| Pediatric Dwarfisms |
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Genetic Pearls of Skeletal Dysplasia
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Autosomal Dominant
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 Achondroplasia |
FGFR-3
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Inhibition of chondrocytes proliferation
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| Apert Syndrome |
FGFR-2 |
Inhibition of chondrocytes proliferation |
| CMT (80-90%) |
PMP22 |
Nerve demyelination |
| Pseudoachondroplasia |
COMP
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Abnormal cartilage formation |
SED congenita
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COL2A1 / Type II collagen
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Defect in cartilage matrix formation
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| Kniest's Syndrome |
Type II collagen |
Type II collagen
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| MED - Type I |
COMP
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Type II collagen
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| MED - Type II |
Type IX collagen |
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| Jansen's metaphyseal chondrodysplasia |
PTHrP
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Functional defect in parathyroid hormone |
| Schmid's metaphyseal chondrodysplasia |
Type X Collagen |
Defect in cartilage matrix formation
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| Cleidocranial dysplasia |
CBFA-1 |
Impaired intramembranous ossification |
| Osteogenesis Imperfecta (Type I, IV) |
COL1A1/COL1A2 |
Type I collagen
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Autosomal Recessive
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Diastophic dysplasia
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DTD (Sulfate Transport Protein)
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Defect in sulfaction of proteoglycan
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| Friedreich's Ataxia |
Frataxin
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| Osteo. Imperfecta (Type II, III) |
COL1A1/COL1A2 |
Type I collagen
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| McKusick metaphyseal |
Unknown
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X Linked Recessive
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SED tarda
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COL2A1
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Type II collagen
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| CMT (10-20%) |
connexin gene |
Nerve demyelination |
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| Epigenetics |
- Overview
- Epigenetic changes include inheritable genetic alteration (developmental or environmental cues) that do NOT involve DNA mutation
- DNA methylation, histone modification, nucleosome location, or noncoding RNA are components of epigenetics
- Osteoarthritis is thought to have epigenetic mechanisms that influence the disease process
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| Translocations |
- Overview
- translocations allow expression of genes (oncogenes) that are usually not active.
- cytogenetic analysis allows for the detection of gene translocations by evaluating the size and number of chromosomes isolated from the cell nucleus.
- Examples
- present in up to 95% of sarcomas.
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Disease
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Translocation
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Gene
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Ewing's sarcoma
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t (11:22)
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Fusion protein (EWS-FLI1) |
| Rhabdomyosarcoma |
t (2:13)
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Pax3-FKHR |
| Myxoid liposarcoma |
t (12:16)
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TLS-CHOP |
| Synovial sarcoma |
t (X:18)
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SYT-SSX1, 2, or 4 fusion protein |
| Clear cell sarcoma |
t (12:22)
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Fusion protein EWS-ATF1
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Chondrosarcoma (Myxoid Variant)
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t (9:22)
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Fusion protein EWS-CHN
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| Tumor Suppressor Genes |
- Definition
- inhibit cell proliferation
- therefore a mutation interfering with normal function causes leads to uncontrolled cell growth
- Examples
- retinoblastoma protein (pRB-1)
- acts as a regulator of gene expression
- recessive suppressor
- both alleles must be mutated to have uncontrolled growth
- Rb mutation in
- 100% of retinoblastomas
- 35% of osteosarcomas
- abnormal state is phosphorylated and unable to bind to DNA to regulate
- p53
- normal protein prevents entrance into S-phase of cell cycle when DNA is damaged
- dominant suppressor
- single allele must be mutated to have uncontrolled growth
- mutation in this gene found in
- 50% of all tumors
- osteosarcoma (20-65%)
- chondrosarcoma
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| Oncogenes |
- Definition
- induce uncontrolled growth
- normal function causes leads to uncontrolled cell
- Examples
- FAK
- Erb-2
- epidermal growth factor variant
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| Tumor Antigens |
- Definition
- tumor antigens are used in the diagnosis, monitoring of treatment response, and are being researched for treatment options as anti-cancer vaccines
- Examples
- carcinoembryonic antigen (CEA)
- carbohydrate antigen 19-9 (CA-19-9)
- carbohydrate antigen 125 (CA-125)
- cancer antigen 15-3 (CA-15-3)
- alpha fetoprotein (AFP)
- can be seen in many cancers, but is most commonly seen in hepatocellular carcinomas
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| Assays |
- Western blot
- detects protein
- Southern blot
- Northern blot
- Southwestern blot
- detects DNA binding proteins
- RT-PCR
- reverse transcription PCR
- highly sensitive, detects low copy number of RNA
- reversed transcribed into complimentary DNA (cDNA)
- may be used together with Northern blot
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Please Rate Educational Value!
