber: Kidney disease, polydactyly, occipital encephalocele.

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118
Q

Glomerulocystic kidney disease:

A. Time of presentation.
B. Histology (2).

A

A. Neonatal period.

B. Dilation of Bowman’s capsule; renal dysplasia.

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119
Q

Brugada’s syndrome:

A. Epidemiology.
B. Typical presentation.
C. Genetic basis.

A

A. Southeast Asia.

B. Healthy young man dying in his sleep.

C. Mutations in various genes that encode ion-channel proteins.

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120
Q

Arrhythmogenic right-ventricular dysplasia:

A. Presentation.
B. Histology.

A

A. Sudden cardiac death in young adult during physical activity.

B. Fibrous and fatty replacement of myocardium.

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121
Q

Arrhythmogenic right-ventricular dysplasia:

A. Genetic defects.
B. Variant.

A

A. Various.

B. Naxos disease: Heart disease, abnormal skin, woolly hair.

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122
Q

Prolonged QT interval: Significance.

A

Can lead to ventricular arrhythmias.

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123
Q

Prolonged QT interval: Inherited syndromes (3).

A

Romano-Ward (AD, no hearing loss).

Jervell Lange-Nielsen (AR, hearing loss).

Andersen-Tawil.

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124
Q

Prolonged QT interval: Metabolic causes.

A

Hypokalemia.

Hypercalcemia.

Hypomagnesemia.

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125
Q

Genes associated with a prolonged QT interval: Most commonly mutated.

A

LQT1.

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126
Q

Which gene is mutated in inherited syndromes of long QT interval in which arrhythmias are induced by ____?

A. sleep
B. auditory or emotional stimulus

A

A. LQT3.

B. LQT2.

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127
Q

Prolonged QT interval: Pharmacological causes (5).

A

Tricyclic antidepressants.
Phenothiazines.
Macrolides.
Antiarrhythmics, classes IA and III.

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128
Q

Andersen-Tawil syndrome:

A. Clinical triad.
B. Gene.

A

A. Episodic paralysis, long QT interval, dysmorphism.

B. LQT7.

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129
Q

Inherited syndromes of long QT interval: Penetrance.

A

Twice as great in females.

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130
Q

Dilated cardiomyopathy: What fraction of cases is genetic?

A

About one third.

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131
Q

Dilated cardiomyopathy, X-linked: Gene.

A

The gene that encodes dystrophin. Also implicated in Duchenne’s muscular dystrophy and Becker’s muscular dystrophy.

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132
Q

Dilated cardiomyopathy, autosomal dominant: Most common gene.

A

MYH7, which encodes the β heavy chain of myosin.

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133
Q

Hypertrophic cardiomyopathy:

A. Incidence.
B. Gross pathology.

A

A. Approaches 1 in 500.

B. Thick interventricular septum.

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134
Q

Hypertrophic cardiomyopathy: Histology (3).

A

Hypertrophy of myocytes.

Disarray of myofibers.

Interstitial fibrosis.

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135
Q

Hypertrophic cardiomyopathy:

A. Most common mutation.
B. Inheritance.

A

A. R403Q in MYH7.

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136
Q

Familial isolated cardiac amyloidosis:

A. Inheritance.
B. Geographic distribution.

A

A. Autosomal dominant.

B. High prevalence in Portugal, Sweden, Japan, and parts of Africa.

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137
Q

Familial isolated cardiac amyloidosis:

A. Gene.
B. Clinical associations (2).

A

A. TTR, which encodes transthyretin.

B. Peripheral neuropathy, leptomeningeal amyloidosis.

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138
Q

Gene that encodes a very early transcription in cardiogenesis.

A

NKX2-5.

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139
Q

Cardiac defects associated with mutations in GATA-4.

A

Septal defects (mostly atrial).

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140
Q

Holt-Oram syndrome:

A. Cardiac defects.
B. Other clinical feature.

A

A. Septal defects (atrial or ventricular).

B. Malformations of upper limb(s).

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141
Q

Holt-Oram syndrome:

A. Inheritance.
B. Gene.

A

A. Autosomal dominant.

B. TBX-5.

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142
Q

DiGeorge’s syndrome: Most common cardiac defects (4).

A

Tetralogy of Fallot.

Interrupted aortic arch.

Ventricular septal defects.

Truncus arteriosus.

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143
Q

DiGeorge’s syndrome:

A. Gene implicated in cardiac defects.
B. Type of mutation.

A

A. TBX-1 on 22q.

B. Microdeletion.

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144
Q

Noonan’s syndrome:

A. Most common cardiac defects (2).
B. Other clinical features (2).

A

A. Right-sided defects, esp. pulmonic stenosis; hypertrophic cardiomyopathy.

B. Lymphatic malformations, prolonged coagulation times.

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145
Q

Noonan’s syndrome: Gene.

A

PTPN11.

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146
Q

Alagille’s syndrome:

A. Most common cardiac defect.
B. Gene.
C. Inheritance.

A

A. Pulmonic stenosis.

B. JAG1.

C. Autosomal dominant.

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147
Q

Trisomy 21: Most common cardiac defect.

A

Malformation of the endocardial cushion leading to ventricular septal defect.

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148
Q

Turner’s syndrome: Most common cardiac defects (4).

A

Bicuspid aortic valve.

Coarctation of the aorta.

Dilatation of the aortic root, which predisposes to aortic dissection.

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149
Q

Williams’ syndrome:

A. Most common cardiac defect.
B. Other clinical manifestations (4).

A

A. Supravalvular aortic (hourglass) stenosis.

B. Dysmorphic facies, mental retardation, hypercalcemia, defects of connective tissue.

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150
Q

Williams’ syndrome:

A. Gene responsible for most of the features.
B. Type of mutation.

A

A. Elastin gene.

B. Microdeletion.

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151
Q

Genes associated with a prolonged QT interval: Potassium channels (2).

A

LQT1, LQT2.

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152
Q

True hermaphroditism: Definition.

A

Presence of both ovarian and testicular tissue, whether separately or together in one organ.

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153
Q

True hermaphroditism: Karyotype.

A

Usually 46,XX, albeit almost always with transposed genetic material that includes the SRY gene.

Sometimes a mosaic of 46,XX and 46,XY.

Never 46,XY.

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154
Q

Pseudohermaphroditism:

A. Definition.

B. Leading causes.

A

A. Discordance between genotypic/gonadal sex and phenotypic (external genital) sex.

B. Males: Androgen insensitivity; females: congenital adrenal hyperplasia.

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155
Q

Androgen-insensitivity syndrome:

A. Inheritance.
B. Hormone levels.

A

A. X-linked.

B. Normal or high testosterone and LH.

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156
Q

Kallmann’s syndrome:

A. Clinical features.
B. Most common pattern of inheritance.
C. Most commonly affected gene and its location.

A

A. Hypogonadism due to decreased gonadotropins; anosmia.

B. X-linked.

C. KAL1 on Xp22.3.

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157
Q

McCune-Albright syndrome: Classic clinical features (4).

A

Polyostotic fibrous dysplasia.

