Inherited Disorders of Connective Tissue Flashcards
What are the features of achondroplasia?
short stature, disproportionate shortening of proximal limbs and fingers, short base of skull, large head, spinal stenosis, normal intelligence, autosomal dominant inheritance
What gene mutation accounts for the majority of cases of achondroplasia?
A single base substitution at position 380 of the gene product for fibroblast growth factor receptor 3 (FGFR3)
What is the normal function of FGFR3?
It is a negative regulator of chondrocyte proliferation and differentiation at the growth plate
How does a mutation in FGFR3 cause achondroplasia?
The mutation consituitively activates the protein (gain of function), which consituitively inhibits cartilage proliferation and reduces growth
What is the role of CNP in achondroplasia?
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
What is hypochondroplasia?
A milder form of achondroplasia with a different mutation site in FGFR3
What is thanatophoric dysplasia?
A severe form of skeletal dysplasia where infants are stillborn or die very early due to respiratory failure from small chest and pulmonary hypoplasia.
What mutations are implicated in thanatophoric dysplasia?
R248C (most cases), Y373C, and K650E (type 2 thanatophoric dysplasia)
What is craniosynotosis?
A group of other rare syndromes that can be caused by FGFR3 mutations
Which inherited disease of connective tissue represents a dominant negative effect?
Osteogenesis imperfecta - it illustrates protein suicide
What is the inheritance pattern of osteogenesis imperfecta?
It depends on the type, but most are autosomal dominant. It also demonstrates the dominant negative effect and protein suicide
What is the inheritance pattern of Marfan syndrome?
Autosomal dominant but 25% of cases are de novo
What are the clinical features of marfan syndrome?
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
What is the normal function of fibrillin-1?
Fibrillin-1 monomersassociate, forming microfibrils that act as a scaffold for elastin
What pathophysiological mechanisms explain the clinical features of Marfan’s syndrome?
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.
Why might ACE-inhibitors have therapeutic effects for patients with marfan’s syndrome?
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.
What is Loeys-Dietz syndrome?
It is a disease that presents similarly to MFS and is also caused by mutations that alter TGF-beta signaling
What is the inheritance pattern of EDS?
Autosomal dominant, 50% de novo
What are the clinical features of ehlers-danlos syndrome?
hypotonia and delayed motor milestones in infancy, hyperelastic skin, fleshy pseudo tumors, joint hypermobility, mitral valve prolapse, flat feet
What is classical ehler’s danlos syndrome?
A condition caused by autosomal dominant mutations in type V collagen that can present with moderate to severe skin involvement
What is hypermobility ehlers danlos syndrome?
A dominant or recessive mutation in collagen genes that leads to joint hypermobility, joint instability, and chronic pain
What is vascular ehlers danlos syndrome?
A dominant defect in type III collagen synthesis that is a severe disease where blood vessels and organs are fragile and prone to tearing
What is kyphoscoliosis?
An autosomal recessive defect due to deficiency in a lysyl hydroxylase enzyme that has progressive spine curvature, fragile eyes, and severe muscle weakness
What is athrochalasis?
A very rare mutation in type-I collagen that leads to loose joints and frequent dislocations (especially in hips)
What is dermatosparaxis?
A very very rare disease that is characterized by fragile and sagging skin
The pathogenesis of achondroplasia involves:
a) haploinsufficiency
b) inactivation of FGFR3
c) decreased chondrocyte proliferation
d) overproduction of fibroblast growth factor
c) decreased chondrocyte proliferation
Early mortality in Marfan syndrome is related to:
a) ectopia lentis
b) scoliosis
c) aortic root dilation
d) tall stature
e) aortic aneurysm rupture
