Osteogenesi

s
Imperfecta
(OI)
Introduction
Osteogenesis imperfecta (OI) , also known
as Brittle Bone Disease, "Lobstein syndrome”
or Fragilitas ossium.

People with OI are born with defective

connective tissue, or without the ability to
make it, usually because of a deficiency of
Type-I collagen.

Occurs in 1:20,000 to 1:60,000 live births. OI

can affect males and females of all races.
Etiology
Penetrance and expressivity  OI is mainly an
in type I OI autosomal
dominant defect. It
can also
be an individual (de
novo or
"sporadic") mutation.
• Phenotypically normal father (arrow) has had two children
by different mates, each of whom is affected with
autosomal dominant type II osteogenesis imperfecta (OI).
Analysis of the father showed that some of his
spermatozoa carried a COL1A1 mutation, indicating
that the explanation for this unusual pedigree is
germline/gonadal mosaicism.
 Researches show that that a mutation of the COL1A1 or
COL1A2 genes, which encode the subunits of type I
collagen, proα 1(I) and proα 2(I), respectively causes OI.
 In type I OI, mutations in COL1A1 allele gives rise to
greatly reduced or no function of mRNA. In most cases,
nonsense mutation occur. Partially synthesized
mRNA precursors that carry the nonsense codon are
recognized and degraded by the cell (‘nonsense-
mediated decay’). It acts as a protective phenomenon
but reduces synthesis of type I collagen.

 Type II OI is usually caused by missense mutations

of a glycine residue that allow the mutant peptide chain
to bind to normal one.

 Collagen mutations that cause type III and type IV OI

are diverse and include glycine substitutions of the
collagen triple helix, a few internal deletions of COL1A1
and COL1A2 that do not significantly disturb triple helix
formation, and some unusual alterations in the non-
triple-helical extensions at the amino and carboxyl
terminals of proα chains.
 Pathogenesis
Molecular assembly of Type I procollagen in the
 OI is a disease of type I Endoplasmic Reticulum
collagen. It is the
major collagen in the
dermis, the connective
tissue capsules of most
organs, and the
vascular and GI
adventitia and is the
only collagen in bone.

 Each mature type I

collagen molecule
contains two α1 chains
and one α2 chain,
encoded by the COL1A1
and COL1A2 genes, Three proα chains that associate with each other beginning
at their carboxyl terminals. An important requirement for
respectively. The
proper assembly of the triple helix is the presence of a
COL1A1 and COL1A2 glycine residue at every third position in each of the proα
genes have 51 and 52 chains.
exons, respectively, of
 The α 1 and α 2 chains are
synthesized as larger precursors
with amino and carboxyl terminal
‘propeptide’ extensions, assemble
with each other inside the cell.
Then, they are secreted as a
heterotrimer type I procollagen
molecule.

 During intracellular assembly, the

3 chains wind around each other
in a triple helix that is stabilized
by interchain interactions
between hydroxy proline and
adjacent carbonyl residues.
Assembly of the triple helix, which
begins at the carboxyl terminal
end of the molecule and post-
translational action of prolyl
hydroxylase starts. Increased
levels of hydroxylation result in a
 Molecular assembly of Type I procollagen in the
Endoplasmic Reticulum

After secretion, the amino and carboxyl terminal propeptides are

proteolytically cleaved, leaving a rigid triple helical collagen
molecule with very short non-triple-helical domains at both ends.
Normal Production

Procollagen chains Collagen

molecules
The COL1A1 gene normally produces twice as many proα
chains as the COL1A2 gene. Therefore, in nonmutant cells,
the ratio of proα 1 to proα 2 chains is 2:1, which
corresponds to the ratio of α1 and α2 chains in intact
collagen molecules.
Types I Osteogenesis Imperfecta

Procollagen chains Collagen

molecules
In type I OI, a mutation in one of the COL1A1 alleles results in
failure to produce proα 1 chains, leading to a 50% reduction in the
total number of proα1 chains, a 50% reduction in the
production of intact type I collagen molecules, and an
excess of unassembled proα 2 chains, which are degraded
inside the cell.
Types II Osteogenesis
Imperfecta

• In type II OI, mutation causes substitution of glycine to bulkier amino acids in

Procollagen chains Collagen
the collagen triple
molecules
helix structure. The larger amino acid side-chains creates a "bulge" the
collagen complex and
secretion of partially assembled collagen molecules (heterotrimers) containing
the mutant chain.
• If the body does not destroy the improper collagen, the relationship between
the collagen fibrils
and hydroxyapatite crystals to form bone is altered, causing brittleness.
• Type II OI is more severe than type I . 75% reduction of production of
intact type I collagen
Types III and Type IV
Osteogenesis Imperfecta
Collagen mutations that cause type III and
type IV OI are diverse and include glycine
substitutions in the amino terminal portion of the
collagen triple helix, a few internal deletions of
COL1A1 and COL1A2 that do not significantly
disturb triple helix formation, and some unusual
alterations in the non-triple-helical extensions at
the amino and carboxyl terminals of proα chains.
Type III OI tend to be isolated family incidents
• Type IV OI can frequently be traced through the
family
Types
Type Phenotype Molecular Pathology
Type I Mild Loss-of-function mutation in proα (I) chain resulting in
decreased amount of mRNA; quality of collagen is
normal; quantity is reduced two fold