Café-au-lait spots.

Precocious puberty.

Other endocrine abnormalities.

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158
Q

McCune-Albright syndrome: Reason for variable expression.

A

All cases are somatic mosaics, the germline mutation being incompatible with life.

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159
Q

Familial hypocalciuric hypercalcemia:

A. Inheritance.

B. Chemical findings (2).

A

A. Autosomal dominant.

B. Hypercalcemia; normal PTH (and normal parathyroid glands).

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160
Q

Congenital hypothyroidism: Clinical features.

A

Normal fetal development due to maternal thyroid hormone.

Postnatal deficiency can impair development of brain.

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161
Q

Congenital hypothyroidism: Causes.

A

Most common: Maternal autoantibodies.

Rare: Genetic; may be related to defects in PAX8 or TSHR.

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162
Q

Diabetes mellitus, type 1: Relevance of HLA type.

A

Relative with for those with HLA-DR3 or -DR4:

2-3 in heterozygotes.

10 in homozygotes.

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163
Q

Maturity-onset diabetes of the young:

A. Inheritance.
B. Clinical presentation.

A

A. Autosomal dominant.

B. Insulin-independent; similar to type 2, but with onset before the age of 25.

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164
Q

Hirschsprung’s disease:

A. Histology.
B. Associated structural chromosomal abnormality.

A

A. Absence of ganglion cells; axons are hypertrophic.

B. Trisomy 21 is found in 10% of children with HD.

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165
Q

Hirschsprung’s disease: Associated syndromes (6).

A 
Neurofibromatosis, type 1.
Multiple endocrine neoplasia, type 2a.
Waardenburg's syndrome.
Congenital central hypoventilation.
Familial dysautonomia.
Smith-Lemli-Opitz syndrome.
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166
Q

Hirschsprung’s disease: Related single-gene defects.

A

RET, GDNF, EDNRB are rarely mutated.

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167
Q

Osler-Weber-Rendu syndrome: Relevance of clinical presentation to age.

A

Children: Epistaxis.

Adolescents: Skin lesions.

Older adults: Gastrointestinal bleeding.

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168
Q

Microvillus-inclusion disease:

A. Importance.
B. Inheritance.

A

A. Leading cause of malabsorption in neonates.

B. Autosomal recessive.

169
Q

Microvillus-inclusion disease:

A. Gross pathology.
B. Histology.

A

A. Paper-thin wall of small intestine.

B. Villous atrophy; apical intracellular inclusions may be stained with PAS, polyclonal CEA, CD10.

170
Q

Esophageal atresia: Most common association.

A

Vertebral, anal, cardiac, tracheal, esophageal, renal, and limb syndrome.

171
Q

Esophageal atresia:

A. Clinical presentations.
B. Commonly associated malformation.

A

A. Polyhydramnios, difficulty in feeding.

B. Distal tracheoesophageal fistula.

172
Q

Pyloric stenosis:

A. Time of presentation.
B. Epidemiology.

A

A. At 1-6 weeks of age.

B. Males of northern European descent; firstborn.

173
Q

Pyloric stenosis: Associations (4).

A

Turner’s syndrome.

Trisomy 18.

Cornelia de Lange syndrome.

Hirschsprung’s disease.

174
Q

Intestinal atresia:

A. Most common anatomic site.
B. Associations.

A

A. Ileum.

B. Down’s syndrome in 30%; most cases are sporadic.

175
Q

Gastroschisis:

A. Definition.
B. Risk factor.

A

A. Extrusion of intestines through the abdominal wall, without a covering.

B. Young mother.

176
Q

Gastroschisis:

A. Association.
B. Chemical abnormality.

A

A. Usually isolated.

B. Very high maternal serum AFP.

177
Q

Omphalocele:

A. Definition.
B. Associations (3).

A

A. Midline extrusion of multiple viscera through abdominal wall, covered by peritoneum and amnion.

B. Cardiac defects, trisomies, Beckwith-Wiedemann syndrome.

178
Q

Celiac disease:

A. Association of disease with HLA alleles.
B. Association of HLA alleles with disease.

A

A. HLA-DQ2 is present in 95% of patients; most of the rest have HLA-DQ8.

B. Only about 1% of those with HLA-DQ2 or HLA-DQ8 have celiac disease.

179
Q

Biliary fibrocystic diseases:

A. Associations (2).
B. Examples (2).

A

A. Autosomal-recessive polycystic-kidney disease, nephronophthisis.

B. Congenital hepatic fibrosis, Caroli’s disease.

180
Q

Congenital hepatic fibrosis:

A. Histology.
B. Complication.

A

A. Interstitial fibrosis, enlarged portal tracts, segmentally dilated bile ducts.

B. Portal hypertension.

181
Q

Caroli’s disease:

A. Histology.
B. Complications.

A

A. Segmentally dilated bile ducts.

B. Biliary cholelithiasis, bacterial cholangitis.

182
Q

Alagille’s syndrome, biliary manifestations:

A. Clinical presentation.
B. Histology.

A

A. Cholestasis, often in a neonate.

B. Noninflammatory loss of interlobular bile ducts.

183
Q

Alagille’s syndrome: Other clinical features (4).

A

Facial dysmorphism.

Butterfly-shaped vertebrae.

Posterior embryotoxon.

Congenital heart disease.

184
Q

Hereditary hemochromatosis: Affected organs and tissues (6).

A 
Liver.
Pancreas.
Pituitary.
Synovium.
Heart.
Skin.
185
Q

Hereditary hemochromatosis: Cause of infertility.

A

Pituitary disease.

186
Q

Hereditary hemochromatosis:

A. Gene and its location.
B. Most common mutations (2).
C. Most common genotypes.

A

A. HFE on 6p21.3.

B. C282Y and H63D.

C. C282Y/C282Y and C282Y/H63D.

187
Q

Hereditary hemochromatosis: Penetrance (2).

A

A. Women are half as likely to develop complications.

B. Most individuals with C282Y/H63D have no disease.

188
Q

Juvenile hemochromatosis: Genes (2).

A

Juvenile hemochromatosis A: HFE2 (hemojuvelin).

Juvenile hemochromatosis B: HAMP (hepcidin).

189
Q

Other inherited diseases (2) of iron overload and their genes.

A

Hemochromatosis, type 3: TFR2 (transferrin receptor).

Familial iron overload: FTH1 (heavy chain of ferritin).

190
Q

Wilson’s disease: Clinical presentation (3).

A

Liver disease, neuropsychiatric disease, or hemolysis.

191
Q

Wilson’s disease: Liver histology (4).

A

Inflammation, steatosis, pseudoglycogenated nuclei, increased copper in hepatocytes.

192
Q

Wilson’s disease:

A. Helpful tests (2).
B. Unhelpful test.

A

A. Plasma ceruloplasmin (decreased), urinary copper excretion (increased).

B. Serum copper.

193
Q

Wilson’s disease:

A. Inheritance.
B. Gene and its product.

A

A. Autosomal recessive.

B. ATP7B; ATPase required in the binding of copper by ceruloplasmin.

194
Q

α₁-Antitrypsin deficiency: Gene and its location.

