SM_245a: Inherited Disorders of Connective Tissue Flashcards Preview

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Flashcards in SM_245a: Inherited Disorders of Connective Tissue Deck (28)
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1

Inherited disorders of connective tissue may result from alterations of ____, ____, ____, and ____

Inherited disorders of connective tissue may result from alterations of extracellular matrix and/or bone, proteins tructure and post-translational modifications (e.g. collagens), glycosaminoglycan structure (e.g. mucopolysaccharidoses), and regulation of signaling pathways

 

 

(may affect cartilage, bone, tendons, ligaments, skin, blood vessel walls, and eye)

2

Describe appearance of bones of a child on radiograph

Radiograph of child's bones

  • Cartilage precursors of bone are not mineralized -> not visible on radiographs
  • Growth plate (metaphysis) appears radiolucent until growth ceases
  • Epiphyses are also lucent and mineralize at predictable times during childhood and adolescence

3

____, ____, and ____ are terms used to describe which limb segment is involved

Rhizomelic, mesomelic, and acromelic are terms used to describe which limb segment is involved

 

 

  • Rhizomelic: proximal
  • Mesomelic: middle
  • Acromelic: distal

4

____ means proximal

Rhizomelic means proximal

5

____ means middle

Mesomelic

6

____ means distal

Acromelic means distal

7

Describe achondroplasia

Achondroplasia

  • Autosomal dominant - mostly new mutations, paternal age effect
  • Most common cause of dwarfism
  • Trident hand
  • Disproportionate shortening of proximal limb segments (rhizomelic)
  • Short base of skull with large head (macrocephaly)
  • Mild ventriculomegaly: true hydrocephalus is rare
    Stenosis of foramen magnum and spinal canal
  • Kyphosis
  • Central and obstructive sleep apnea, cor pulmonale
  • Normal intelligence

8

Achondroplasia has ____ hand

Achondroplasia has trident hand

9

Achondroplasia is caused by autosomal dominant mutations in _____, usually _____

Achondroplasia is caused by autosomal dominant mutations in Fibroblast Growth Factor Receptor 3 (FGFR3), usually Gly380Arg

10

Describe the pelvis in achondroplasia

Pelvis in achondroplasia

  • Horizontal acetabular roof
  • "Paddle without a handle"
  • Deep sacro-sciatic notch

11

Achondroplasia is characterized by ____ chondrocyte proliferation

Achondroplasia is characterized by decreased chondrocyte proliferation

12

In achondroplasia, FGF _____ to FGFR3, inhibiting _____ 

In achondroplasia, FGF binds constitutively to FGFR3, inhibiting chondrocyte proliferation

13

Achondroplasia mutation occurs in _____ and is _____

Achondroplasia mutation occurs in FGFR3 and is gain of function

 

 

(most patients have Gly -> Arg at position 380)

14

Pathogenesis of achondroplasia involves _____

Pathogenesis of achondroplasia involves decreased chondrocyte proliferation

15

Describe thanatophoric dysplasia 

Thanatophoric dysplasia

  • Autosomal dominant
  • FGFR3 mutation
  • Long trunk
  • Usually stillborn
  • Flat vertebral ossification
  • Wide space between vertebral ossification

16

Describe osteogenesis imperfecta

Osteogenesis imperfecta

  • Abnormal type I collagen (alpha-1 or alpha-2 chain)
  • Autosomal dominant: haploinsufficiency and dominant negative mutations
  • Wide range of severity: from lethal to nuisance
  • Fractures with minimal trauma
  • Fractures tend to decrease after puberty
  • May be treated with bisphosphonates

17

Osteogenesis imperfecta involves _____ sclera

Osteogenesis imperfecta involves blue sclera

18

Describe perinatal lethal osteogenesis imperfecta

Perinatal lethal osteogenesis imperfecta

  • Short limb dwarfism
  • Poor skull ossification
  • Congenital fractures: long bones, accordion-like ribs, compression of spine
  • Type I collagen defect
  • Autosomal dominant: most are de novo
  • Recurrences due to gonadal mosaicism

19

____ are skull bones with abnormal ossification

Wormian bones are skull bones with abnormal ossification

20

Describe classical type Ehler's-Danlos syndrome

Classical type Ehler's-Danlos syndrome

  • In infancy: hypotonia and delayed motor milestones
  • Soft velvety skin, hyperelastic, fragile, tears and bruises easily, widened "cigarette paper" scars
  • Molluscoid pseudo tumors (fleshy lesions associated with scars over pressure areas)
  • Joint hypermobility, dislocations
  • Mitral valve prolapse
  • Hiatal hernia, anal prolapse
  • Pes planus (flat feet)

 

21

Describe collagen mutations in classical Ehler's Danlos syndrome

Collagen mutations in classical type Ehler's-Danlos syndrome

  • Usually mutations in type 5 collagen - either alpha-1 (COL5A1) or alpha-2 (COL5A2) chain
  • Most mutations generate a null allele
  • Haploinsufficiency of type 5 collagen appears to be the mechanism causing the disorder

22

Classical type Ehler's-Danlos syndrome is usually related to mutations in _____, either the _____ or _____ chain

Classical type Ehler's-Danlos syndrome is usually related to mutations in type 5 collagen, either the alpha-1 (COL5A1) or alpha-2 (COL5A2) chain

 

(haploinsufficiency)

23

Describe Marfan syndrome

Marfan syndrome

  • Autosomal dominant - 30% of cases are new mutations
  • Variable expressivity, fully penetrant
  • Dolichostenomelia and other skeletal abnormalities: scoliosis, arachnodactyly, pectus, joint laxity
  • Ocular abnormalities: ectopia lentis (lens dislocation), myopia
  • Cardiovascular disease: MVP, aortic root dilation, dissection
  • Long and lean
  • Pectus carinatum, pes planus
  • Pulmonary, skin/integument, CNS manifestations

24

Cardiovascular manifestations of Marfan syndrome are _____, _____, _____, and _____

Cardiovascular manifestations of Marfan syndrome are dilation of aorta, aortic dissection, aortic regurgitation, and abdominal aortic aneurysm

25

Describe Fibrillin-1

Fibrillin-1

  • Present in both elastic and non-elastic tissues: skin, lung, kidney, vasculature, cartilage, tendon, muscle, cornea, and ciliary zonule
  • Monomers contain tandem repeats of cb-EGF-like regions
  • Monomers associate to form connective tissue microfibrils in intercellular matrix via cysteine
  • Acts as scaffold for deposition of tropoelastic in elastic fiber formation

26

Early mortality in Marfan syndrome is related to ____

Early mortality in Marfan syndrome is related to aortic aneurysm rupture

27

Excess ____ signaling can cause emphysema, mitral valve prolapse, aortic aneurysm, and myopathy

Excess TGF-beta signaling can cause emphysema, mitral valve prolapse, aortic aneurysm, and myopathy

28

Describe multiple epiphyseal dysplasia

Multiple epiphyseal dysplasia

  • Very common bone dysplasia
  • Normal to moderately shortened stature with normal body proportions
  • Prominent joints, early arthritis
  • At least five different loci: cartilage oligomeric matrix protein (COMP), COL9A1, COL9A2, COL9A3, matrilin 3 (MATN3)

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