anne
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11. In the pedigree AD disease illustrating a syndrome associated with various neoplasms, individuals whose symbols are solid black have manifestations of the syndrome. The neoplasms and their ages at onset in the affected individuals are as follows:
Pedigree number Type of neoplasm Age at onset (years)
I-2 carcinoma of breast (right) 28
carcinoma of breast (left) 36
II-2 carcinoma of breast 51
II-3 myxofibrosarcoma 48
III-2 medulloblastoma 5
III-4 rhabdomyosarcoma 8
This pedigree illustrates
A) anticipation
B) genetic heterogeneity
C) incomplete penetrance
D) multifactorial inheritance
E) variable expressivity
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| rida
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Variable Expressivity
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| usmle prep
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what si the ans anne??
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| anne
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we dont have ans
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| bobby
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B is more likely
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| Quinn
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...I say E....why would it be genetic heterogeneity?
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| Salman23
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it cant be variable expression because variable expression is a milder expression of the same disease...recall the example of NF, a person with 100 neurofibormas and another with only 1 or 2....
I will go for anticipation...notice the third generation has an earlier onset of the disease. If pleiotropy would have been a choice, I would have gone for that.
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| rida
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I agree with you that it could be anticipation because according to kaplan, it says anticipation is when individuals in the most recent generations of a pedigree develop a disease at an earlier age or with greater severity than do those in earlier generations, but my only questions is, this family had different diseases with each generation, and i thought with anticipation, its the same disease, but just a more severe form at an earlier age, for example, huntington shows anticipation, recent generations show more trinucleotide repeats than earlier generationis, but they still have huntington.......
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| Malaysian
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I feel its variable expressibility.Its unlikely anticipation because Gen.2 got the disease later in age compared to Gen. 1
Have no clue what genetic heterogeneity is.....is it pleiotropy by any chance???
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| kmp
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i think it is variable expressivity
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| mjl1717
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Variable express.-Differences in the observed effects of a given allele or
genotype in different individuals
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| Alina T
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Genetic heterogeneity : different diseases with similar findings but different pathogenesis
Ex: Marfan and homocystinuria
Pleiotropy: one disease affecting multiple organ systems.
Ex: sickle cell disease.
(that was for Malaysian, btw!) 
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| Malaysian
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Thanks alot Alina....you're great!!!!
Since quite a number of diseases affect more than 1 organ-systems......therefore most diseases are pleiotropics then????
Are the 10 types of Ehler-Danlos and different types osteogenesis imperfecta all genetic heterogeneity???
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| Alina T
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Well, I don't have a qualified answer for that second q (assuming that the first one was a rethorical one ), i'll just give an "innocent" opinion.
Ehlers Danlos and osteogenesis imperfecta are different diseases with same pathogenesis (defect in collagen structure/synthesis), only affecting different types of collagen.
That's my 1 am thinking... :!:
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| sjain4
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Anticipation has to do with trinucleotide repeats. As the number of repeats gets increased in subsequent generations, the disease manifests at earliear ages. E.g. Hungtington's.
I believe the answer is variable expressivity.
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| drhouse
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there is no way ans can be variable expression.
the only right ans in many cancer in same family members is multi factorial inheritence
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| edie
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drhouse wrote:
there is no way ans can be variable expression.
the only right ans in many cancer in same family members is multi factorial inheritence
I concur...
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| mytime
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drhouse wrote:
there is no way ans can be variable expression.
the only right ans in many cancer in same family members is multi factorial inheritence
I concur too! This family has mutations of tumor suppressor genes most likely and on top of that has other environmental factors influencing.
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| mytime
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p53
p53 is a well-known tumor-suppressor gene. In 1993 it was named "Molecule of the Year" by Science magazine. p53 has been found to be the most common mutation in cancers, suggesting that it is of great importance in the suppression of cancer. Normally p53 exists in an inactive state. When there is damage to the DNA, p53 is activated and halts the cell cycle. When activated, p53 forms a transcription factor as a tetramer, and binds to several gene promoters. These genes cause disruption of the cell cycle to allow time for DNA repair, or if the damage is too severe, trigger the steps leading to apoptosis (programmed cell death). If p53 is damaged or mutated, it will remain in the inactive state allowing DNA damage to accumulate within a cell, thus increasing the risk for cancer formation. p53 has been called the "gatekeeper" to the cell cycle because of its critical role in cell regulation.
LI-FRAUMENI SYNDROME
Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant familial cancer syndrome associated with an increased risk for various types of cancer including; sarcomas, breast cancer, brain cancer, leukemia, adrenal cortical carcinoma, melanoma, colon cancer and pancreatic cancer. This syndrome was originally referred to as sarcoma, breast, leukemia, adrenal gland (SBLA) syndrome, however research has noted that the spectrum of tumors associated with Li-Fraumeni is broader than originally thought. Li-Fraumeni Syndrome is a highly penetrant syndrome, with a 50% risk for cancer by age 40, and a 90% risk for cancer by the age of 60. Individuals with Li-Fraumeni are also at risk to develop multiple primary tumors.