Perinatal Structural mutation in proα1(I) or proα2 (I) chain that

Type II 1 has mild effect on heterotrimer assembly; quality of
lethal collagen is severely abnormal; quantity often reduced
also
Structural mutation in proα1 (I) or proα2 (I) chain that
Type III 2 Progressi has mild effect on heterotrimer assembly; quality of
ve collagen is severely abnormal; quantity can be
deforming normal
Type IV Deformin Structural mutation in the proα2 (I), or, less
frequently, proα1(I) chain that has little or no effect
g with on heterotrimer assembly; quality of collagen is
normal usually abnormal; quantity can be normal
scleras
1
Sporadic (autosomal dominant)
2
Autosomal recessive in rare
cases.
Clinical Symptoms
Type I
 Collagen is of normal quality but is
produced in insufficient quantities:
 Bones fracture easily, loose joints, poor
muscle tone
 Slight tendency toward spinal curvature
 Discolouration of the sclera (whites of the
eyes), usually giving them a blue-gray
color.
 Triangular face
 Early loss of hearing in some children
 Slight protrusion of the eyes
 Most fractures occur before puberty;
occasionally women will have fractures
after menopause
 IA and IB are defined by the
Type II

 Collagen is not of a sufficient quality or

quantity
 Most cases die within the first year of life
due to respiratory failure or intracerebral
hemorrhage
 Very small stature with under developed
lungs and extremely severe respiratory
problems
 Severe bone deformity and small stature
 Type II can be further subclassified into
groups A, B, C, which are distinguished by
radiographic evaluation of the long bones
and ribs.
Type IIA demonstrates broad and short long
bones with broad and beaded ribs.
Type IIB demonstrates broad and short long
bones with thin ribs that have little or no
beading.
Type IIC demonstrates thin and longer long
Type III

 Collagen quantity is sufficient but is not of a high

enough quality
 Bones fracture easily, sometimes even before
birth
 Bone deformity, often severe
 Respiratory problems possible
 Short stature, spinal curvature and sometimes
barrel-shaped rib cage
 Loose joints
 Poor muscle tone in arms and legs
 Discolouration of the sclera (the 'whites' of the
eyes)
 Early loss of hearing possible
 Type III is distinguished among the other
classifications as being the "Progressive
Deforming" type, wherein a neonate presents
with mild symptoms at birth and develops the
aforementioned symptoms throughout life.
Type IV

 Collagen quantity is sufficient but is not of a high

enough quality
 Bones fracture easily, especially before puberty
 Short stature, spinal curvature and barrel-shaped rib
cage
 Bone deformity is mild to moderate
 Early loss of hearing
 Similar to Type I, Type IV can be further subclassified
into types IVA and IVB characterized by absence (IVA)
or presence (IVB) of dentinogenesis imperfecta.
 Under the microscope, investigators noticed that some people who are
clinically within the Type IV group had a distinct pattern to their
bone. When they reviewed the full medical history of these people,
they found that groups had other features in common. They named
these groups Types V and VI OI. The mutations causing these forms of
OI have not been identified, but people in these two groups do not
have mutations in the type I collagen genes.

Type V

 Same clinical features as Type IV. Distinguished

histologically by "mesh-like" bone appearance. Further
characterized by the "V Triad" consisting of:
a) radio-opaque band adjacent to growth plates,
b) hypertrophic calluses at fracture sites, and
c) calcification of the radio-ulnar interosseous
membrane.
 OI Type V leads to calcification of the membrane
between the two forearm bones, making it difficult to
turn the wrist. Another symptom is abnormally large
amounts of repair tissue (hyperplasic callus) at the site
of fractures. At the present time, the cause for Type V is
unknown, though doctors have determined that it is
Type VI

 Clinically similar to Type IV in appearance and symptoms

of OI.
 Bone has a distinctive “fish-scale” appearance when
viewed under the microscope.
 The alkaline phosphatase (an enzyme linked to bone
formation) activity level is slightly elevated in OI Type VI.
This can be determined by a blood test. 
 Diagnosed by bone biopsy.
 Whether this form is inherited in a dominant or recessive
manner is unknown, but researchers believe the mode of
inheritance is most likely recessive.
 Eight people with this type of OI have been identified.
Recessive Forms of OI
 Two forms of OI that are inherited in a recessive manner were discovered
in 2006. Both types are caused by genes that affect collagen formation.
These forms provide information for people who have severe or
moderately severe OI but who do not have a primary collagen mutation.

