SM_245a: Inherited Disorders of Connective Tissue Flashcards
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)
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

____, ____, 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

____ means proximal
Rhizomelic means proximal

____ means middle
Mesomelic

____ means distal
Acromelic means distal

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

Achondroplasia has ____ hand
Achondroplasia has trident hand

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
Describe the pelvis in achondroplasia
Pelvis in achondroplasia
- Horizontal acetabular roof
- “Paddle without a handle”
- Deep sacro-sciatic notch

Achondroplasia is characterized by ____ chondrocyte proliferation
Achondroplasia is characterized by decreased chondrocyte proliferation

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

Achondroplasia mutation occurs in _____ and is _____
Achondroplasia mutation occurs in FGFR3 and is gain of function
(most patients have Gly -> Arg at position 380)

Pathogenesis of achondroplasia involves _____
Pathogenesis of achondroplasia involves decreased chondrocyte proliferation
Describe thanatophoric dysplasia
Thanatophoric dysplasia
- Autosomal dominant
- FGFR3 mutation
- Long trunk
- Usually stillborn
- Flat vertebral ossification
- Wide space between vertebral ossification

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
Osteogenesis imperfecta involves _____ sclera
Osteogenesis imperfecta involves blue sclera

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

____ are skull bones with abnormal ossification
Wormian bones are skull bones with abnormal ossification

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)
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
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)
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

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

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

Early mortality in Marfan syndrome is related to ____
Early mortality in Marfan syndrome is related to aortic aneurysm rupture
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

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)
