Osteogenesis imperfecta

Osteogenesis imperfecta (OI and sometimes known as brittle bone disease, or "Lobstein syndrome"[1]) is a
congenital bone disorder characterized by brittle bones that are prone to fracture. 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.
[2]
Eight types of OI can be distinguished. Most cases are caused by mutations in
the COL1A1 andCOL1A2 genes.

Diagnosis of OI is based on the clinical features and may be confirmed by collagen or DNA testing. There is no
cure for OI. Treatment is aimed at increasing overall bone strength to prevent fracture and maintain mobility.
The incidence of OI is estimated to be one per 20,000 live births.

Osteogenesis Imperfekta adalah suatu keadaan dimana tulang-tulang menjadi rapuh secara
abnormal. Osteogenesis imperfekta merupakan suatu penyakit keturunan.
Penyakit ini terjadi akibat adanya kelainan pada jumlah atau struktur kolagen tipe I, yang merupakan
bagian penting dari tulang dll

Types
Of the eight different types of OI, Type I is the most common, though the symptoms vary from person to
person.

Mode of
Type Description Gene OMIM
inheritance

autosomal
Null COL1A1 allel
I mild 166240 (IA), 166200 (IB) dominant, 60%
e
de novo [3]

autosomal
severe and usually lethal in the 166210 (IIA), 610854 (IIB dominant,
II COL1A1, COL1A2,
perinatal period ) ~100% de
novo [3]

autosomal
considered progressive and
III COL1A1, COL1A2 259420 dominant, ~100%
deforming
de novo [3]
 autosomal
IV deforming, but with normal sclerae COL1A1, COL1A2 166220 dominant, 60%
de novo [3]

shares the same clinical features of

IV, but has autosomal
V IFITM5 610967
unique histologic findings ("mesh- dominant [3][4]
like")

shares the same clinical features of

IV, but has autosomal
VI SERPINF1 610968
unique histologic findings ("fish recessive [3]
scale")

associated with cartilage autosomal

VII CRTAP 610682
associated protein recessive [3]

severe to lethal, associated with the autosomal

VIII LEPRE1 610915
protein leprecan recessive

Type I[edit]

Blue sclera in osteogenesis imperfecta.

Collagen is of normal quality but is produced in insufficient quantities:

 Bones fracture easily

 Slight spinal curvature

 Loose joints

 Poor muscle tone

 Discoloration of the sclera (whites of the eyes), usually giving them a blue-gray color. The blue-gray
color of the sclera is due to the underlying choroidal veins which show through. This is due to the sclera
being thinner than normal because of the defective Type I collagen not forming correctly.

 Early loss of hearing in some children[5]

 Slight protrusion of the eyes

IA and IB are defined to be distinguished by the absence/presence of dentinogenesis imperfecta (characterized

by opalescent teeth; absent in IA, present in IB). Life expectancy is slightly reduced compared to the general
population due to the possibility of fatal bone fractures and complications related to OI Type I such as basilar
invagination.[citation needed]

Type II[edit]
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

 Severe respiratory problems due to underdeveloped lungs

 Severe bone deformity and small stature

Type II can be further subclassified into groups A, B, and 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 bones with thin and beaded ribs.

Type III[edit]
Collagen improperly formed, enough collagen is made but it is defective

 Bones fracture easily, sometimes even before birth

 Bone deformity, often severe

 Respiratory problems possible

 Short stature, spinal curvature and sometimes barrel-shaped rib cage

 Triangular face[6]

 Loose joints(double jointed)

 Poor muscle tone in arms and legs

 Discolouration of the sclera (the 'whites' of the eyes are blue)

 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.
Lifespans may be normal, albeit with severe physical handicapping.

Type IV[edit]
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.

Type V[edit]

OI Type V in an adult
OI Type V in a child

Having the same clinical features as Type IV, it is 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.[7]

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.
Other features of this condition include radial head dislocation, long bone bowing and mixed hearing loss.

At least some cases of this type are caused by mutations in the interferon induced transmembrane protein
5 (IFITM5) gene.[4]

Type VI[edit]
With the same clinical features as Type IV, it is distinguished histologically by "fish-scale" bone appearance.
Type VI has recently been found to be caused by a loss of function mutation in the Serpin F1 gene. Serpin F1,
a member of the serpin family, is also known as pigment epithelium derived factor (PEDF), the most powerful
endogenous antiangiogenic factor in mammals.

Type VII[edit]
In 2006, a recessive form called "Type VII" was discovered (phenotype severe to lethal). Thus far it seems to
be limited to a First Nations people in Quebec.[8] Mutations in the gene CRTAP causes this type.[9] Although
Type VII is associated with First Nations people in northern Quebec, the reference cited in this review is not
supportive of that fact. It does not mention anything about First Nations, aboriginal, Native American, American
Indian, or indigenous peoples.

Type VIII[edit]
OI caused by mutation in the gene LEPRE1 is classified as type VIII.[9]

Other genes[edit]
A family with recessive osteogenesis imperfecta has been reported to have a mutation in the TMEM38B gene
on chromosome 9.[10] This gene encodes TRIC-B, a component of TRIC, a monovalent cation-specific channel
involved in calcium release from intracellular stores.

It is extremely likely that there are other genes associated with this disease that have yet to be reported.