A

SERPINA1 on 14q31.

195
Q

α₁-Antitrypsin deficiency:

A. Number of alleles.
B. Most common genotypes in the healthy.
C. Most common genotypes in the diseased.

A

A. About 75.

B. MM&raquo_space; MS, MZ.

C. ZZ, SZ, SS.

196
Q

α₁-Antitrypsin deficiency:

A. Possible manifestations other than in lung and liver (2).
B. Histology of lung.

A

A. Panniculitis, vasculitis.

B. Panacinar emphysema with basilar predominance.

197
Q

α₁-Antitrypsin deficiency: Inheritance.

A

Autosomal recessive.

198
Q

Gilbert’s syndrome: Gene, product, and mutation.

A

UGT1A1; UDP-glucoronosyltransferase; mutation in 5’ TATA box of the promoter.

199
Q

Gilbert’s syndrome: Incidence.

A

5% of the population.

200
Q

Crigler-Najjar syndrome:

A. Gene and its product.
B. Types of disease.

A

A. UGT1A1; UDP-glucoronosyltransferase.

B. In type 1, complete lack of enzyme results in severe neonatal jaundice; in type 2: there is some enzyme, and jaundice appears later.

201
Q

Dubin-Johnson syndrome: Gene.

A

MRP2 (multidrug-resistance protein 2).

202
Q

Cystic fibrosis:

A. Gene and its location.
B. Most common mutation.

A

A. CFTR, which encodes a chloride channel; 7q31.2.

B. ΔF508.

203
Q

Cystic fibrosis:

A. Frequency of carriers.
B. Incidence.

A

In the Caucasian population:

A. 1 in 25.

B. 1 in 2000.

204
Q

Cystic fibrosis:

A. Frequent initial manifestation.
B. Another possible early sign.

A

A. Meconium ileus.

B. Nasal polyps in children.

205
Q

Cystic fibrosis:

A. Cause of infertility.
B. Cause of liver disease.
C. Causes of bronchiectasis (3).

A

A. Congenital bilateral absence of vas deferens.

B. Biliary obstruction.

C. Staphylococcus aureus, Burkholderia cepacia, Pseudomonas aeruginosa.

206
Q

Cystic fibrosis: Chemical abnormalities (3).

A

Hyponatremia.

Hypochloremia.

Metabolic alkalosis.

207
Q

Cystic fibrosis: Possible gastrointestinal manifestations (2).

A

Chronic diarrhea.

Rectal prolapse.

208
Q

Pearson’s syndrome:

A. Clinical dyad.
B. Histology.

A

A. Pancreatitis and marrow failure.

B. Sideroblastic anemia with vacuoles in precursors.

209
Q

Pearson’s syndrome:

A. Inheritance.
B. Mutation.

A

A. Autosomal dominant.

B. Microdeletion within mitochondrial DNA.

210
Q

Shwachman-Diamond syndrome:

A. Clinical features.
B. Histology.
C. Gene.

A

A. Marrow failure, exocrine pancreatic insufficiency.

B. Pancreatic fatty change with sparing of islets.

C. SBDS.

211
Q

Johanson-Blizzard syndrome: Clinical features (4).

A

Pancreatic exocrine deficiency and fatty change.

Hypothyroidism.

Deafness.

Hypoplasia of nasal alae.

212
Q

Alzheimer’s disease of early onset:

A. Frequency.
B. Familial cases.

A

A. 5% of cases of Alzheimer’s disease.

B. Half of cases of early onset are familial.

213
Q

Alzheimer’s disease of early onset:

A. Mutation.
B. Another clinical situation that may be associated with this mutation.

A

A. Amplification of APP gene.

B. Alzheimer’s disease in trisomy 21.

214
Q

Alzheimer’s disease: Gene involved in usual (late-onset) disease.

A

APOE (apolipoprotein E), particularly the E4 allele.

215
Q

Pick’s disease:

A. Synonym.
B. Gene.

A

A. Frontotemporal dementia with Parkinsonism.

B. MAPT (microtubule-associated protein tau).

216
Q

Parkinson’s disease: Genes implicated in familial cases.

A

PARK1 through PARK13.

217
Q

Dementia with Lewy bodies: Clinical features (4).

A

Dementia plus at least 2 of the following 3:

Cognitive fluctuation.

Visual hallucinations.

Parkinsonism.

218
Q

Huntington’s disease:

A. Gene, location, and mutation.
B. Characteristic feature of inheritance.

A

A. HTT on 4p; repeat of CAG.

B. Anticipation: Longer trinucleotide repeats, earlier onset, and more severe disease in later generations.

219
Q

Huntington’s disease: Relevance to number of repeats to phenotype.

A

Fewer than 28: Normal.

28-35: Premutation.

35-40: Allele with reduced penetrance.

More than 40: Disease.

220
Q

Huntington’s disease: A possible determinant of phenotype other than number of repeats.

A

Paternal inheritance show strong correlation with early onset.

221
Q

Cerebral autosomal-dominant arteriopathy with subcortical infarctions and leukoencephalopathy: Clinical features.

A

Migraine headaches, transient ischemic attacks, stroke-like events, progression to dementia.

222
Q

CADASIL:

A. Radiographic features.
B. Histology.
C. Diagnosis.

A

A. Multiple hyperintense lesions throughout brain.

B. Granular eosinophilic deposits in vascular media.

C. Skin biopsy (vascular changes).

223
Q

Charcot-Marie-Tooth disease:

A. Inheritance.
B. Mutation.

A

A. Autosomal dominant.

B. Duplication of a 1.5-megabase region of DNA on 17p11.2 that contains the PMP22 gene.

224
Q

Charcot-Marie-Tooth disease:

A. Affected nerves.
B. Histology.

A

A. Sensory and motor.

B. Prominent “onion bulb” formation.

225
Q

Spinal muscular atrophy:

A. Affected nerves.
B. Most severe type.

A

A. Lower motor neurons.

B. Type 1 (Werdnig-Hoffmann disease).

226
Q

Spinal muscular atrophy:

A. Inheritance.
B. Gene.

A

A. Autosomal recessive.

B. SMN1 (survival motor neuron).

227
Q

Dystrophinopathies:

A. Inheritance.
B. Gene, location, mutation.

A

A. X-linked recessive, with a sporadic mutation in one third of cases.

B. DMD on Xp21.1; mutation in promoter.

228
Q

Duchenne’s muscular dystrophy:

A. Time of onset.
B. Histology.

A

A. Before age 5.

B. Scattered hypereosinophilic small rounded fibers; no dystrophin by IHC.

229
Q

Becker’s muscular dystrophy: Clinical features.

A

Less severe than Duchenne’s disease and presents later.

