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Flashcards in Inherited Disorders of Connective Tissue Deck (27)
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1
Q

What are the features of achondroplasia?

A

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

2
Q

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

A

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

3
Q

What is the normal function of FGFR3?

A

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

4
Q

How does a mutation in FGFR3 cause achondroplasia?

A

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

5
Q

What is the role of CNP in achondroplasia?

A

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

6
Q

What is hypochondroplasia?

A

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

7
Q

What is thanatophoric dysplasia?

A

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

8
Q

What mutations are implicated in thanatophoric dysplasia?

A

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

9
Q

What is craniosynotosis?

A

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

10
Q

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

A

Osteogenesis imperfecta - it illustrates protein suicide

11
Q

What is the inheritance pattern of osteogenesis imperfecta?

A

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

12
Q

What is the inheritance pattern of Marfan syndrome?

A

Autosomal dominant but 25% of cases are de novo

13
Q

What are the clinical features of marfan syndrome?

A

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

14
Q

What is the normal function of fibrillin-1?

A

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

15
Q

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

A

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.

16
Q

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

A

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.

17
Q

What is Loeys-Dietz syndrome?

A

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

18
Q

What is the inheritance pattern of EDS?

A

Autosomal dominant, 50% de novo

19
Q

What are the clinical features of ehlers-danlos syndrome?

A

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

20
Q

What is classical ehler’s danlos syndrome?

A

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

21
Q

What is hypermobility ehlers danlos syndrome?

A

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

22
Q

What is vascular ehlers danlos syndrome?

A

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

23
Q

What is kyphoscoliosis?

A

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

24
Q

What is athrochalasis?

A

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

25
Q

What is dermatosparaxis?

A

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

26
Q

The pathogenesis of achondroplasia involves:

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

A

c) decreased chondrocyte proliferation

27
Q

Early mortality in Marfan syndrome is related to:

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

A