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3.0
t-9025
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Average 3.0 of 9 Ratings
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Qbank (6 Questions)
TAG
(OBQ08.156)
Which of the following laboratory tools is used to detect genetic translocations for prenatal screening?
Review Topic
DISCUSSION:
Cytogenetic analysis performed for prenatal testing involves analyzing entire chromosomes, obtained from the nucleus of the cell, to determine changes in chromosomal size and number (e.g. Down Syndrome, trisomy 21). Western blot analysis and ELISA are used to identify absence/presence of specific proteins from a solution. Northern blot analysis is used to identify absence/presence of specific RNA from a solution. Flow cytometry identifies specific proteins on the cellular surface in order to sort cells with/without this protein from each other. The review article by Bridge reviews specific molecular biological techniques used in orthopaedics for diagnostic purposes. Rubin et al. reviews the many molecular translocations seen in sarcomas - including ewing’s sarcoma: chromosomes 11 and 22 [t(11;22)]; and synovial sarcoma: chromosomes X and 18 [t(X;18)]. Illustration A is a visual mnemonic to remember the applications of commonly used tests in molecular biology.
Illustrations:
A
REFERENCES:
1.
Bridge JA. Cytogenetic and molecular cytogenetic techniques in orthopaedic surgery. J Bone Joint Surg Am. 1993 Apr;75(4):606-14.
PMID:8478390 (Link to Abstract)
2.
Rubin BP, Fletcher JA. Molecular alterations in sarcomas. Curr Opin Orthopedics. 2001. 12-519-525
|
Please Rate Educational Value!
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2.0
q-542
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Average 2.0 of 13 Ratings
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TAG
(OBQ07.82)
What serum marker is most closely associated with colorectal carcinoma?
Review Topic
DISCUSSION:
Carcinoembryonic antigen (CEA) is most closely associated with colorectal carcinoma.
Lang reviews the science behind identification and utilization of cancer antigens for diagnosis, treatment response monitoring, and vaccine purposes.
Incorrect answers:
1.Carbohydrate antigen 19-9 (CA-19-9) is seen in pancreatic cancer. 3.Carbohydrate antigen 125 (CA-125) is seen in ovarian cancer.
4.Cancer antigen 15-3 (CA-15-3) is seen in breast cancer.
5.Alpha fetoprotein (AFP) can be seen in many cancers, but is most commonly seen in hepatocellular carcinomas.
REFERENCES:
1.
Lang JM, Andrei AC, McNeel DG. Prioritization of cancer antigens: keeping the target in sight. Expert Rev Vaccines. 2009 Dec;8(12):1657-61.
PMID:19943761 (Link to Abstract)
|
Please Rate Educational Value!
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1.0
q-743
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Average 1.0 of 19 Ratings
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TAG
(OBQ07.266)
Which of the following chromosomal translocations is associated with osteosarcoma?
Review Topic
DISCUSSION:
Answer 1: Synovial cell sarcoma is characterized by translocation t(X;18)(p11;q11) in more than 90% of cases which causes the fusion gene is called the SYT-SSX1, SYT-SSX2, or SYT-SSX4. Answer 2: The consistent cytogenetic abnormality in myxoid liposarcoma is translocation t(12;16)(q13;p11.2). This involves fusion of the transcription factor gene CHOP, which is essential for adipocytic differentiation, to the translocated in liposarcoma (TLS) gene on chromosome 16. Answer 3: Translocation t(11;22) is one of a series of related translocations occurs in more than 95% of the Ewing sarcoma family of tumors. This translocation joins the Ewing sarcoma gene EWS on chromosome 22 to a gene of the ETS family, friend leukemia insertion (FLI1) on chromosome 11, creating an aberrant activating transcriptional factor. Answer 4: The alveolar subtype of rhabdomyosarcoma accounts for 31% of rhabdo cases and involves a unique translocation occurs between the FKHR gene on chromosome 13 and either the PAX3 gene on chromosome 2 (70%) or the PAX7 gene on chromosome 1 (30%). Osteosarcoma has no associated chromosomal translocation, but often has a mutation in Rb gene (retinoblastoma gene).
REFERENCES:
1.
Buckwalter JA, Einhorn TA, Simon SR (eds): Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2000, pp 427-441
|
Please Rate Educational Value!
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3.0
q-927
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Average 3.0 of 10 Ratings
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TAG
(OBQ06.95)
A mutation of the retinoblastoma gene RB-1 leads to the development of malignancies such as retinoblastoma and osteosarcoma. Which term best characterizes the RB-1 gene?
