Inherited Disorders of Connective Tissue Flashcards by Jing Ji

What can give rise to disorders of connective tissue?

alterations of:

EC matrix and/or bone

protein structure and post-translational modifications

glycosaminoglycan structure

regulation of signaling pathways

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What structures are affected by disorders of connective tissue?

cartilage

bone, tendons, ligaments

skin

blood vessel walls

eye

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What are the radiologic findings in achondroplasia?

horizontal acetabular roof in the pelvis

narrowing of pedicle distance

long fibula

stenosis of foramen magnum

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What is the incidence of achondroplasia? How is the gene passed down?

incidence 1:26,000 - 1:28,000

80% de novo

autosomal dominant

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What are the features of achondroplasia?

metaphyseal dysplasia

short stature

disproportionate shortening of proximal limb segments (rhizomelia), short fingers

short base of skull, large head

spinal stenosis

normal intelligence

autosomal dominant inheritance

rhizomelic defect

mild ventrulomegaly

kyphosis

central and obstructive apnea, cor pulmonale

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What is the molecular basis of achondroplasia?

a single base substitution resulting in a glycin -> arginine at position 380 of the gene product of fibroblast growth factor receptor 3 (FGFR3)

gene has been found in more than 98% of individuals with achondroplasia

paternal age effect

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What is the function of FGFR3?

acts as a negative regulator of chondrocyte proliferation and differentation at the growth plate

the achondroplasia mutation apparently constitutively activates this function

this results in a gain of function, and constitutive inhibition of cartilage proliferation, and therefore, reduced growth in endochondral bone

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What are the pelvic defects in achondroplasia?

horizontal acetabular roof

“paddle without a handle”

deep sacro-sciatic notch

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What are the spinal findings in achondroplasia?

moving head down to sacrum, the pedicles do not get further and further apart as in normal individuals

see the opposite effect instead

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Which zone of bone development is affected in achondroplasia?

zone of hypertrophy

insufficient number of chondrocytes due to decreased chondrocyte proliferation

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What is the role of C-natriuretic peptide?

binds to the Natriuretic Binding Receptor B (NPR-B) and in hitibts the downstream effects of FGFR3 activation

inhibits the FGFR3 reltated inhibition of chondrocyte proliferation, thereby enhancing chondrocyte proliferation andbone growth

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What are the molecular mechanisms of type I hypochondroplasia? What are the resulting phenotypic effects?

associated with asn -> lys (N540K) in FGFR3 in ~70% of patients

there is evidence of locus heterogeneity

phenotype is similar, but milder than achondroplasia

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What is the phenotype of type I thanatophoric dysplasia?

very severe skeletal dysplasia

long trunk

flat vertebral ossification

wide space between vertebral ossification

infants are either stillborn or die early in infancy from respiratory failure because of the very small chest and pulmonary hypoplasiaa

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What are the molecular mechanisms underlying type I thanatophoric dysplasia?

arg -> cys (R248C) underlies ~45% of cases and tyr -> cys (Y373C) in 20% in FGFR3

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What is the phenotype and molecular mechanisms of thanatophoric dysplasia, type 2?

phenotype is less severe than type 1

caused by lys -> glu (K650E) in the FGFR3 gene

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What diseases can arise from mutations of the FGFR3 gene?

achondroplasia

hypochondroplasia

thanatophoric dysplasia types 1 and 2

cransiosynostosis, muenke Nonsyndrome Coronal Craniosynostosis

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What is the incidence of osteogenesis imperfect, and how is it passed on?

incidence 1:14,000 - 1:17000

60-100% de novo

autosomal dominant

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What is the molecular basis of osteogenesis imperfecta?

dominant negative muation lead ing to “protein suicide”

mutation of the COL1A1 and COL1A2 genes, both of which encode type I collagen

What are some of the clinical manifestations of osteogenesis imperfecta

hearing loss

dentinogenesis imperfecta

germline mosaicism mimicks autosomal recessive inheritance

wide range of severity, from lethal to nuisance

fractures with minimal trauma

fractures tend to decrease after puberty

Wormian Bones

can see bony islands in the skull

What are the features of perinatal lethal osteogenesis imperfecta?

short limb dwarfism

poor skull ossification

congenital features - long bones, accordion-like ribs, compression of spine

recurrences due to gonadal mosaicism

fractures in the ribs prevent proper breathing

What is the incidence and method of inheritance of Marfan Syndrome?

incidence 1:5,000 - 1:10,000

25% de novo

autosomal dominant - variable expressitivity, but fully penetrant

What is the molecular defect in Marfan Syndrome?

fibrillin-1 defect (encoded by FBN1)

What are the clinical features of Marfan Syndrome?