230
Q

Myotonic muscular dystrophy:

A. Inheritance and type of mutation.
B. Manifestations outside skeletal muscle (4).

A

A. Autosomal dominant; trinucleotide repeat.

B. Dysmotility of smooth muscle; cataracts, abnormalities of cardiac conduction, endocrine disease.

231
Q

Malignant hyperthermia:

A. Presenting clinical feature.
B. Gene.

A

A. Hypercarbia during anesthesia.

B. RYR1 (ryanodine receptor).

232
Q

Mitochondrial disorders: Common clinical features (5).

A

Ocular abnormalities.

Skeletal myopathy.

Cardiomyopathy.

Encephalopathy.

Sensorineural deafness.

233
Q

Mitochondrial disorders: Inheritance.

A

Mitochondrial (maternal) or Mendelian, depending on whether the mitochondrial or nuclear genome is affected.

234
Q

Mitochondrial disorders: Screening tests (4).

A

Lactic acid in plasma or CSF.

Urinary organic acids.

Ketones.

Acylcarnitines.

235
Q

Mitochondrial disorder: Microscopy (2).

A

Muscle biopsy . . .

Light: Ragged red fibers on trichrome stain.

Electron: “Parking lot” inclusions.

236
Q

Mitochondrial disorders: Reason for diversity of clinical presentation.

A

Heteroplasmy.

237
Q

Kearns-Sayre syndrome:

A. Inheritance.
B. Endocrine abnormalities (2).
C. Neurological abnormality.

A

A. Mitochondrial.

B. Diabetes mellitus, hypoparathyroidism.

C. Cerebellar ataxia.

238
Q

MELAS:

A. Meaning.
B. Clinical presentation.

A

A. Mitochondrial encephalopathy with lactic acid and stroke-like episodes.

B. Initially normal development; progressive neurological deterioration with stroke-like episodes and seizures.

239
Q

MELAS: Mutation.

A

Point mutation in mitochondrial gene MT-TL1.

240
Q

Mutation: Cri du chat syndrome.

A

Microdeletion on 5p15.2.

241
Q

Mutation: Prader-Willi syndrome.

A

Microdeletion of 15q11.2 on the paternal chromosome.

242
Q

Mutation: Angelman’s syndrome.

A

Microdeletion of 15q11.2 on the maternal chromosome.

243
Q

Smith-Magendis syndrome:

A. Characteristic behavioral abnormalities.
B. Mutation.

A

A. Self-mutilation, embolokoilomania.

B. Microdeletion on 17p11.2.

244
Q

Mutation: Wolf’s syndrome.

A

Microdeletion on 4p.

245
Q

Miller-Dieker syndrome.

A. Characteristic physical anomalies (3).
B. Mutation.

A

A. Microcephaly, lissencephaly, vertical furrowing of brow.

B. Microdeletion on 17p13.

246
Q

APC gene:

A. Location.
B. Relevance to colon cancer.

A

A. 5q.

B. Mutated in 85% of colorectal carcinomas; mutation is an early step in carcinogenesis.

247
Q

APC gene:

A. Most common mutation.
B. Variant.

A

A. Truncation.

B. Normal APC gene; mutation in gene for β-catenin.

248
Q

Familial adenomatous polyposis:

A. Mutation.
B. Natural history of colon polyps (2).

A

A. Germline mutation in APC.

B. More than 100 adenomatous polyps by age 35; cancer in most by age 50.

249
Q

Familial adenomatous polyposis: Other neoplasms (5).

A

Gastric fundic-gland polyps.

Ampullary tumors (adenomas, adenocarcinomas).

Small-bowel adenocarcinomas.

Thyroid cancer.

Fibromatosis.

250
Q

Colon cancers associated with mutated APC:

A. Typical side.
B. Typical histology (4).

A

A. Left.

B. Origin in a tubular adenoma; pseudostratified nuclei; dirty necrosis; infiltrative advancing edge.

251
Q

Other syndromes associated with germline mutation in APC (3).

A

Attenuated familial adenomatous polyposis.

Gardner’s syndrome.

252
Q

Attenuated familial adenomatous polyposis: Mutation.

A

Affects the 5’ or 3’ end of the APC gene.

253
Q

Gardner’s syndrome: Clinical features (5).

A

Typical features of FAP, plus

Epidermal cysts.

Jaw osteomas.

Fibromatoses.

Congenital hypertrophic of the retinal pigmented epithelium.

254
Q

Turcot’s syndrome: Clinical features.

A

Colonic adenomas, tumors of the CNS.

255
Q

Enzymes of mismatch repair:

A. Names.
B. Relevance to colon cancer.

A

A. MSH2/MSH6, MLH1/PMS2 (dimers).

B. Mutated in 15% of cases.

256
Q

Mutations in enzymes of mismatch repair can lead to mutations in what genes of colon cancer (3)?

A

BRAF, KRAS, p16INK4a.

257
Q

Microsatellite instability:

A. Definition.
B. Relevance to colon cancer.

A

A. Alteration in length of microsatellite-repeat sequences.

B. MSI is a surrogate marker for dysfunction of enzymes of mismatch repair.

258
Q

Mutations in genes for enzymes of mismatch repair: Germline vs. sporadic.

A

Germline: Inactivation of coding sequence.

Sporadic: Hypermethylation of promoter.

259
Q

Germline mutations in genes for enzymes of mismatch repair:

A. Affected genes.
B. Syndrome.

A

A. MLH1 and MSH2 (90% of cases).

B. Lynch’s syndrome (HNPCC).

260
Q

Syndromes arising from a germline mutation in the genes for enzymes of mismatch repair (3).

A

Lynch’s.

Turcot’s.

Muir-Torre.

261
Q

Colon cancers arising from dysfunction in genes of mismatch repair:

A. Typical side.
B. Typical histology (6).

A

A. Right.

B. Origin in sessile serrated polyp; large, exophytic mass; mucinous differentiation; lack of dirty necrosis; lymphocytes infiltrate tumor or form nodules (“Crohn-like” pattern); pushing border.

262
Q

Diagnosis of mismatch repair in a colon cancer: Methods (3).

A

Immunohistochemistry.

Testing for microsatellite instability.

Full-gene testing.

263
Q

Turcot’s syndrome: Gene.

A

Any that encode enzymes of mismatch repair.

APC is mutated in a syndrome of colon polyps and medulloblastoma that has been incorrectly called Turcot’s syndrome [OMIM].

264
Q

Gene mutation(s) to be inferred from IHC that is negative for

A. MLH1 and PMS2.
B. PMS2 only.
C. MSH2 and MSH6.
D. MSH6 only.

A

A. MLH1.

B. PMS2.

C. MSH2.

D. MSH6.

265
Q

Testing for microsatellite instability: Procedure.

A

DNA from the tumor and DNA from normal tissue or peripheral blood are compared with respect to 5 microsatellites.

266
Q

Mutations that impart resistance to treatment with monoclonal antibodies to EGFR (2).

A

BRAF: V600E.

KRAS: Mutations in exon 12 or 13.

267
Q

Overexpression of Her2 in gastric and gastroesophageal carcinomas:

A. Frequency.
B. Detection.

A

A. 20% and 30%, respectively.

B. Either IHC or FISH may be used.

268
Q

Grading of overexpression of Her2 in gastric adenocarcinomas: 0+.

