Genetic Abnormalities

Question 1

Duchenne Muscular Dystrophy

Answer 1

• 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

Question 2

X-Linked Hypophosphatemic Rickets

Answer 2

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

Question 3

Primary ABC

Answer 3

• 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

Question 4

Multiple Hereditary Exostosis

Answer 4

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 (2^o to shortened fibula) and patellar dislocation
    • Ankle valgus (2^o 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
• 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

Question 5

Ewing Sarcoma

Answer 5

t(11:22) [11:22 chromosomal translocation]

• Produces EWS/FLI1 identified by PCR

Question 6

Atypical Lipoma

AKA Well differentiated liposarcoma

Answer 6

• MDM2 amplification (distinguishes from lipoma)
• CDK4 also amplified

Question 7

Liposarcoma

Classification

Subtypes

Imaging

Histology

Genetics

Treatment

Answer 7

1. Classification - Malignant (fat)
2. 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
    
    4. 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

Question 8

Synovial Sarcoma

Classification

Age

Presentation

Location

Imaging

Histology

Genetics

Treatment

Answer 8

1. Classification - Malignant
   * Unknown origin - not synovial
2. Age = 15-40
3. Presentation
   * Slow growing mass, 50% have pain
4. 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

5. Imaging

• Radiographs = calcification in ~20%
• MRI = indeterminate
  
  • T1 = low signal
  • T2 = high signal

6. Histology

• Biphasic appearance with two cell types
  
  • Spindle cells
  • Epithelial cells

7. Genetics

• t(X;18) chromosomal translocation
• SYT-SSX1, 2, or 4 fusion protein

8. 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

Question 9

Myxoid Lipsarcoma

Answer 9

t(12;16) translocation

• FUS-DDIT3(CHOP)

Question 10

Alveolar Rhabdomyosarcoma

Answer 10

t(2;13)

• PAX3-FKHR

Question 11

Neurofibromatosis

Answer 11

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

Question 12

Dupuytren’s Disease

Answer 12

Autosomal Dominant

Question 13

What are the associated translocations?

Myxoid Lipsarcoma

Ewing Sarcoma

Synovial Sarcoma

Myxoid Chondrosarcoma

Rhabdomyosarcoma

Answer 13