Pathophysiology[edit]
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.[11] This deficiency arises from an amino acidsubstitution of glycine to bulkier
amino acids in the collagen triple helix structure. The larger amino acid side-chains create steric hindrance that
creates a bulge in the collagen complex, which in turn influences both the molecular nanomechanics and the
interaction between molecules, which are both compromised.[12] As a result, the body may respond by
hydrolyzing the improper collagen structure. 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. [13]Another
suggested disease mechanism is that the stress state within collagen fibrils is altered at the locations of
mutations, where locally larger shear forces lead to rapid failure of fibrils even at moderate loads as the
homogeneous stress state found in healthy collagen fibrils is lost. [12] These recent works suggest that OI must
be understood as a multi-scale phenomenon, which involves mechanisms at the genetic, nano-, micro- and
macro-level of tissues.

As a genetic disorder, OI has historically been viewed as an autosomal dominant disorder of type I collagen.
Most cases have been caused by mutations in the COL1A1 and COL1A2 genes. In the past several years,
there has been the identification of autosomal recessive forms. [14] Most people with OI receive it from a parent
but in 35% of cases it is an individual (de novo or "sporadic") mutation.[citation needed]

Diagnosis[edit]
There is no definitive test for OI. The diagnosis is usually suggested by the occurrence of bone fractures with
little trauma and the presence of other clinical features. Skin biopsy can be performed to determine the
structure and quantity of type I collagen. DNA testing can confirm the diagnosis, however it cannot exclude it,
because not all mutations causing OI are known and/or tested for. OI type II is often diagnosed by ultrasound
during pregnancy, where already multiple fractures and other characteristic features may be present.

An important differential diagnosis of OI is child abuse, as both may present with multiple fractures in various
stages of healing. Differentiating them can be difficult, especially when no other characteristic features of OI are
present. Other differential diagnoses include rickets, osteomalacia, and other rare skeletal syndromes.

Diagnosis[edit]
Hereditary cause for osteoperosis - Osteopenia seen on radiographs
Skull radiographs

 intrasutural(wormian) bones

 dentinogenesis imperfecta

Chest

 Superior rib notching

Limbs

 thin and undertubulated gracile) bones which are normal in length or shortened

 thickened or deformed bones (due to multiple fractures)

 Cause of pathological fractures:

 * Banana fracture’: pathological fractures tend to be oriented transversely within long bones

 * Shaft fractures and metaphyseal abnormalities with florid or exuberant callus formation that can
mimic an osteosarcoma

 * Cause of multiple rib fractures and requires exclusion before making a diagnosis of non-accidental
injury in a neonate

Angiogram Arterial carotid and vertebral artery dissection

Treatment[edit]
There is no cure for OI. Treatment is aimed at increasing overall bone strength to prevent fracture and maintain
mobility. Bisphosphonates can increase bone mass, and reduce bone pain and fracture. In severe cases,
bones are surgically corrected, and rods are placed inside the bones, particularly to enable infants to learn to
walk.

Bone infections are treated as and when they occur with the appropriate antibiotics and antiseptics.

Bisphosphonates[edit]
In 1998, a clinical trial demonstrated the effectiveness of intravenous pamidronate, a bisphosphonate which
had previously been used in adults to treat osteoporosis. In severe OI, pamidronate reduced bone pain,
prevented new vertebral fractures, reshaped previously fractured vertebral bodies, and reduced the number of
long-bone fractures.[15]
Although oral bisphosphonates are more convenient and cheaper, they are not absorbed as well, and
intravenous bisphosphonates are generally more effective, although this is under study. Some studies have
found oral and intravenous bisphosphonates, such as oral alendronate and intravenous pamidronate,
equivalent.[16] In a trial of children with mild OI, oral risedronate increased bone mineral densities, and reduced
nonvertebral fractures. However, it did not decrease new vertebral fractures. [17] [18]

Bisphosphonates are less effective for OI in adults.[19]

Surgery[edit]
Metal rods can be surgically inserted in the long bones to improve strength, a procedure developed by Harold
A. Sofield, MD, at Shriners Hospitals for Children in Chicago. During the late 1940s, Sofield, Chief of Staff at
Shriners Hospitals in Chicago, worked there with large numbers of children with OI and experimented with
various methods to strengthen the bones in these children. [20] In 1959, with Edward A. Miller, MD, Sofield wrote
a seminal article describing a solution that seemed radical at the time: the placement of stainless steel rods into
the intramedullary canals of the long bones to stabilize and strengthen them. His treatment proved extremely
useful in the rehabilitation and prevention of fractures; it was adopted throughout the world and still forms the
basis for orthopedic treatment of OI.

Spinal fusion can be performed to correct scoliosis, although the inherent bone fragility makes this operation
more complex in OI patients. Surgery for basilar impressions can be carried out if pressure being exerted on
the spinal cord and brain stem is causing neurological problems.

Physiotherapy[edit]
Physiotherapy is used to strengthen muscles and improve motility in a gentle manner, while minimizing the risk
of fracture. This often involves hydrotherapy and the use of support cushions to improve posture. Individuals
are encouraged to change positions regularly throughout the day to balance the muscles being used and the
bones under pressure.

Children often develop a fear of trying new ways of moving due to movement being associated with pain. This
can make physiotherapy difficult to administer to young children.