A

Biopsy: No staining.

Resection: Expression in <10% of tumor cells.

269
Q

Grading of overexpression of Her2 in gastric adenocarcinomas: 1+.

A

Biopsy: Any cluster of (at least 5) tumor cells with faint staining.

Resection: Faint staining of at least 10% of cells in any part of the membrane.

270
Q

Grading of overexpression of Her2 in gastric adenocarcinomas: 2+ (equivocal).

A

Biopsy: Any cluster of tumor cells with weak or moderate staining of the basolateral or lateral membrane.

Resection: Weak or moderate staining of at least 10% of cells in the basolateral or lateral membrane.

271
Q

Grading of overexpression of Her2 in gastric adenocarcinomas: 3+.

A

Biopsy: Any cluster of tumor cells with strong staining of the basolateral or lateral membrane.

Resection: Strong, complete staining of at least 10% of tumor cells in the basolateral or lateral membrane.

272
Q

Juvenile polyposis:

A. Inheritance.
B. Location of polyps.
C. Risk of colon cancer.

A

A. Autosomal dominant.

B. Large bowel, small bowel, stomach.

C. Moderate.

273
Q

Peutz-Jeghers syndrome:

A. Inheritance.
B. Risk of malignancy.

A

A. Autosomal dominant.

B. Significantly increased.

274
Q

Peutz-Jeghers syndrome: Classically associated tumors of the reproductive tracts (3).

A

Ovarian sex-cord tumor with annular tubules.

Cervical minimal-deviation adenocarcinoma.

Testicular calcifying Sertoli-cell tumor.

275
Q

Peutz-Jeghers syndrome: Oropharyngeal manifestations (2).

A

Mucocutaneous pigmentation.

Nasal polyps in some patients.

276
Q

Testing for microsatellite instability: Interpretation.

A

At least unstable microsatellites: MSI-high.

One unstable microsatellite: MSI-low.

No unstable microsatellites: Microsatellite-stable.

277
Q

Peutz-Jeghers syndrome: Gene and its location.

A

STK11/LKB1 on 19p.

278
Q

Gastrointestinal stromal tumors:

A. How many lack a mutation in KIT?

B. Which other genes may be mutated?

A

A. 5%.

B. Most that lack a mutation in KIT have a mutation in PDGFRA; those that lack both mutations may have a mutation in SDH (succinate dehydrogenase).

279
Q

GIST: Relevance of location of mutation in KIT to response to therapy.

A

Exon 11: Very likely to respond to imatinib.

Exons 9, 13, 17: About 30-40% likely to respond.

280
Q

Do GISTs without a mutation in KIT respond to imatinib?

A

Up to 30% of such tumors may respond.

281
Q

Mutation of PDGFRA in GISTs:

A. Most common mutation.
B. Relevance to imatinib.

A

A. D842V.

B. No response; however, other mutations in PDGFRA may be more responsive.

282
Q

GIST: Associated syndromes (3).

A

Carney’s triad: GIST, pulmonary chondroma, extraadrenal paraganglioma.

Neurofibromatosis, type 1.

Familial GIST syndrome (germline mutation in KIT).

283
Q

Pancreatic ductal adenocarcinoma: Syndromes that impart increased risk (7).

A

Peutz-Jeghers.
Familial atypical mole-melanoma syndrome.
Hereditary pancreatitis.

Familial adenomatous polyposis.
BRCA2 syndrome.
Ataxia-telangiectasia.
Lynch’s syndrome.

284
Q

Amplification of Her2 in breast cancer:

A. Frequency.
B. Histology.
C. Clinical outcome.
D. Treatment.

A

A. About 20% of breast cancers.

B. High nuclear grade.

C. Poor.

D. Trastuzumab, doxorubicin.

285
Q

Amplification of Her2 in breast cancer: When a cell gets a positive score by IHC.

A

When there is circumferential staining of the membrane.

286
Q

Use of FISH to test for amplification of Her2 in breast cancer: Procedure.

A

The number of signals of Her2 is compared with the number of signals of CEP 17 (chromosome 17) and a ratio assigned.

287
Q

Use of FISH to test for amplification of Her2 in breast cancer: Interpretation.

A

Ratio
>2.2: Positive for amplification.

<1.8: Negative.

1.8-2.2: Equivocal – count more cells; proceed to IHC is indicated.

288
Q

BRCA genes:

A. Locations.
B. Function.
C. Inheritance.

A

A. BRCA1: 17q21; BRCA2: 13q12-13.

B. Suppression of tumors.

C. Autosomal dominant.

289
Q

Mutated BRCA gene(s):

A. Lifetime risk of breast cancer.
B. Other organs in which cancer can occur (6).

A

A. 80%.

B. Ovary, fallopian tube, colon, uterus, pancreas; prostate.

290
Q

Mutated BRCA gene(s):

A. Overall frequency in women with breast cancer.

B. Frequency in Ashkenazi Jewish women.

A

A. About 5%.

B. About 25%.

291
Q

Mutated BRCA gene(s): Risk of developing cancer in the other breast.

A

25%.

292
Q

Genes other than BRCA in which mutations confer an increased risk of breast cancer (4).

A

P53, PTEN, STK11, CDH1.

293
Q

Breast cancer, luminal A:

A. Morphology.
B. ER, PR, Her2.
C. Other IHC staining (2).

A

A. Low-grade, ductal.

B. ER+, PR±; Her2−.

C. Low Ki-67; CK8/18+.

294
Q

Breast cancer, luminal A:

A. Treatment.
B. Prognosis.

A

A. Sensitive to endocrine therapy; responds variably to chemotherapy.

B. Overall good.

295
Q

Breast cancer, luminal B:

A. Morphology.
B. ER, PR, Her2.
C. Other IHC staining (2).

A

A. High-grade, ductal.

B. ER+, PR±, Her2+.

C. Moderate to high Ki-67; CK8/18+.

296
Q

Breast cancer, luminal B:

A. Treatment.
B. Prognosis.

A

A. Often sensitive to endocrine therapy, variably responsive to chemotherapy.

B. Not as good as that of luminal A.

297
Q

Breast cancer, Her2-positive only:

A. Other IHC staining.
B. Treatment.

A

A. High Ki-67.

B. Trastuzumab.

298
Q

Breast cancer, basal-like:

A. ER, PR, Her2.
B. Other IHC staining (3).

A

A. Triple negative.

B. High Ki-67, CK5/6+, p63+.

299
Q

Breast cancer, basal-like:

A. Treatment.
B. Genetic association.

A

A. Aggressive chemotherapy.

B. BRCA1.

300
Q

von Hippel-Lindau syndrome: Inheritance.

A

Autosomal dominant.

301
Q

von Hippel-Lindau syndrome: Tumors (7).

A

Clear-cell renal-cell carcinoma.
Hemangioblastoma of CNS.

Pheochromocytoma.
Pancreatic islet-cell tumor.
Pancreatic cyst.

Cystadenoma of epididymis or of broad ligament.
Papillary tumor of the endolymphatic sac.