Type VII
 The first described cases resemble Type IV OI in many
aspects of appearance and symptoms.
 In other instances the appearance and symptoms are
similar to Type II lethal OI, except infants had white sclera,
a small head and a round face.
 Short stature.
 Short humerus (arm bone) and short femur (upper leg
bone) 
 Coxa vera is common (the acutely angled femur head
affects the hip socket).
 Results from recessive inheritance of a mutation to the
CRTAP (cartilage-associated protein) gene. Partial function
of CRTAP leads to moderate symptoms while total absence
of CRTAP was lethal in all 4 identified cases.
Type VIII

 Resembles lethal Type II or Type III OI in appearance

and symptoms except that infants have white sclera.
 Severe growth deficiency.
 Extreme skeletal under mineralization.
 Caused by a deficiency of P3H1 (Prolyl 3-hydroxylase
1) due to a mutation to the LEPRE1 gene (protein
leprecan).
Diagnosis
In addition to a complete medical history and physical
examination, diagnostic procedures for OI may include
a skin biopsy to evaluate the amount and structure of
collagen or molecular (DNA) tests. However, this test is
complicated and not many qualified facilities are
available to perform the procedure. It is not unusual for
results of the biopsy to take up to six months.

 Additional diagnostic tests may include:

 X-ray
 Examination of the ear, nose, and throat (to detect
hearing loss)
 Bone mineral density, as measured with dual-energy x-
ray absorptiometry (DEXA)
 Prenatal ultrasonography
 Biochemical (collagen) or molecular (DNA) tests
Imaging Studies

 Obtain a radiographic skeletal survey after birth.

 In mild (type I) OI:
thinning of the long bones with thin cortices. Several
wormian bones may be present. No deformity of long
bones is observed.
 In extremely severe (type II) OI:
beaded ribs, broad bones, and numerous fractures
with deformities of the long bones. Platyspondylia
may also be revealed.
 Moderate and severe (types III and IV) OI:
cystic metaphyses, or a popcorn appearance of the
growth cartilage. Normal or broad bones are revealed
early, with thin bones revealed later. Fractures may
cause deformities of the long bones. Old rib fractures
may be present. Vertebral fractures are common.
• Prenatal ultrasonography to detect
limb-length
abnormalities at 15-18 weeks'
gestation.
• Mild forms may result in normal sonogram
findings.
• Features include supervisualization of
intracranial
contents caused by decreased
 Differentiating between
mineralization of OI and child abuse. Mild OI is most
likely to be confused with child abuse. The sclera and teeth are normal in
many calvaria (also
patients calvarial
with compressibility),
OI. A family history is often not present.
bowing of the
 Some key
long differentiations
bones, decreased (if no other
bone lengthstigmata of OI are present):
 Considerof
(especially the types of fractures. Although any type of long bone
fracture
the canand
femur), occur in OI, certain
multiple types are rare. Metaphyseal corner
rib fractures.
fractures (common in child abuse) are rare in OI.
 In children with OI, fractures may continue to occur while they are in
protective custody; however, this scenario is hard to evaluate.
 Child abuse can also be differentiated from OI on the basis of
nonskeletal manifestations, such as retinal hemorrhage, visceral
intramural hematomas, intracranial bleeds of various ages,
pancreatitis, and splenic trauma.
 Collagen analysis is useful in difficult cases, but a negative result does not
rule out OI.
Treatment
 At present there is no cure for OI.

Bisphosphonates
 e.g. alendronate (Fosamax),
pamidronate (Aredia), zoledronic
acid (Reclast)).
Calcitonin (CT)
Increased vitamin D
intake
Growth hormone (GH)
Physiotherapy
Physical aids
Potential for gene
Treatment
 At present there is no cure for OI.

Bisphosphonates
 e.g. alendronate (Fosamax),
pamidronate (Aredia), zoledronic
acid (Reclast)).
Pamidronate last about three hours
and Calcitonin
therapy (CT)
is repeated every 3 to
6 months, and lasts for the life of
Increased
the patient. Common vitamin D
side effects
intake
include bone pain, low calcium
levels, nausea, and dizziness.
Growth hormone (GH)
According to recent results,
Physiotherapy
extended periods of pamidronate,
(i.e.; 6 years) can actually weaken
Physical
bones, so patientsaids
are
recommended
Potential to get
forbone
gene
Surgery

 Surgery is done only when

there are:
 fractures
 bowing of bone
 scoliosis
 heart problems
 Surgery may also be
considered to maintain
the ability to sit or stand.

 Metal rods can be surgically

inserted in the long bones
to improve strength.
“Rodding Surgery” was
adopted throughout the
world and still forms the
basis for orthopedic
treatment of OI.
Surgery

Surgery may
also be
considered to
maintain the
ability to sit or
X-ray after “Rodding stand.
Potential for cell and gene therapy
Potenti
al for
stem
cell
therap
y
Prevention
 For both type I and type IV OI, the most important question in
the clinical setting often relates to the natural history of the
illness.
 Reproductive decision making in families at risk for OI –
consider the life of the child.
 A definitive diagnosis may be made using a skin punch
biopsy. Family members may be given a DNA blood test.
 If there is a family history of OI, chorionic villus sampling may
be done during pregnancy to determine if the baby has the
condition. However, because so many different mutations can
cause OI, some forms cannot be diagnosed with a genetic test.
 On ultrasound from a 16-weeks-fetus, severe form of type II OI
can be seen
 After-birth precautions:
 Consultations
 Lifestyles changes: Avoid smoking and steroid or
osteoporosis-causing medications, Diet, Exercise,