SM_245a: Inherited Disorders of Connective Tissue

Question 1

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

Answer 1

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)

Question 2

Describe appearance of bones of a child on radiograph

Answer 2

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

Question 3

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

Answer 3

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

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

Question 4

____ means proximal

Answer 4

Rhizomelic means proximal

Question 5

____ means middle

Answer 5

Mesomelic

Question 6

____ means distal

Answer 6

Acromelic means distal

Question 7

Describe achondroplasia

Answer 7

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

Question 8

Achondroplasia has ____ hand

Answer 8

Achondroplasia has trident hand

Question 9

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

Answer 9

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

Question 10

Describe the pelvis in achondroplasia

Answer 10

Pelvis in achondroplasia

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

Question 11

Achondroplasia is characterized by ____ chondrocyte proliferation

Answer 11

Achondroplasia is characterized by decreased chondrocyte proliferation

Question 12

In achondroplasia, FGF _____ to FGFR3, inhibiting _____

Answer 12

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

Question 13

Achondroplasia mutation occurs in _____ and is _____

Answer 13

Achondroplasia mutation occurs in FGFR3 and is gain of function

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

Question 14

Pathogenesis of achondroplasia involves _____

Answer 14

Pathogenesis of achondroplasia involves decreased chondrocyte proliferation

Question 15

Describe thanatophoric dysplasia

Answer 15

Thanatophoric dysplasia

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

Question 16

Describe osteogenesis imperfecta

Answer 16

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

Question 17

Osteogenesis imperfecta involves _____ sclera

Answer 17

Osteogenesis imperfecta involves blue sclera

Question 18

Describe perinatal lethal osteogenesis imperfecta

Answer 18

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

Question 19

____ are skull bones with abnormal ossification

Answer 19

Wormian bones are skull bones with abnormal ossification

Question 20

Describe classical type Ehler’s-Danlos syndrome

Answer 20

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)

Question 21

Describe collagen mutations in classical Ehler’s Danlos syndrome

Answer 21

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

Question 22

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

Answer 22

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)

Question 23

Describe Marfan syndrome

Answer 23

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

Question 24

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

Answer 24

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

Question 25

Describe Fibrillin-1

Answer 25

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

Question 26

Early mortality in Marfan syndrome is related to ____

Answer 26

Early mortality in Marfan syndrome is related to aortic aneurysm rupture

Question 27

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

Answer 27

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

Question 28

Describe multiple epiphyseal dysplasia

Answer 28

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)