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99 Cards in this Set
- Front
- Back
Pick-up rate of HNPCC with genetic testing
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about 60-70%
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What is Gardner syndrome?
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FAP plus:
desmoid tumors osteomas supernumerary teeeth CHRPE soft tissue skin tumors |
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What percent of FAP mutations are de novo?
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up to 30%
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What type of protein is encoded by MYH?
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base excision repair (not tumor supressor)
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2 common MYH mutations accounting for 85% of European cases.
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Y165C
G382D |
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MYH mutation common to Indian families
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E466X
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MYH mutation common to Pakistani families
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Y90X
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MYH mutation common to Italian families
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1395delGGA
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What should be done for someone with multiple polyps +/- colon cancer?
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take family history
get age of onset quantify the number of polyps upper endoscopy to r/o cancers define size and location of polyps confirm histology genetic eval based on results |
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Asterdam criteria: 3-2-1 rule
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THREE relatives affected with HNPCC-associated cancer, one a 1st degree relative of the other 2
TWO generations ONE cancer before 50 |
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Bethesda criteria
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Meet any ONE of these:
Amsterdam criteria met patient under 50 multiple HNPCC tumors in patient patient has at least one first degree relative with HNPCC tumor under 50 patient has 2 first or 2nd degree relatvies with HNPCC tumors at any age patient under 60 and has cancer indicative of MSI |
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Testing protocol for HNPCC based on meeting criteria
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If Amsterdam met, go on with gene testing
If Bethesda met but not Amsterdam, begin with MSI/IHC as screening test If abnormal, then go on to germline testing |
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Chemoprevention for Lynch syndrome
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NSAIDS
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Turcot variant of Lynch is associated with mutations in which genes?
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PMS2/MLH1
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Very early onset colorectal cancer may be due to what syndrome?
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Li-Fraumeni, or homozygous MMR mutations
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Which MMR gene is most often seen in homozygous form?
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PMS2, MSH6 less often
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Features of homozygous MMR mutations
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Not typical Lynch-like features
very early onset colorectal cancer leukemia brain tumors cafe-au-lait spots |
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Features of Peutz-Jeghers
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GI hamartomas
lip/mouth pigmentation colon, stomach, pancreatic, esophageal cancers cervical adenocarcinoma malignum ovarian stromal tumors STK11 gene lung, small bowel, breast cancers |
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Gene assoc. with Peutz-Jeghers, and its location
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STK11 on chromosome 19
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Highest cancer risk in Peutz-Jeghers
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colon-40% lifetime risk
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Which BRCA gene is assoc. with pancreatic cancer? Which mutation?
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BRCA2
AJ mutation 6174delT |
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How many new breast cancer diagnoses each year? How many deaths?
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200,000 cases
40,000 deaths 1700 males cases, 460 deaths |
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American Cancer Socitey's recommendations for breast cancer screening
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Annual mammograms over 40
Annual clinical exams over 40, every 3 years over 20 Self-exams monthly at 20 |
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Breast findings assoc. with no increased risk of cancer
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duct ectasia
fibrocystic disease papillomas, simple fibroadenomas, lipomas infections |
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Breast findings assoc. with small increased risk of cancer
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ductal hyperplasia without atypia
complex fibroadenomas sclerosing adenosis diffuse pappillomatosis |
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Pathology grades for a tumor
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grade 1= well-differentiated
grade 2= moderately differentiated grade 3= poorly differentiated |
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Define tumor stages 0-IV
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stage 0=in situ
stage I=tumor <2 cm, no nodes stage II=tumor2-5 cm, +/- nodes stage III=locally advanced + nodes stage IV=distant metastases |
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Treatment for DCIS
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excisional lumpectomy + radiation
If estrogen receptor +, give Tamoxifen |
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With LCIS, how does the risk for invasive caner increase over time?
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1% increase per year
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Name some drugs used in breast cancer chemotherapy
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adriamycin, epirubicin
cytoxan Methotrexate, 5-flurouracil taxol, Taxotere Navelbine |
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BRCA1 and 2 account for what % of HEREDITARY breast AND ovarian cancer?
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about 90%
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Name some functions of the normal BRCA1 and BRCA2 genes
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DNA repair
cell cycle checkpoint control ubiquitylation (tagginf proteins for degradation by proteosome) transcriptional regulation |
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Lifetime risk of breast cancer for a woman with a BRCA1 mutation? second primary breast cancer?ovarian cancer?
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50-85%, often early age of onset
second primary =40-60% ovarian =30-45% |
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Other cancers associated with BRCA1
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colon, pancreatic, male breast
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What kind of factors could greatly underestimate a woman's risk for cancer via the Gail model?
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cancer on dad's side
dad's sisters and mom affected (none of the woman's 1st degree relatives) ovarian cancer very early onset |
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Protective factors for breast cancer
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4+ hours per week of exercise
breastfeeding ideal bpdy weight, esp. after menopause having kids before 30 |
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Claus tables take only what single factor into account when estimating risk?