302
Q

von Hippel-Lindau syndrome: Gene and its location.

A

VHL on 3p25-26.

303
Q

Birt-Hogg-Dubé syndrome: Inheritance.

A

Autosomal dominant.

304
Q

Birt-Hogg-Dubé syndrome: Tumors (5).

A

Renal-cell carcinoma resembling chromophobe.

Cystic pulmonary lesions with spontaneous PTX.

Fibrofolliculomas, trichodiscomas, acrochordons.

305
Q

Birt-Hogg-Dubé syndrome: Gene, location, product.

A

BHD (FLCN) on 17p11.2 encodes folliculin.

306
Q

Familial clear-cell renal-cell carcinoma: Mutation.

A

Germline mutation of 3p.

307
Q

Familial papillary renal-cell carcinoma: Gene, location, type of mutation.

A

c-MET on 7q31; gain of function.

308
Q

Tuberous sclerosis: Renal tumors.

A

Angiomyolipoma.

Renal-cell carcinoma.

309
Q

Sporadic clear-cell renal-cell carcinoma:

A. IHC.
B. Genetic abnormalities.

A

A. Positive: CD10, vimentin, RCC.

B. −3p first; mutations in 14q, 9p, 8p, 6q may follow.

310
Q

Sporadic papillary renal-cell carcinoma:

A. IHC.
B. Genetic abnormalities.

A

A. Positive: CD10, vimentin, AMACR, CK7.

B. +7, +17, −Y.

311
Q

Sporadic chromophobe renal-cell carcinoma: IHC.

A

Positive: CD117, CK7.

Negative: Vimentin.

Variable: CD10.

312
Q

Sporadic chromophobe renal-cell carcinoma: Genetic abnormality.

A

Hypodiploidy.

313
Q

Collecting-duct carcinoma: IHC.

A

Positive: High-molecular-weight cytokeratin.

Negative: CD10, vimentin.

314
Q

Collecting-duct carcinoma: Genetic abnormality.

A

−1q.

315
Q

Renal medullary carcinoma: IHC.

A

Positive: CEA.

Negative: CD10, vimentin.

316
Q

Renal-cell carcinoma with translocation involving Xp11.2: IHC.

A

Positive: TFE3 (nuclear), CD10.

317
Q

Renal-cell carcinoma with translocation involving Xp11.2: Translocations.

A

t(X;1).

t(X;17).

318
Q

Renal-cell carcinoma with translocation involving Xp11.2:

A. Histology (3).
B. Behavior.

A

A. Nested and papillary architecture; clear cells; psammoma bodies.

B. Indolent.

319
Q

Mucinous, tubular, and spindle-cell carcinoma: IHC.

A

Positive: Vimentin.

Negative: CD10.

320
Q

Mucinous, tubular, and spindle-cell carcinoma: Genetic abnormality.

A

Loss of 1, 4, 6, 8, 13, 14.

321
Q

Angiomyolipoma: IHC.

A

Positive: HMB45.

322
Q

Angiomyolipoma: Genetic abnormality.

A

Loss of heterozygosity for TSC2 on 16p.

323
Q

Wilms’ tumor: Genetic abnormality.

A

Mutation of WT1 on 11p13.

324
Q

Wilms’ tumors: Associated syndrome and its genetic abnormality.

A

WAGR.

Microdeletion involving WT1 and the adjacent PAX6.

325
Q

Synovial sarcoma: Gene.

A

Expression of TLE1 is correlated with the presence of the translocation but is not entirely specific.

326
Q

Low-grade fibromyxoid sarcoma:

A. Related tumor.
B. Translocation.

A

A. Hyalinizing spindle-cell tumor with giant rosettes.

B. t(7;16)(q34;p11). Also seen in HSTGR, which is on a continuum with LGFMS.

327
Q

Translocation: Chondroid lipoma.

A

t(11;16)(q13;p12-13) :: C11orf95-MKL2.

328
Q

Genetic defect: Schwannoma.

A

−22q12 :: NF2.

329
Q

Most common translocation: Ewing’s sarcoma/PNET.

A

t(11;22)(q24;q12) :: FLI1-EWS.

330
Q

Second most common translocation: Ewing’s sarcoma/PNET.

A

t(21;22)(q22;q12) :: ERG-EWS.

331
Q

Other translocations: Ewing’s sarcoma/PNET (3).

A

t(7;22)(p22;q12) :: ETV1-EWS.

t(17;22)(q21;q12) :: ETV4-EWS.

t(2;22)(q33;q12) :: FEV-EWS.

332
Q

Genetic defects (2): Neuroblastoma.

A

−1p, +17.

333
Q

Translocations (2): Alveolar rhabdomyosarcoma.

A

t(2;13)(q35;q14) :: PAX3-FOXO1.

t(1;13)(p36;q14) :: PAX7-FOXO1.

334
Q

Genetic defect: Alveolar soft-part sarcoma.

A

der(17)t(X;17)(p11;q25) :: TFE3-ASPSCR1.

335
Q

Translocation: Desmoplastic small round-cell tumor.

A

t(11;22)(p13;q12) :: WT1-EWS.

336
Q

Translocation: Myxoid and round-cell liposarcoma.

A

t(12;16)(q13;p11) :: DDIT3-TLS.

337
Q

Translocation: Low-grade fibromyxoid sarcoma / hyalinizing spindle-cell tumor with giant rosettes.

A

t(7;16)(q33;p11) :: CREB3L2-TLS.

338
Q

Translocation: DFSP / giant-cell fibroblastoma.

A

t(17;22)(q22;q13) :: COL1A1-PDGFB.

339
Q

Translocation: Infantile fibrosarcoma / congenital mesoblastic nephroma.

A

t(12;15)(p12;q25) :: ETV6-NTRK3.

340
Q

Translocation: Extraskeletal myxoid chondrosarcoma.

A

t(9;22)(q22;q12) :: NR4A3-EWS.

341
Q

Translocations (2): Angiomatoid fibrous histiocytoma.

A

t(12;22)(q13;q12) :: ATF1-EWS.

t(2;22)(q33;q12) :: CREB1-EWS.

342
Q

Translocations (2): Clear-cell sarcoma.

A

t(12;22)(q13;q12) :: ATF1-EWS.

t(2;22)(q33;q12) :: CREB1-EWS.

??????

343
Q

Translocations (2): Synovial sarcoma.

A

t(X;18)(p11.2;q11.2) :: SSX1-SYT, SSX2-SYT.

???????

344
Q

Translocation (2): Inflammatory myofibroblastic tumor.

A

t(1;2)(q25;p23) :: TPM3-ALK.

t(2;19)(p23;p13) :: TPM4-ALK.

345
Q

Most common translocation: Lipoma.

A

t(3;12)(q29;q15) :: LPP-HMGA2.

346
Q

Chromosomal region most often affected in well-differentiated liposarcoma / atypical lipomatous tumor.

A

12q14-q15.

