Minggu, 26 Oktober 2008

Osteogenesis Imperfecta

Osteogenesis Imperfecta

Dr Harry Sunaryo SpOT

Osteogenesis imperfecta (OI) is a
genetically determined disorder of
connective tissue characterized by
bone fragility. The disease state
encompasses a phenotypically and
genotypically heterogeneous group
of inherited disorders resulting
from mutations in genes coding for
type I collagen. Osteogenesis imperfecta
has been grouped clinically
with other heritable disorders of
connective tissue, including Ehlers-
Danlos syndrome, Marfan syndrome,
homocystinuria, Weill-
Marchesani syndrome, cutis laxa,
pseudoxanthoma elasticum, fibrodysplasia
ossificans progressiva,
and the chondrodysplasias, but
molecular studies are beginning to
allow more precise delineation.
Osteogenesis imperfecta is most
closely related to type VIIA and
type VIIB Ehlers-Danlos syndrome,
which also result from mutations in
type I collagen genes.
The clinical disease state is manifested
in tissues in which the principal
matrix protein is type I collagen
(mainly bone, dentin, sclerae,
and ligaments). The phenotypic
manifestations are variable in
severity, ranging from perinatal
lethal forms with crumpled bones
and severe deformity to clinically
silent forms with subtle osteopenia
and no deformity (Table 1). The
various classifications of OI will be
discussed in the ÒClassificationsÓ
section, but in general, clinical subtypes
represent a series of syndromes
related to classes of molecular
defects, each with a reasonably
well-defined phenotypic pattern.
Osteogenesis imperfecta is ubiquitous
in ethnogeographic distribution.
The prevalence of OI is approximately
16 cases per million
index patients. Sillence type I OI is
by far the most common clinical
subtype except in southern Africa,
where type III is more common.
The incidence of the mild type I
(tarda) form is estimated at 3 to 5
per 100,000; that of the severe
deforming type III form, 1 to 2 per

Osteogenesis imperfecta (OI) is a genetically determined disorder of connective
tissue characterized by bone fragility. The disease state encompasses a phenotypically
and genotypically heterogeneous group of inherited disorders that result
from mutations in the genes that code for type I collagen. The disorder is manifest
in tissues in which the principal matrix protein is type I collagen (mainly
bone, dentin, sclerae, and ligaments). Musculoskeletal manifestations are variable
in severity along a continuum ranging from perinatal lethal forms with
crumpled bones to moderate forms with deformity and propensity to fracture to
clinically silent forms with subtle osteopenia and no deformity. The differential
diagnosis includes other entities with multiple fractures, deformities, and
osteopenia. Classification is based on the timing of fractures or on multiple clinical,
genetic, and radiologic features. Molecular genetic studies have identified
more than 150 mutations of the COL1A1 and COL1A2 genes, which encode for
type I procollagen. Various systemic treatments have been attempted; however,
these interventions have been ineffective or inconclusive or are still experimental.
Gene therapy has the potential to increase the synthesis of type I collagen in mild
variants and to correct mutations in severe variants, but there are a great number
of technical difficulties to overcome. The goals of treatment of OI are to maximize
function, minimize deformity and disability, maintain comfort, achieve relative
independence in activities of daily living, and enhance social integration.
Attainment of these goals requires a team approach to tailor treatment needs to
the severity of the disease and the age of the patient. Nonoperative management
is the mainstay of orthopaedic treatment, with the goals of preventing and treating
fractures and enhancing locomotion. Operative intervention is indicated for
recurrent fractures or deformity that impairs function.