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family history
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Name 4 syndromes associated with hereditary breast cancer
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HBOC, Li-Fraumeni, Cowden, Peutz-Jeghers
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BRCA1 and 2 account for what % of HEREDITARY breast cancer?
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about 50%
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In an MSI study, what are the uidelines for determining whether the tumor is MSI-high or not?
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more than 30% unstable=MSI high
less than 30% = MSI low 0% unstable =MSI-stable |
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Another name for microsatellites
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SSRs-simple sequence repeats
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The repeated sequence in microsatelites are how long?
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1-6 base pairs
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In MSI testing, what do you do if the tumor is found to be MSI-high?
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Do IHC testing to determine which gene to sequence OR sequence MLH1 and MSH2
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In MSI testing, what do you do if the tumor is found to be MSI-low or stable?
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Consider colon cancer surveillance, consider IHC testing
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IHC is most useful for which genes, and why?
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MSH2 and MSH6, because most patients with MSH2 mutations have germline mutations. Sporadic patients often have MLH1-negative tumors.
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Limits of IHC testing
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1. If tumor is MSI-high and no mutations are found by IHC, may need to seq. all genes
2. Can't detect missense mutations if protein still localizes. |
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What would you do for a tumor in which MSI is high and IHC is abnormal, but sequencing yields no results?
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Up to 20% have large deletions or rearrangements. Do MLPA or Southern.
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What is the possible order of complete testing that may be necessary to find a mutation causing HNPCC?
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1. MSI and IHC
2. methylation studies if MLH1 if abnormal 3. Gene scanning followed by sequencing 4. MLPA or Southern to look for deletions |
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Name some problems with protein truncation testing
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A large deletion won't show a band, and only the normal allele will be seen, so will look normal. Same is true for RNA processing mutations, or anything that doesn't lead to a truncated protein. Would result in a false negative.
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What are some examples of when to use linkage analysis?
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1. When no mutation is identified in any affected family member
2. If the affected family member isn't available, but others are 3. non-disclosing prenatal diagnosis for adult-onset conditions (rule out inheritance of affected grandparent's chromosome) |
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Linkage is still used to diagnose what condition?
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DMD/BMD
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Cancer risk factors in an indivdual that indicate the need for referral to genetics
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1. bilateral primary tumors
2. multifocal tumors 3. atypical age/sex/site 4. rare tumor 5. tumor assoc. with birth defect, genetic disease, precursor lesion |
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What indicates a genetics referral for cancer in one's family?
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1. a first-degree relative with a cancer, who has any of the individual risk factors
2. Two first-degree relatives with any cancer |
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Penetrance of MEN1 and MEN2
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Almost 100% by age 50
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Diagnostic criteria for NF1
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2 of these manifestations:
--6 cafe-au-lait spots over 15mm postpubertal --1 plexiform neurofibroma or 2 other neurofibromas --axillary or inguinal freckling --2 Lisch nodules --optic pathway tumor --characteristic osseous dysplasia --affected first-degree relative |
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Diagnostic criteria for NF2
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Bilateral vestibular schwannomas
OR a first degree relativve with NF2 and you have 1. unilateral vestibular schwannoma under 30 years OR 2. Two of the following: mengioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract |
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Name some categories of protooncogenes
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1. tyrosine kinases (ERBB2/HER2, RET, ABL)
2. Guanine nucleotide exchangers and bindig proteins (NF1, BCR) 3. Nucelar proteins and Tx factors (GLI, MYC, WT1) 4. Cell cycle/DNA damage response (ATM, MLH1, MSH2, TP53) |
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Name some tumor suppressor genes
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APC, NF1, NF2, BRCAs, VHL, RB1
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Explain the difference in inheritance of protooncogenes vs. tumor suppressors
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Protooncogenes are dominant in that they take only 1 hit to cause cancer. Not inherited. Tumor suppressors require 2 mutations, so are recessive on some level. May be inherited or not inherited.
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What is the cancer risk associated with mosaic trisomy 8?
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preleukemia
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Name some chromosome abnormalities assoc. with increased cancer risk?
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mosaic tri 8
tri 21 del 11q13 (WT) del 13q14 (RB) Turner Klinefelter |
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What is the cancer risk associated with Turner syndrome?
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endometrial adenosquamous carcinoma
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What is the cancer risk associated with Klinefelter?
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nongonadal germ cell tumor and breast cancer
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What is Boveri's 1914 hypothesis about cancer?
