Inherited Disorders of Connective Tissue

Question 1

What are the features of achondroplasia?

Answer 1

short stature, disproportionate shortening of proximal limbs and fingers, short base of skull, large head, spinal stenosis, normal intelligence, autosomal dominant inheritance

Question 2

What gene mutation accounts for the majority of cases of achondroplasia?

Answer 2

A single base substitution at position 380 of the gene product for fibroblast growth factor receptor 3 (FGFR3)

Question 3

What is the normal function of FGFR3?

Answer 3

It is a negative regulator of chondrocyte proliferation and differentiation at the growth plate

Question 4

How does a mutation in FGFR3 cause achondroplasia?

Answer 4

The mutation consituitively activates the protein (gain of function), which consituitively inhibits cartilage proliferation and reduces growth

Question 5

What is the role of CNP in achondroplasia?

Answer 5

C-natruiretic peptide binds to its receptor, which has inhibitory downstream effects that act on FGFR3 and is a potential future area of treatment for achondroplasia

Question 6

What is hypochondroplasia?

Answer 6

A milder form of achondroplasia with a different mutation site in FGFR3

Question 7

What is thanatophoric dysplasia?

Answer 7

A severe form of skeletal dysplasia where infants are stillborn or die very early due to respiratory failure from small chest and pulmonary hypoplasia.

Question 8

What mutations are implicated in thanatophoric dysplasia?

Answer 8

R248C (most cases), Y373C, and K650E (type 2 thanatophoric dysplasia)

Question 9

What is craniosynotosis?

Answer 9

A group of other rare syndromes that can be caused by FGFR3 mutations

Question 10

Which inherited disease of connective tissue represents a dominant negative effect?

Answer 10

Osteogenesis imperfecta - it illustrates protein suicide

Question 11

What is the inheritance pattern of osteogenesis imperfecta?

Answer 11

It depends on the type, but most are autosomal dominant. It also demonstrates the dominant negative effect and protein suicide

Question 12

What is the inheritance pattern of Marfan syndrome?

Answer 12

Autosomal dominant but 25% of cases are de novo

Question 13

What are the clinical features of marfan syndrome?

Answer 13

arm span > height, long fingers/toes, scoliosis, narrow face, mitral valve prolapse/aortic root dilation/dissecting aneurisum of aorta, stretch marks, widened dural sac, spontaneous pneumothorax

Question 14

What is the normal function of fibrillin-1?

Answer 14

Fibrillin-1 monomersassociate, forming microfibrils that act as a scaffold for elastin

Question 15

What pathophysiological mechanisms explain the clinical features of Marfan’s syndrome?

Answer 15

Haploinsufficiency of fibrillin-1. Fibrillin-1 regulates the activity of TGF-beta by binding to it and inhibiting it. Failure of proper fibrillin-1 function leads to altered heart development through excess TGF-beta signaling.

Question 16

Why might ACE-inhibitors have therapeutic effects for patients with marfan’s syndrome?

Answer 16

Angiotensin II does some of the same things as TGF-beta. If there is too much TGF-beta in marfan’s (due to lack of fibrillin-1 binding), blocking angiotensin II could decrease the negative effects of excess TGF-beta signaling.

Question 17

What is Loeys-Dietz syndrome?

Answer 17

It is a disease that presents similarly to MFS and is also caused by mutations that alter TGF-beta signaling

Question 18

What is the inheritance pattern of EDS?

Answer 18

Autosomal dominant, 50% de novo

Question 19

What are the clinical features of ehlers-danlos syndrome?

Answer 19

hypotonia and delayed motor milestones in infancy, hyperelastic skin, fleshy pseudo tumors, joint hypermobility, mitral valve prolapse, flat feet

Question 20

What is classical ehler’s danlos syndrome?

Answer 20

A condition caused by autosomal dominant mutations in type V collagen that can present with moderate to severe skin involvement

Question 21

What is hypermobility ehlers danlos syndrome?

Answer 21

A dominant or recessive mutation in collagen genes that leads to joint hypermobility, joint instability, and chronic pain

Question 22

What is vascular ehlers danlos syndrome?

Answer 22

A dominant defect in type III collagen synthesis that is a severe disease where blood vessels and organs are fragile and prone to tearing

Question 23

What is kyphoscoliosis?

Answer 23

An autosomal recessive defect due to deficiency in a lysyl hydroxylase enzyme that has progressive spine curvature, fragile eyes, and severe muscle weakness

Question 24

What is athrochalasis?

Answer 24

A very rare mutation in type-I collagen that leads to loose joints and frequent dislocations (especially in hips)

Question 25

What is dermatosparaxis?

Answer 25

A very very rare disease that is characterized by fragile and sagging skin

Question 26

The pathogenesis of achondroplasia involves:

a) haploinsufficiency
b) inactivation of FGFR3
c) decreased chondrocyte proliferation
d) overproduction of fibroblast growth factor

Answer 26

c) decreased chondrocyte proliferation

Question 27

Early mortality in Marfan syndrome is related to:

a) ectopia lentis
b) scoliosis
c) aortic root dilation
d) tall stature
e) aortic aneurysm rupture