100,000 births; that of the lethal
perinatal type II (congenita) form, 1
per 40,000 to 60,000 births. The
intermediate type IV form is rare,
with an unknown frequency.1,2
The disease was first described
scientifically by Ekman in 1788,
who detailed involvement in four
generations of a family in Sweden
for his doctoral thesis. Since then,
more than 40 different names and
eponyms have been used, including
mollities ossium, fragilitas ossium,
osteopsathyrosis idiopathica,
osteomalacia congenita, osteoporosis
fetalis, Eddome syndrome, van
der Hoeve syndrome, Vrolik disease,
and Lobstein disease.1,2 The
term Òosteogenesis imperfectaÓ
was first used by Vrolik in 1849
when describing the pathologic
features of involved bone.
The disease likely dates back to
antiquity; an Egyptian mummy
from 1000 BC has been described as
having a wormian bone mosaic of
the skull, amber-colored teeth, and
severely bowed legs. It is speculated
that Ivar the Boneless, mastermind
behind the Scandinavian
invasion of England in the 9th century,
had OI. Legend has it that he
was unable to walk and was carried
into battle on a shield. Unfortunately,
his skeleton is not available,
as it was exhumed and burned by
William the Conqueror.1
Basic clinical and genetic studies
have identified the phenotypic characteristics
of OI, leading to the development
of classification schemes
and management strategies. More
recently, biochemical and molecular
genetic studies have characterized
many of the protein defects and collagen
mutations in OI, elucidating
the genotypic characteristics of this
disease. This article reviews the
clinical manifestations, diagnosis,
classification, molecular basis, and
management of OI.
Clinical Manifestations
Musculoskeletal System
The musculoskeletal features of
OI are variable in their extent and
severity, depending on the clinical
subtype and reflecting the underlying
genotypic heterogeneity. Gross
skeletal features include short
stature (with dwarfing in severe
forms), kyphoscoliosis, pectus
excavatum, and trefoil-shaped
pelvis with protrusio acetabuli.
The skull is often misshapen, with
a broad forehead, flattened posterior
cranium, overhanging occiput,
bulging calvaria, and triangular
facial shape. Depending on the
severity of disease, there may be
marked long-bone deformity with
anterior bowing of the humerus,
tibia, and fibula and lateral bowing
of the femur, radius, and ulna.
The overall incidence of spine
deformity in OI is approximately
60%, ranging from 90% for congenita
forms to 10% to 40% for tarda
forms.3 Thoracic scoliosis is the
most common deformity and arises
secondary to osteoporosis, compression
fractures, and ligamentous
laxity. The deformity of the thorax
associated with multiple rib fractures,
spinal deformity, molding of
Osteogenesis Imperfecta