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All malignancies have abnormal chromosomes (or genes)
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Name 4 cytogenetic rearrangements that can be associated with familial cancer
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12;13 (familial retinoblastoma)
8;N (familial renal cell carcinoma) 11;N (familial Wilms tumor) 14;22 (familial meningioma) |
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Explain the Philadel[phia chromosome
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Translocation 9;22 in chronic myelogenous leukemia (CML), results in variable fusion between Abelson protooncogene, abl, and BCR gene (a protein kinase)
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Explain cancer translocation btwn 15;17
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In acute progranulocytic leukemia, results in fusion protein of zinc protein type (PNL) with retinoic acid receptor alpha (RARA); make leukemia sensitive to retinoic acid therapy--may be curative
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Name that cancer type:
t(X;8) t(12;16) |
t(X;8)=synovial cell sarcoma
t(12;16)=liposarcoma |
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Name 3 cancer types associated with t(11;22)
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Ewing sarcoma
skin tumor peripheral neuroepithelioma |
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Genes associated with Lynch syndrome
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MLH1/3
MSH2/6 PMS1/2 |
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Syndrome associated with papillary renal cell carcinoma
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MET (protooncogene)
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2 main genes associated with Li Fraumeni syndrome
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TP53, CHK2
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Guidelines to meet for Li Fraumeni
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1. Any sarcoma under 45 years
2. 1st degree relative with any cancer under 45 years 3. 1st or 2nd degree relative with any cancer under 45 oR sarcoma at any age |
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Describe the common findings of phakomatoses
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1. congenital and hereditary developmental anomalies
2. tumor-like malformations with blastomatous tendencies 3. pigmentary patches and/or angiomas 4. tissues of ectodermal origins (skin, eye, nervous) 5. some mesodermal and endodermal elements |
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type of phakomatosis in Sturge-Weber
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encephalotrigeminal angiomatosis
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Frequency of NF1 vs. NF2
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NF1=1 in 4000
NF2=1 in 40,000 |
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Gene and location of NF1 vs. NF2
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NF1= neurofibromin (17q)
NF2= merlin (22q) |
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Tumor types in NF1 vs. NF2
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NF1=neurofibroma, glioma, sarcoma, pheochroma
NF2=vestibular schwannoma, mengioma |
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Skin findings in NF1 vs. NF2
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NF1=cafe-au-lait spots, skin-fold freckling, dark spots
NF2=rare spots, neurofibromas |
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Cognitive impairment in NF1 vs. NF2
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NF1=hand-eye coordination impaired
NF2=normal |
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Calcifications on brain MRI
Teeth pits What syndrome? |
Tuberous sclerosis
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Name the primary diagnostic features of tuberous sclerosis
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cortical tubers
subependymal hamartomas retinal hamartomas angiofibroma (skin) ungual fibroma (nails) |
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What feature of tuberous sclerosis might show up on prenatal ultrasound?
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rhabdomyoma in heart
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What are subependymal hamartomas in tuberous sclerosis?
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Growths on lining of the brain ventricles
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Name the 2 genes and locations assoc. with tuberous sclerosis
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TSC1=hamartin, 9q34
TSC2=tuberin, 16p13 |
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In von Hippel-Lindau, angiomas can appear in which 3 areas?
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liver
adrenal gland retina |
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Major features of von Hippel-Lindau
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retinal ,liver, and adrenal angiomas
cerebellar and spinal cord hemangioblastomas other tumore: pheochromocytoma, carcinoma of kidney, pancreas, endolymphatic sac (in cochlea of ear) cysts of kidney, pancreas (acinar and islet cell), epididymis |
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Gene and location of von Hippel-Lindau
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VHL, chromosome 3, elongin binding protein
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What is Klippel-Trenaunay-Weber syndrome?
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Skin hemangioma of limb, extends to trunk. Hypertrophy of involved limb. Varicose vein. At risk for high-output heart failure. Congenital but NOT hereditary.
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Describe Proteus syndrome
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hemihypertrophy, gigantism of digits, lipoma, angioma, nevus, conjunctival dermoid, skull hyperstosis, renal and lulng cysts, hyperpigmentation spots, plantar hyperkeratosis
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Features of Gorlin syndrome (nevoid basal cell carcinoma syndrome)
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multiple basal cell carcinomas
pits of palms and soles cysts of jaw bone and phalanges' rib anomalies (fused, bifid) medulloblastoma ovarian fibroma and cancer, even very young may see eyelid tumors, axillary tags, synophrys |
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Gene and location of Gorlin syndrome.
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Patched on 9q
Due to haploinsufficiency |
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Features of Cowden syndrome
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Warty papules at mucocutaneous junctions
papillomas in mouth and tongue palmar hyperkeratoses thyroid neoplasia breast cancer colon cancer and polyps meningioma |
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Name some syndromes assoc. with PTEN gene
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Cowden
Lhermitte-Duclos juvenile intestinal polyposis Bannayan-Riley-Ruvalcaba Ruvalcaba-Myhre-Smith Somatic: endometrial and prostate carcinoma, melanoma |
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What syndrome?
macrocephaly freckles, esp. in mouth and around eyes cutaneous myxomas Sertoli cell tumors |
Carney complex (LAMB or NAME)
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Features of Carney complex
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Myxoma of skin
myxoid breast fibroadenoma lentigenes or blue nevi pigmented nodular adrenal disease Sertoli cell tumor, pituitary adenoma Schwannoma |
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What is Carney triad (no relation to Carney complex)?
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Gastric tumor (leiomyosarcoma)
pulmonary chondroma extra-adrenal paraganglioma mostly affects young women, low familiality |
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Another name for ataxia telangiectasia
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Louis-Bar syndrome
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Heterozygotes for ataxia telangiectasia (carriers) may have increased risk of what?
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breast cancer
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