Genetic Abnormalities Flashcards

1
Q

Duchenne Muscular Dystrophy

A
  • 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
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2
Q

X-Linked Hypophosphatemic Rickets

A

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
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3
Q

Primary ABC

A
  • 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
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4
Q

Multiple Hereditary Exostosis

A

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
  • 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
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5
Q

Ewing Sarcoma

A

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

  • Produces EWS/FLI1 identified by PCR
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6
Q

Atypical Lipoma

AKA Well differentiated liposarcoma

A
  • MDM2 amplification (distinguishes from lipoma)
  • CDK4 also amplified
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7
Q

Liposarcoma

Classification

Subtypes

Imaging

Histology

Genetics

Treatment

A
  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
      1. 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
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8
Q

Synovial Sarcoma

Classification

Age

Presentation

Location

Imaging

Histology

Genetics

Treatment

A
  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
  1. Imaging
  • Radiographs = calcification in ~20%
  • MRI = indeterminate
    • T1 = low signal
    • T2 = high signal
  1. Histology
  • Biphasic appearance with two cell types
    • Spindle cells
    • Epithelial cells
  1. Genetics
  • t(X;18) chromosomal translocation
  • SYT-SSX1, 2, or 4 fusion protein
  1. 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
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9
Q

Myxoid Lipsarcoma

A

t(12;16) translocation

  • FUS-DDIT3(CHOP)
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10
Q

Alveolar Rhabdomyosarcoma

A

t(2;13)

  • PAX3-FKHR
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11
Q

Neurofibromatosis

A

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
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12
Q

Dupuytren’s Disease

A

Autosomal Dominant

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13
Q

What are the associated translocations?

Myxoid Lipsarcoma

Ewing Sarcoma

Synovial Sarcoma

Myxoid Chondrosarcoma

Rhabdomyosarcoma

A
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