Review Topic
DISCUSSION:
A tumor suppressor is a gene whose presence normally prevents neoplasia and whose absence leads to unregulated cell growth. Two well-studied tumor suppressor genes include p53 and RB-1. P53 normally suppresses cell division by blocking the cell cycle if genetic damage is present. If it is absent or mutated, the p53 suppressing effect no longer regulates cell growth and neoplasm results. In a similar fashion, a mutation in RB-1, or the retinoblastoma gene, may leads to retinoblastoma and osteosarcoma.
REFERENCES:
1.
Buckwalter JA, Einhorn TA, Simon SR (eds): Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2000, pp 19-76.
|
Please Rate Educational Value!
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2.0
q-206
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Average 2.0 of 12 Ratings
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TAG
(OBQ04.268)
Which of the following sarcomas is correctly paired with its most common translocation?
Review Topic
DISCUSSION:
Chromosomal translocations are characteristically associated with several sub-types of soft tissue sarcomas. The most common clear cell sarcoma translocation is t(12:22). A histologic example is found in illustration A.
Many sarcomas have distinct translocations which can help identify them via cytogenetic testing. The most common are alveolar rhabdomyosarcoma:t(2;13), synovial sarcoma:t(X;18), Ewing’s sarcoma: t(11,22), myxoid liposarcoma:t(12;16), and chondrosarcoma:t(9;22). Histologic examples are in Illustrations B through F, respectively. Osteosarcoma does not have a characteristic translocation.
In a review article, Rabbits described many fusion proteins resulting from chromosomal translocations. As many are nuclear proteins, future molecular based therapies are being developed to target steps from oncogene transcription to RNA translation. Solomon et al reviewed chromosome aberrations in rare and common tumors. A broader understanding of chromosomal abnormalities and fusion proteins will aid gene-targeted diagnosis and therapies.
REFERENCES:
1.
Rabbitts TH. Chromosomal translocations in human cancer. Nature. 1994 Nov 10;372(6502):143-9
PMID:7969446 (Link to Abstract)
2.
Solomon E, Borrow J, Goddard AD. Chromosome aberrations and cancer. Science. 1991 Nov 22;254(5035):1153-60
PMID:1957167 (Link to Abstract)
|
Please Rate Educational Value!
|
2.0
q-1373
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Average 2.0 of 14 Ratings
|
Level of Evidence 5 and Other Journal Articles (includes Case Reports, Expert Opinions,
Personal Observations, and Biomechanic Studies)
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Neu C, Stewart M. On the horizon from the ORS. J Am Acad Orthop Surg. 2008;16:432-434. Maher SA, Hidaka C, Cunningham ME, Rodeo SA. What’s new in orthopaedic research. J Bone Joint Surg Am. 2008 Aug;90(8):1800-8
PMID:18676928 (Link to Abstract)
-
Lang JM, Andrei AC, McNeel DG. Prioritization of cancer antigens: keeping the target in sight. Expert Rev Vaccines. 2009 Dec;8(12):1657-61.
PMID:19943761 (Link to Abstract)
-
Rabbitts TH. Chromosomal translocations in human cancer. Nature. 1994 Nov 10;372(6502):143-9
PMID:7969446 (Link to Abstract)
-
Solomon E, Borrow J, Goddard AD. Chromosome aberrations and cancer. Science. 1991 Nov 22;254(5035):1153-60
PMID:1957167 (Link to Abstract)
Textbooks
- Review of Orthopaedics, 6th Edition, Mark D. Miller MD, Stephen R. Thompson MBBS MEd FRCSC, Jennifer Hart MPAS PA-C ATC, an imprint of Elsevier, Philadelphia, Copyright 2012
- AAOS Comprehensive Orthopaedic Review, Jay R. Leiberman. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2009
- Orthopaedic Knowledge Update 10, John M Flyn. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2011
- Hoppenfeld SP. Surgical Exposures in Orthopaedics: The Anatomic Approach. Lipponcott, Williams, and Wilkins, Philadelphia, PA, Copyright 2009
- Orthopaedic In-training Examination (OITE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
- Self-Assessment Examination (SAE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
Undefined
-
Bridge JA. Cytogenetic and molecular cytogenetic techniques in orthopaedic surgery. J Bone Joint Surg Am. 1993 Apr;75(4):606-14.
PMID:8478390 (Link to Abstract)
-
Rubin BP, Fletcher JA. Molecular alterations in sarcomas. Curr Opin Orthopedics. 2001. 12-519-525
-
Buckwalter JA, Einhorn TA, Simon SR (eds): Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2000, pp 427-441
-
Buckwalter JA, Einhorn TA, Simon SR (eds): Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2000, pp 19-76.
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