Genetic Abnormalities Flashcards
Duchenne Muscular Dystrophy
- X-linked recessive
- Xp21.2 dystrophin gene defect due to point deletion and nonsense mutation
- Dystrophin absence leads to:
- Poor muscle fiber regeneration
- Progressive replacement of muscle tissue with fibrous and fatty tissue
X-Linked Hypophosphatemic Rickets
X-linked dominant
- Most common form
- Results from mutation in PHEX gene
- Leads to increased levels of FGF23, which decreases renal phosphate absorption and suppresses renal 25-(OH)-1α-hydroxylase activity
Autosomal dominant
- results from mutation in FGF23
- leads to decreased FGF23 degradation
Autosomal recessive
- results from mutation in dentin matrix protein 1 (DMP1) gene
- leads to impaired osteocyte maturation and bone mineralization, and increased levels of FGF23
Primary ABC
- Neoplasms driven by upregulation of the ubiquitin-specific protease USP6 (Tre2) gene on 17p13 when combined by translocation with a promoter pairing
- Most commonly described translocation t(16;17)(q22;p13) leading to juxtaposition of promoter region CDH11 on 16q22
Multiple Hereditary Exostosis
Autosomal dominant mutation in EXT 1, EXT 2
- EXT-1 has more serious disease manifestations
- Higher rate of chondrosarcoma
- More exostoses
- More limb malalignment with less forearm and knee range of motion
- More pelvic and flatbone involvement
Associated with:
- Short stature
- Metaphyseal widening
- Primarily sessile lesions
- Long bone deformities
- Higher risk of malignant transformation (5-10% Chondrosarcoma)
- Proximal lesions more likely to undergo malignant transformation than distal lesions
Symptoms:
- Limb deformities
- Most common sites of deformity include the knee, forearm, and ankle
- Femoral shortening and limb-length discrepancy
- Coxa valga
- Knee valgus (2o to shortened fibula) and patellar dislocation
- Ankle valgus (2o to shortened fibula)
- Upper extremity deformities are well tolerated and lead to little loss of function
- Ulnar shortening
- Radial bowing and radial head dislocation
- May be treated with exostosis excision, ulnar lengthening and radial closing wedge osteotomy
- Most common sites of deformity include the knee, forearm, and ankle
- Joint pain
- May have symptoms of premature OA
Physical exam:
- Most common deformities include:
- Ulnar shortening and radial bowing
- Radial head dislocation
- Ulnar deviation of the hand
Ewing Sarcoma
t(11:22) [11:22 chromosomal translocation]
- Produces EWS/FLI1 identified by PCR
Atypical Lipoma
AKA Well differentiated liposarcoma
- MDM2 amplification (distinguishes from lipoma)
- CDK4 also amplified
Liposarcoma
Classification
Subtypes
Imaging
Histology
Genetics
Treatment
- Classification - Malignant (fat)
- Subtypes
- Well differentiated
- Myxoid liposarcoma
- Can metastasize to sites other than lung including retroperitoneum (mets to fat)
- CT chest/abdo/pelvics required for staging
- Round cell liposarcoma
- Pleomorphic liposarcoma
- Dedifferentiated liposarcoma
3. Imaging - MRI
- Well differentiated appear same as lipoma
- High grade appear as soft tissue sarcoma
- Histology
- The lipoblast (signet ring-type cell) is a hallmark of liposarcomas
5. Genetics - t(12;16)
6. Treatment - Well differentiated = marginal resection
- Intermediate and high grade = treat as soft tissue sarcoma
- Wide surgical resection with cuff of normal tissue (>1cm)
- Radiation - Pre (~50Gy) or postop (~66Gy)
- Chemotherapy for high grade, large tumours and mets
Synovial Sarcoma
Classification
Age
Presentation
Location
Imaging
Histology
Genetics
Treatment
- Classification - Malignant
* Unknown origin - not synovial - Age = 15-40
- Presentation
* Slow growing mass, 50% have pain - Location
- Arises near joints but rarely involves a joint
- Most common = knee, shoulder, arm, elbow, foot
- Most common malignant sarcoma of the foot
- Can metastasize to regional lymph nodes
- Lung mets still more common
- Imaging
- Radiographs = calcification in ~20%
- MRI = indeterminate
- T1 = low signal
- T2 = high signal
- Histology
- Biphasic appearance with two cell types
- Spindle cells
- Epithelial cells
- Genetics
- t(X;18) chromosomal translocation
- SYT-SSX1, 2, or 4 fusion protein
- Treatment
- Same as soft tissue sarcoma
- Wide surgical resection with cuff of normal tissue (>1cm)
- Radiation - Pre (~50Gy) or postop (~66Gy)
- Chemotherapy for high grade, large tumours and mets
Myxoid Lipsarcoma
t(12;16) translocation
- FUS-DDIT3(CHOP)
Alveolar Rhabdomyosarcoma
t(2;13)
- PAX3-FKHR
Neurofibromatosis
Autosomal dominant
- Inactivation of NF1 tumor suppressor gene (17q11.2)
- Loss of expression of protein neurofibromin
- Neurofibromin negatively regulates RAS-mediated pathway
- Loss of neurofibromin leads to increased RAS activity
- Affects RAS-dependent MAPK activity which is essential for osteoclast function and survival
Dupuytren’s Disease
Autosomal Dominant
What are the associated translocations?
Myxoid Lipsarcoma
Ewing Sarcoma
Synovial Sarcoma
Myxoid Chondrosarcoma
Rhabdomyosarcoma