347
Q

Tumors of the head and neck caused by HPV:

A. Epidemiology.
B. Anatomic location.
C. Clinical course.

A

A. Young nonsmokers.

B. Oropharynx.

C. Indolent.

348
Q

Tumors of the head and neck caused by HPV:

A. Tumor biology.
B. Testing.

A

A. Genes E6 and E7 of HPV get incorporated into the cellular genome and suppress p53 and Rb, respectively, with over-expression of p16.

B. IHC for p16.

349
Q

Multiple endocrine neoplasia, type 1:

A. Endocrine tumors (3).
B. Non-endocrine tumors (4).

A

A. Pituitary adenoma (esp. prolactinoma), parathyroid adenoma, pancreatic islet-cell tumor.

B. Facial angiofibroma, collagenoma, lipoma, meningioma.

350
Q

Multiple endocrine neoplasia, type 1: Genetic abnormality.

A

Germline mutation of MEN1 at 11q13.

351
Q

Significance of sporadic mutations of MEN1.

A

Seen in 15-20% of sporadic parathyroid adenomas, islet-cell tumors, and gastrinomas.

352
Q

Multiple endocrine neoplasia, type 2A:

A. Tumors.
B. Genetic abnormality.

A

A. Parathyroid adenoma, pheochromocytoma, medullary thyroid carcinoma.

B. Mutation in affecting exons 10 and 11 of RET on 10q.

353
Q

Multiple endocrine neoplasia, type 2B:

A. Tumors.
B. Genetic abnormality.

A

A. Pheochromocytoma, medullary thyroid carcinoma, mucosal neuromas / ganglioneuromas, marfanoid body type.

B. Mutation in affecting exon 16 of RET on 10q.

354
Q

Medullary thyroid carcinoma: Histology in multiple endocrine neoplasia.

A

Not distinctive, but accompanied by hyperplasia of C cells and by many microscopic foci of medullary carcinoma.

355
Q

Papillary thyroid carcinoma:

A. Mutated genes.
B. Result of these genes.
C. Distribution of these genes.

A

A. BRAF, RET, RAS.

B. Unregulated stimulation of mitogen-associated protein kinases.

C. Mutually exclusive.

356
Q

Papillary thyroid carcinoma:

A. Most common mutation.
B. Frequency of this mutation in subtypes of PTC.

A

A. V600E of BRAF.

B. 80% in tall-cell variant, 60% in conventional PTC, 10% in follicular variant.

357
Q

Papillary thyroid carcinoma: Frequency of mutations in RET in sporadic cases.

A

About 40%.

358
Q

Papillary thyroid carcinoma: Mutation associated with more aggressive behavior.

A

Mutations in BRAF.

359
Q

Melanoma: Most commonly mutated genes (2) and the clinical significance of each.

A

C-KIT: 30% of cases; tumors may respond to imatinib.

BRAF: Common in cutaneous melanomas that are not associate with sun-induced damage; may respond to inhibitor of BRAF kinase.

360
Q

Diffuse gliomas:

A. Types.
B. Gene that are mutated early in tumorigenesis.

A

A. Astrocytoma, oligodendroglioma.

B. IDH1, IDH2.

361
Q

Diffuse gliomas: Differentiating mutations.

A

Astrocytoma: Mutations in TP53 on 17p13.

Oligodendroglioma: Deletions of 1p, 19q.

362
Q

Diffuse gliomas: Mutation associated with progression to glioblastoma.

A

Loss of material from 10q.

363
Q

Diffuse gliomas:

A. Mutations associated with higher grade.
B. Amplification of EGFR.

A

A. Loss of 9p and 10q.

B. Present in higher grades of astrocytoma but not in oligodendroglioma.

365
Q

Primary glioblastoma: Genetic abnormalities (3).

A

Amplification of EGFR.

Mutation in PTEN.

Loss of 10q.

No mutation of TP53.

366
Q

MGMT gene and brain cancer:

A. Relation to tumorigenesis.
B. Relation to prognosis.

A

A. In some glioblastomas, MGMT is silenced through hypermethylation of the promoter.

B. Decreases efficacy of temozolomide and radiotherapy.

367
Q

Oligodendroglioma vs. astrocytoma: Radiology.

A

Oligodendroglioma: Peripheral, well-circumscribed.

Astrocytoma: Central, infiltrative.

368
Q

Oligodendroglioma vs. astrocytoma: Histology.

A

Oligodendroglioma: Round, regular nuclei; few glial processes; perineural satellitosis; microcysts filled with mucin.

Astrocytoma: Elongated, irregular nuclei; abundant glial processes.

369
Q

Oligodendroglioma vs. astrocytoma: Immunohistochemistry.

A

Astrocytoma is more likely to have strong expression of GFAP and p53.

370
Q

Oligodendroglioma vs. astrocytoma: Prognosis.

A

Oligodendroglioma: Better; loss of 1p and 19q confers a better prognosis.

Astrocytoma: Worse.

371
Q

Oligodendroglioma vs. astrocytoma: WHO types.

A

Oligodendroglioma: Grade II (oligodendroglioma); grade III (a aplastic oligodendroglioma).

Astrocytoma: Grade II (low-grade); grade III (high-grade); grade IV (glioblastoma).

372
Q

Pilocytic astrocytoma:

A. Genetic abnormality.
B. Frequency of this abnormality.

A

A. Mutations in BRAF, often with no other genetic abnormality.

B. Found in up to 80% of tumors, but rare in diffuse astrocytoma.

373
Q

Retinoblastoma:

A. Genetic abnormality.
B. Is this abnormality sporadic or germline?

A

A. Mutation in RB1 on 13q14.

B. 90% are sporadic.

374
Q

Retinoblastoma: Associated tumors (3).

A

Osteosarcoma.

Tumors of the pineal gland.

Primitive neuroectodermal tumor.

375
Q

Meningioma:

A. Mutation.
B. Gene and its product.

A

A. −22, particularly affecting 22q12.2.

B. NF2; merlin.

376
Q

Meningioma: Relevance of mutation to subtype (4).

A

Abnormalities of NF2 are found in

80% of transitional and fibroblastic tumors,

25% of meningothelial types,

virtually no secretory meningiomas.

377
Q

Meningioma: Most common genetic abnormality in tumors of higher grade.

A

−1p.

378
Q

Medulloblastoma: Syndromes associated with higher risk.

A

Turcot’s, Gorlin’s, Li-Fraumeni.

379
Q

Medulloblastoma: Most common genetic abnormalities in sporadic cases (2).

A

i(17q).

−17p: Associated with more aggressive behavior.

380
Q

Rhabdoid tumor: Genetic abnormality.

A

Loss of SMARCB1 on 22q11.2, which encodes INI1.

381
Q

Mutations of EGFR in lung adenocarcinoma:

A. Most commonly affected exons.
B. Epidemiology.

A

A. Exons 18-21, which encode part of the tyrosine-kinase domain.

B. Young Asian female; never-smokers.

382
Q

Mutations of EGFR in lung adenocarcinoma:

A. Therapy.
B. Causes of secondary resistance (2).

A

A. Tumors respond to inhibitors of the tyrosine kinase of EGFR but not to monoclonal antibodies to EGFR.

B. T790M of EGFR; mutations in other genes such as MET.

383
Q

Which type of lung adenocarcinoma has the highest rate of mutation of KRAS?