Clinical Features and Classification of Osteogenesis Imperfecta
Sillence Shapiro
Type13 Type12 Type Features Inheritance
I Tarda B Mild form Blue sclerae, normal teeth (Sillence subtype IA) Autosomal dominant,
or dentinogenesis imperfecta (Sillence new mutations
subtype IB), mild bone fragility, fractures
after walking, minimal deformity
II Congenita A Lethal Blue sclerae, stillborn or neonatal death, Autosomal recessive,
perinatal numerous intrauterine fractures, new mutations,
crumpled long bones, severe deformity mosaicism
III Congenita B, Severe Normal sclerae, dentinogenesis imperfecta, Autosomal recessive,
tarda A deforming often fractures at birth, frequent fractures, new mutations,
frequent deformity, short stature, spine deformity mosaicism
IV . . . Intermediate Normal sclerae, normal teeth (Sillence subtype Autosomal dominant
form IVA) or dentinogenesis imperfecta (Sillence
subtype IVB), moderate bone fragility, moderate
deformity, short stature, phenotypic variability
the soft thorax, and pectus excavatum
or carinatum can be sufficiently
severe to compromise respiratory
function. Ligamentous laxity results
in hypermobile joints with
joint dislocations, patellar tendon
ruptures, and pes planus. There is
often a secondary muscular hypotonia
and underdevelopment related
to tendon or ligament anomalies
and reduced activity.
The hallmark of OI is bone
fragility. As with the other phenotypic
features of OI, the propensity
to fracture is extremely variable,
with manifestations ranging from
innumerable fractures in utero and
at birth to their virtual absence in
an adult. The timing and number
of fractures is included in some
classification schemes. In general,
the more severe forms of OI are
characterized by earlier and more
numerous fractures. These fractures
often occur after minor trauma
and can present with little pain.
Fractures generally heal with abundant
callus; however, the reparative
bone is also abnormal, and
fractures frequently lead to malunion
and pseudarthroses with
resultant long-bone deformity. The
incidence of fractures decreases
after puberty and rises again in
women after menopause and in
men after age 60.
The radiographic features of OI
are also proportional to disease
severity. The radiologic hallmark
of OI is diffuse osteopenia associated
with multiple fractures and
deformities. Generalized osteopenia
is seen in almost every case,
and there is often equal involvement
of the appendicular and axial
skeletons.
The long bones of the lower extremities
are usually more severely
affected than those of the upper
extremities. The long bones most
often appear slender; however, they
may show focal areas of thickened
cortices secondary to callus buttressing
or telescoping of fractures.
The metaphyses of the long bones
can be trumpet-shaped and cystic in
appearance. In severe cases, Òpopcorn
Ó calcifications appear in childhood
in the metaphyseal/epiphyseal
regions as displaced, fragmented
physeal cartilage undergoes
endochondral ossification. These
calcifications commonly resolve
after skeletal maturity, when all cartilage
is transformed to bone.
The vertebrae in OI often demonstrate
flattening or are biconcave
secondary to multiple microfractures.
Kyphoscoliosis often results.
The skull is characterized by
wormian bones, as first described
by the Danish anatomist Olaus
Wormius in 1643. This appearance
represents small, independent areas
of primary ossification within
membranous bones arranged in a
mosaic pattern .
Hyperplastic callus formation is
rare but can occur in patients with
OI. It often presents as pain, an
enlarging mass, and erythema, and
can be difficult to distinguish from
osteosarcoma radiographically,
clinically, and even histologically.
The histopathologic features of
OI also vary depending on disease
severity. Overall, there is a generalized
decrease in bone tissue, with
the bone structure demonstrating a
mixture of woven and lamellar patterns.
The histologic appearance of
bone in OI patients follows the normal
developmental and structural
pattern but rarely achieves the fully
compacted lamellar state. The more
severe the involvement, the more
immature the structural pattern. In
more severe forms of OI, the bone
appears histologically as a woven
bone matrix devoid of any organized
lamellar pattern .
There are plump osteoblasts crowded
along prominent osteoid seams,
large oval osteocytes surrounded by
small amounts of matrix, and morphologically
normal osteoclasts.
Histologic sections from patients
with less severe OI show a definite
tendency to lamellar bone formation
. The lamellation and
osteon formation can be rudimentary,
partially compacted, or fully
compacted in localized areas. Osteoid
seams are prominent, and
there is hypercellularity, with larger
than normal osteocytes and
osteoblasts in the areas of woven
bone. There is a correlation between
the degree of osteonal maturity
and bone strength as indicated
by ambulatory status.
The articular cartilage appears
normal. The physis often shows
disorganization of the proliferative
and hypertrophic zones with
increased permeation of cartilage
by metaphyseal blood vessels. The
metaphysis is composed of a
scanty, woven primary spongiosa.
There is increased bone turnover as
defined by tetracycline-labeling
studies. Callus bone is largely
woven. Ultrastructural studies
show a predominantly random
1 Anteroposterior (AP) skull radiograph
demonstrates wormian bone mosaic
pattern.
arrangement of thinner collagen
fibers consistent with the lightmicroscopic
woven pattern.4,5
Other Systems
The effects of OI are not limited
to bone, but also involve tissues in
which the primary matrix protein
is type I collagen (dentin, sclerae,
skin, and ligaments). System involvement
(e.g., otologic, neurologic,
and respiratory) is secondary to
deformity and to primary metabolic
abnormalities.
Dentinogenesis imperfecta is
characterized by soft, translucent
brownish teeth. The teeth are
affected in a nonuniform manner,
with involvement usually greater
in the primary teeth than in the secondary
teeth. The enamel wears
easily, and the teeth are carious,
shortened, and susceptible to
cracking. On x-ray films, the
crowns are bulbous, and there is
obliteration of pulp chambers.
About 30% of individuals with all
types of OI have significant dental
involvement. The Sillence classification
scheme subclassifies type I
and type IV OI on the basis of the
presence or absence of dentinogenesis
imperfecta. Dental treatment
includes crowning, dentures, and
intraosseous implants.
The blue sclerae in OI are the
result of increased corneal translucency
(secondary to abnormal collagen),
which reveals the underlying
uveal pigment and blood vessels.
This color changes with age,
becoming more grayish in adulthood.
The pericorneal region of the
sclera is often white and opaque,
resulting in a ÒSaturnÕs ringÓ
appearance, and there may be opacities
in the periphery of the cornea,
giving an arcus juvenilis appearance.
Hypermetropia is common.
The skin in OI is often thin,
translucent, and easily distensible,
resembling the atrophic skin of
elderly patients owing to collagen
insufficiency of the dermal layer.
Surgical scars commonly heal with
widening and prominence. Ligamentous
laxity is a characteristic
feature of OI. Pes planus is the
principal clinical manifestation, but
other disorders of hyperlaxity, such
as subluxating patellae and dysplastic
hips, are occasionally seen.
There is increased vascular fragility,
and a minority of patients demonstrate
nonprogressive aortic root
dilatation. Valvular disease, in particular
mitral valve prolapse, is
much less common than in Marfan
syndrome, but has been reported.6