Clinical Criteria
The classic definition of Li-Fraumeni in a family requires: - One individual with a sarcoma diagnosed under the age of 45 AND
- A first degree relative of the above individual diagnosed with any cancer under the age of 45 AND A first or second degree relative diagnosed with any cancer under the age of 45 or a sarcoma at any age.
Slightly different criteria have been established for Li-Fraumeni-like Syndrome (LFL), which shares some, but not all of the features of Li-Fraumeni Syndrome. One set of criteria established for LFL is:
- A proband with any childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed before 45 years of age AND
- A first- or second-degree relative with a typical LFS cancer (sarcoma, breast cancer, brain tumor, adrenal cortical tumor, or leukemia) at any age AND A first- or second-degree relative with any cancer under the age of 60 years.
Genetics
Li-Fraumeni is diagnosed based on the established clinical criteria listed above. More than 50% of individuals meeting the diagnostic criteria will have an identifiable mutation in the TP53 gene (also known as the p53 gene). The p53 gene is located at 17p13.1 and most of the mutations that have been identified occur in exons 5-8 of the gene. p53 is a well-known tumor-suppressor gene. Normally p53 exists in an inactive state. When there is damage to the DNA, p53 is activated and halts the cell cycle. When activated, p53 forms a transcription factor as a tetramer, and binds to several gene promoters. These genes cause disruption of the cell cycle to allow time for DNA repair, or if the damage is too severe, trigger the steps leading to apoptosis (programmed cell death). If p53 is damaged or mutated, it will remain in the inactive state allowing DNA damage to accumulate within a cell, thus increasing the risk for cancer formation.
Some families with Li-Fraumeni or Li-Fraumeni-like Syndrome who have tested negative for mutations in the p53 gene have been identified as having a mutation in the CHEK2 gene. The CHEK2 gene is a tumor suppressor gene that is within the p53 pathway and is located on chromosome 22 at locus q12.1. The CHEK2 gene is typically activated in the event of DNA damage. CHEK2 encodes for a serine threonine protein kinase that is required as a DNA checkpoint. Mutations in CHEK2 appear to inhibit its ability to stop the cell cycle when DNA damage is present. There have been only a few families who have been identified with a CHEK2 mutation, therefore it is unknown whether CHEK2 mutations are associated with the same cancer risks attributed to p53 mutations.
Surveillance
There are no current screening recommendations for individuals with Li-Fraumeni that have been proven to decrease the mortality associated with Li-Fraumeni, with the exception of breast cancer screening. Proposed screening recommendations for children at risk for Li-Fraumeni include complete blood count (CBC), urinalysis, complete physical exam, abdominal ultrasound, and additional surveillance based on family history. It is recommended that women at risk for Li-Fraumeni receive twice yearly clinical breast exams and annual mammograms (or ultrasound/MRI) beginning around the ages of 20-25. Additional surveillance based on family history is recommended for all adults at risk for Li-Fraumeni Syndrome.
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| mytime
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Hmmmmmmmmm the q sud have been which of the following it is not so I cud have gone with A.
From whatever I cud read up... Peneterance is age and cancer type specific in this cancer by age 40 60% ppl. have it by 60 90%.........so maybe we can rule that out as well. Even though D and B are possibilities but not as likely as genetics. Variable expression is what they want. Sorry I changed my choice.  
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| kingusmle
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i would go by genetic heterogeneity
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| mytime
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Another similar q. I came across
A 29-year-old woman feels a nodule in her neck. On examination there is a firm 2 cm mass in the right lobe of her thyroid. A fine needle aspiration shows cells consistent with papillary carcinoma. 2 years ago she had a lobular carcinoma excised from her left breast. Her 31-year-old sister was recently diagnosed with endometrial carcinoma. Over 3 generations, 16 of 24 close relatives have had a malignancy, most diagnosed before age 35.
Which of the following most likely explains the increased risk for cancer in these people?
A Autosomal dominant cancer syndrome
B Defective DNA repair syndrome
C Germline mosaicism
D Multifactorial inheritance
E Teratogen F Viral infection
(D) CORRECT. Cancer that runs in families often does not have a clearly defined pattern of inheritance and does not have a specific genetic marker. Familial cancers should be suspected when cancers occur at a younger age, multiple family members are involved, and multiple sites are involved. The sites of involvement (breast, colon, thyroid, kidney, ovary) are similar to those for sporadic cancers.
Edited by new_n_lost on 08/01/07 - 05:19 PM. Reason: Made the Question Proper
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| mytime
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So I guess my first guess was rt.!!!!
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| new_n_lost
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I will Go for Anticipation cos the Age is decreasing in the Generations esp the last one and
its not Mulitifactorial Inheritence cos The Children of 2 Separate Siblings r getting Affected roughly around the same age. Now they both cant have the same or similiar Nongenetic factors which cause the mutation in the Gene.
Keep in Mind that we r Discussing Li Fraumeni Syndrome.
I will look on Variable Expression and others also.
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| new_n_lost
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wht i was trying to say abt Multifactorial Inheritance is that Multiple Factors Cause the Same Result.
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