A

Mucinous adenocarcinoma.

384
Q

Mutations of ALK in lung adenocarcinoma: Genetic basis.

A

Interstitial inversion in 2p leads to EML4-ALK translocation.

385
Q

Mutation of ROS1 in lung adenocarcinoma:

A. Frequency.
B. Therapy.

A

A. Present in 1-2% of tumors.

B. May respond to tyrosine-kinase inhibitors.

386
Q

Lynch’s syndrome:

A. Associated female genitourinary malignancies (2).
B. Risk of each.

A

Endometrial (esp. lower uterine segment): 50%.

Epithelial ovarian (esp. clear-cell type): 10%.

387
Q

Hereditary breast/ovarian cancer:

A. Genes.
B. Risk of ovarian cancer.
C. Precursor lesion.

A

A. BRCA1, BRCA2.

B. Tenfold.

C. Serous tubal intraepithelial carcinoma.

388
Q

Factors that determine malignant transformation due to HPV.

A

Ease of integration of HPV DNA.

Alleles of the viral genes E6 and E7.

389
Q

Tuberous sclerosis: Cutaneous abnormalities (4).

A

Facial angiofibroma.

Subungual or perungual fibroma.

Hypomelanotic macule.

Connective-tissue nevus.

390
Q

Tuberous sclerosis: Major ocular abnormality.

A

Retinal hamartoma.

391
Q

Tuberous sclerosis: Major CNS abnormalities (3).

A

Cerebral cortical tuber.

Subependymal nodule.

Subependymal giant-cell astrocytoma.

392
Q

Tuberous sclerosis: Cardiovascular abnormalities (2).

A

Cardiac rhabdomyoma.

Lymphangioleiomyomatosis.

393
Q

Tuberous sclerosis: Major renal abnormality.

A

Angiomyolipoma.

394
Q

Tuberous sclerosis: Oral abnormalities (2).

A

Dental enamel pits.

Gingival fibromas.

395
Q

Tuberous sclerosis: Associated malignancies.

A

Renal cancers, esp. clear-cell RCC.

396
Q

Tuberous sclerosis: Inheritance (2).

A

Autosomal dominant.

60% of mutations arise de novo.

397
Q

Tuberous sclerosis: Genes, locations, products.

A

TSC1, 9q34, hamartin (80% of cases).

TSC2, 16p13, tuberin (20%).

398
Q

Gorlin’s syndrome:

A. Major features (3).
B. Associated malignancies (3).

A

A. Odontogenic keratocysts, multiple basal-cell carcinomas, bifid ribs.

B. Medulloblastoma, meningioma, rhabdomyosarcoma.

399
Q

Gorlin’s syndrome:

A. Inheritance.
B. Gene and its location.

A

A. Autosomal dominant.

B. PTCH1 on 9q22.3.

400
Q

Neurofibromatosis, type 1:

A. Inheritance (2).
B. Gene, location, product.

A

A. Autosomal dominant; half of cases are sporadic.

B. NF1, 17q11.2, neurofibromin.

401
Q

Neurofibromatosis, type 1: Cutaneous abnormalities (3).

A

Café-au-lait macules, neurofibromas, freckling of groin or axilla.

402
Q

Neurofibromatosis, type 1: Ocular abnormality.

A

Lisch nodules.

403
Q

Neurofibromatosis, type 1: Common bony abnormalities (2).

A

Dysplasia of wing of sphenoid; vertebral dysplasia.

404
Q

Neurofibromatosis, type 1: Associated malignancies (7).

A 
Pheochromocytoma.
Ampullary adenocarcinoma.
Leukemia.
MPNST.
Medulloblastoma.
Optic glioma.
Breast cancer.
405
Q

Neurofibromatosis, type 2:

A. Inheritance (2).
B. Gene, location, product.

A

A. Autosomal dominant; 30% of cases are sporadic.

B. NF2, 22q, merlin.

406
Q

Neurofibromatosis, type 2:

A. Characteristic tumor.
B. Other tumors (3).

A

A. Schwannoma of both vestibular nerves.

B. Meningiomas, ependymomas, pilocytic astrocytomas.

407
Q

Beckwith-Wiedemann syndrome: Site of genetic abnormality.

A

11p15.5, where maternally derived alleles are preferentially expressed.

408
Q

Beckwith-Wiedemann syndrome: Fetal abnormalities (4).

A

Macrosomia, polyhydramnios, large placenta, long umbilical cord.

409
Q

Beckwith-Wiedemann syndrome: Other abnormalities (4).

A

Hemihypertrophy, macroglossia, omphalocele, anterior creases or pits on ears.

410
Q

Beckwith-Wiedemann syndrome: Associated tumors.

A

Hepatoblastoma, nephroblastoma (Wilms’ tumor).

411
Q

Chromosomal-breakage syndromes:

A. Molecular basis.
B. Examples (5).

A

A. Defects in mechanisms of DNA repair.

B. Bloom’s syndrome, ataxia-telangiectasia, Fanconi’s syndrome, Nijmegen syndrome, xeroderma pigmentosa.

412
Q

Cowden’s syndrome:

A. Gastrointestinal abnormality.
B. Abnormalities of soft tissue.

A

A. Hamartomatous intestinal polyps.

B. Multiple lipomas and fibromas.

413
Q

Cowden’s syndrome: Mucocutaneous abnormalities (4).

A

Facial trichilemmomas.

Papillomas.

Palmoplantar keratoses.

Palmoplantar hyperkeratotic pits.

414
Q

Cowden’s syndrome: Other abnormalities.

A

Genitourinary abnormalities.

415
Q

Cowden’s syndrome: Abnormalities of the CNS (3).

A

Microcephaly.

Mental retardation.

Cerebellar dysplastic gangliocytoma (Lhermitte-Duclos lesion).

416
Q

Cowden’s syndrome: Tumors (4).

A

Follicular carcinoma of thyroid gland.

Carcinomas of breast, colon, endometrium.

417
Q

Cowden’s syndrome:

A. Gene and its location.
B. Related syndromes (2).

A

A. PTEN on 10q23.

B. Bannayan-Riley-Ruvalcaba, Proteus.

418
Q

Carney’s complex: Cutaneous abnormalities (3).

A

Nevi.

Lentigines.

Myxomas.

419
Q

Carney’s complex: Cardiovascular abnormality.

A

Cardiac myxoma.

420
Q

Carney’s complex: Endocrine tumors (3).

A

Follicular adenoma of thyroid gland.

Pituitary adenoma.

Primary pigmented nodular adrenocortical disease.

421
Q

Carney’s complex:

A. Genitourinary tumor.
B. Other syndrome in which this tumor is seen.

A

A. Large-cell calcifying Sertoli-cell tumor.

B. Peutz-Jeghers.

422
Q

Carney’s complex: Neurological tumor.

A

Psammomatous melanotic schwannoma.

Clinical pathology (8 decks)

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