tall statur with “asthenic” habitus

long arms and legs relative to truncal length

arm span -> height, and decreased upper:lower segment ratio

arachnodactyly, pes planus, joint hypermobility

pectus excavatum or carinatum

scoliosis

narrow face, high arched plate

ectopia lentis

mitral valve prolapse, aortic root dilation, dissecting aneurysm of ascending aorta

dermal striae atrophica (strech marks)

lumosacral dural ectasia (widenin of the dural sac)

spontaneous pneumothorax (tear in lung causing accumulation of air between lung and pleura

What is the role of fibrillin-1? What happens when it is mutated?

monomers responsible for forming microfibrils that act as a scaffold for elastin - found in both elastic and non-elastic tissues mutations affecting fibrillin-1 result in decreased fibrillin-1 elastin in the extracellular matrix and decrease elastic fiber fragmentation shares significant homology wiht latent transforming growth factor beta binding proteins (LTBPs) and binds TGF-beta, regulating its activity

cardiovascular manifestations of Marfan's Syndrome

dilatation of aorta aortiic dissection aortic regurgitation abdominal aortic aneurysm

What is the function of LTBPs?

binds transforming growth factor beta (TGFbeta) and regulates its activity

What is the role of TGFbeta signaling in development?

animal studies have clearly demonstrated that TGFbeta signaling plays an important role in both development and aortic size/wall architecture increased levels causes downstream events which contribute to marfan syndrome

Loeys-Dietz Syndrome

syndrome has some similarities to MFS, including the propensity toward aortic dissection also caused by mutations that alter TGFbeta signaling, namely in the genes encoding the receptors of TGFbeta, TGFBR1, ang TGFBR2

What is the incidence of classical Ehlers Danlos Syndrome? How is it inherited?

incidency 1:20,000 50% de novo autosomal dominant

What are the clinical features of classical Ehlers-Danlos Syndrome?

in infancy, hypotonia and delayed motor milestones soft, velvety skin that is hyperplastic and fragile, tears and bruises easily widened "ciarette paper" scars molluscoid pseudo tumors (fleshy lesions associated with scars over pressre areas) joint hypermobility, dislocations mitral valve prolapse hiatal hernia, anal prolapse pes planus (flat feet)

What is the molecular basis of classical Ehlers-Danlos Syndrome?

most cases are caused by mutations in type 5 collagen, in either alpha-1 (COL5A1) or alpha-2 (COL5A2) chain most of the mutations generate a null allele, and therefore haploinsufficiency of type 5 collagen appears to be the mechanism causing the disorder

What are the six subcategories of Ehlers-Danlos Syndrome?

classical hypermobility vascular kyphoscoliosis arthrochalasis dermatosparaxis

What are the defining features of hypermobility Ehlers-Danlos Syndrome?

affects 1 in 10,000 to 15,000 autosmal dominant or recessive **mutations in COL3A1 or TNXB** **joint hypermobility is the hallmark of this type**, with less skin manifestations **joint instability and chronic musculoskeletal pain** are particularly prominent in this type

What are the defining features of vascular Elers-Danlos Syndrome?

affects 1 in 100,000 to 250,000 people autosomal dominant defect in the the type-III collagen synthesis (COL3A1) considered one of the **most serious forms** because **blood vessels and organs are fragile** and prone to tearing (rupture) **characteristic facial appearance** - large eyes, small chin, sunken cheeks, thin nose and lips, lobeless ears small stature with slim build and thin, pale, translucent skin with very easy bruising and propensity to develop ecchymoses

What are the defining features of kyphoscoliosis Ehlers-Danlos Syndrome?

autosomal recessive defect due to deficiency of an enzyme called **lysyl hydroxzylase (PLOD1)** fewer than 60 cases reported characterized by **progressive curvature of the spine (scoliosis), fragile eyes, and severe muscle weakness**

What are the defining features of arthrochalasis Ehlers-Danlos Syndrome?

very rare, about 30 cases reported **affects type-1 collagen (COL1A1 and COL1A2)** characterised by **very loose joints and dislocations involving both hips**

What are the defining features of dermatosparaxis Ehlers-Danlos Syndrome?

about 10 cases reported **ADAMSTS2 mutation** characterised by **extremely fragile and sagging skin**

What are the radiological features of Cumurati-Engelmann?

widened diaphyses

What are the radiologic features of McKusick and Jansen syndromes?

metaphyseal chondrodysplasia

rhizomelia

either a disproportion of the length of the proximal limb, such as the shortened limbs of achondroplasia, or some other disorder of the hip or shoulder

mesomelic dysplasia

deformity of the middle parts of a limb

acromelia

a form of dwarfism in which shortening is most evident in themost distal segment of the limbs