Osteogenesis Imperfecta

Question 1

What is the prevalance of OI?

Answer 1

1 in 10000

Question 2

Most types of OI are the result of?

Answer 2

collagen abnormalities

Question 3

What is the inheritance mode of OI?

Answer 3

mostly autosomal dominant but some forms are autosomal recessive

Question 4

What are some clinical features of OI?

Answer 4

short stature, post-puberty and pre-senile hearing loss, dentinogenesis imperfecta, large head, blue/purple sclerae, fractures

Question 5

What are some of symptoms and clinical manifestations of Type I OI?

Answer 5

most common type, mild, fractures after birth which decrease after puberty onset and increase again after age 50, blue sclerae (these are the collagen lining and it is thinner allowing the underlying coroid to show through), may have short stature

Question 6

What might you see in a patient with Type I OI in an x-ray?

Answer 6

wormian bone skull (look like extra sutures), mild bowed extremities, flat “codfish” vertebrae

Question 7

What are some other symptoms of Type I OI?

Answer 7

variable- hearing loss due to otosclerosis of ear bones (50%), dentinogenesis imperfect, joint hyper mobility, limb length discrepancy

Question 8

What are some characteristic of type II OI?

Answer 8

sever, lethal perinatal, fractures in utero, blue sclerae (if not blue but all other symptoms are similar, think type VIII), small for gestational age, macrocephaly (large head), wormian bones

Question 9

What is the outlook for type II OI?

Answer 9

80% die within a week (survival to 1 yo is rare). Cause of death is respiratory insufficiency due to rib fractures that retard rib growth that slow lung growth and a smaller chest size

Question 10

What is the mode of inheritance of Type II OI?

Answer 10

new mutation AD

Question 11

What are some characteristics of type III OI?

Answer 11

sever progressively deforming (live but with severe deformities and fractures, 200+), short statures, blue sclerae, respiratory failure, utero fractures, hearing loss, deformities of articulation between skull and atlas, broadness of forehead

may be associated with amniotic banding

Question 12

What is the MOI of type III OI?

Answer 12

new mutation AD

Question 13

What are some characteristics of type IV OI?

Answer 13

severity between I and III, fractures rare at birth, wormian bones, vertebral involvement is greater than with type I with flat vertebrae, short stature, hearing loss variable, sclerae NORMAL TO GREY, dentinogenesis imperfecta variable

Question 14

What is the MOI of type IV OI?

Answer 14

AD

Question 15

Other characteristics of OI?

Answer 15

easily bruising of skin, mitral valve prolapse, gross motor delays, reduced life expectancy, cognitive skills intact and normal, pregnancy affected in sever types- hard to carry child to full term, long bones more often affected than skull bones

Question 16

How is OI tested?

Answer 16

analysis of structure and quantity of Type I collagen produced in vitro by cultures dermal fibroblasts

detects:
98% of type I OI
and 85% of types II and III OI

Question 17

What genes are affected by OI?

Answer 17

COL1A1 and COL1A2 genes

Question 18

What do the COL1A1 and COL1A2 genes code for?

Answer 18

pro-alpha col (1)– chromosome 17– and (2) proteins– chromosome 7

Question 19

What is the structure of type I collagen?

Answer 19

2 strands of a1 and i strand of a2

Question 20

What are the molecular bases of Type I OI? What do mutations result in?

Answer 20

a range of mutations that result in:

• premature termination sequences
• decreased stability of mRNA of proa1
• decrease the amount of proa1 chains
• decrase the amount of Type I collagen structure by altering ratio of chains

Question 21

What are the molecular bases of Type II-IV OI? What do mutations result in?

Answer 21

mutations alter structure of the collagen by causing a substitution of glycine in the triple helix of either proa1 or proa2.

Mutations in the carboxy terminal is typically lethal

Question 22

What are the molecular mutation detection rates of types I-IV OI?

Answer 22

I-100%
II-98%
III-70%
IV-80%

Question 23

What are some of the characteristic of Type VIII OI?

Answer 23

Autosomal RECESSIVE (so it carries a higher risk of recurrence than type II and can be pre-natalilly diagnosed), normal sclerae, several congenital lethal type

Question 24

What causes OI type VIII?

Answer 24

abnormality in the 3’-hydoxylation of a single proline (residue 986) in the pro alpha 1 chains of Type I precollagen

Question 25

What proteins are involved in hydroxylation of residue 986 and can cause type VIII if malfunctioning?

Answer 25

prolyl 3-hydroxylase
cartilage-associated protein
cyclophilin B

Question 26

How can prenatal diagnosis of OI be performed?

Answer 26

biochemical- CVS at 10 weeks

If defect known- CVS at week 10 or amniocentesis at week 14

fetal ultrasound in 2nd trimester (can’t really see type I or IV with this)

Question 27

What is the treatment for OI?

Answer 27

limiting physical activity, physical therapy, mobility devices, repairing middle ear bones to combat hearing loss, biphosphonates to combat bone loss