Histologic appearance of bone specimens from patients
with OI of varying severity (hematoxylin-eosin; original magnification,
´65). Top left, Femoral cortex biopsy specimen
from a patient with type I OI demonstrates a near-normal
lamellar structure. Top right, Femoral cortex osteotomy specimen
from a patient with type III OI demonstrates a mixed pattern
of woven and lamellar bone. Bottom, Femoral cortex
specimen obtained at autopsy of a patient with type II OI
demonstrates a scanty, disorganized, woven matrix with large
osteocytes.
The onset of hearing loss in OI
begins in adolescence and becomes
problematic for nearly 50% of
affected adults. It is seen primarily
in the type I benign autosomal
dominant variant. Hearing loss
can be conductive, sensorineural,
or mixed. The extent of deafness is
variable; however, loss in the highfrequency
range is characteristic.
Treatment usually involves prosthetic
stapedial footplate replacement
or stapedectomy. Other otologic
findings include recurrent
middle ear infections and sinusitis,
tinnitus from stapedial fixation,
vertigo from labyrinthine involvement,
and speech delay.
Intelligence is usually normal.
Low-pressure hydrocephalus can
be seen in some severe forms of OI.
The anterior fontanel remains
open, and there is general dilation
of the ventricles with cortical atrophy.
This process is usually selflimiting
and does not require
shunting. Basilar impression occurs
predominantly in Sillence type
III and type IV OI. There is brainstem
and spinal cord compression
at the foramen magnum, resulting
in progressive cerebellar disturbance
and lower cranial nerve dysfunction;
this may require cranial
decompression, which has had
variable results.
Metabolic abnormalities, present
to a variable extent in patients
with OI, are characterized by hypermetabolism,
heat intolerance,
elevated body temperature, increased
sweating, and resting
tachypnea and tachycardia. These
findings are generally attributed
to high metabolic activity and
turnover of the connective tissue
cells. Hyperthermia can occur
during anesthesia; rarely, true
malignant hyperthermia may
occur. There is evidence of uncoupling
of oxidative phosphorylation
in leukocytes and defects in platelet
adhesion and clot retraction in
patients with OI.7,8
Diagnosis
The diagnosis of OI is still based
primarily on clinical and radiographic
criteria. Fibroblast cell culture
from skin biopsy specimens
can now be used to detect collagen
molecular abnormalities (discussed
in the ÒMolecular BasisÓ section) in
approximately 85% of patients with
OI. The differential diagnosis of OI
in infancy is relatively limited.
Hypophosphatasia presents with
multiple fractures, deformities, and
osteopenia. Other disorders, such
as achondrogenesis, achondroplasia,
pyknodysostosis, rickets, Menkes
syndrome, and homocystinuria,
have their own distinguishing
features.
Diagnosis in childhood and adolescence
can be more difficult due
to less severe involvement. The
differential diagnosis includes
leukemia, fibrous dysplasia, and
idiopathic juvenile osteoporosis.
Idiopathic juvenile osteoporosis is
an extremely rare disorder with
onset at puberty. It is characterized
by generalized osteopenia and
propensity to fracture. Spontaneous
remission has been reported.
It can be distinguished from OI by
its onset in adolescence, the presence
of normal sclerae and teeth,
and a negative family history.
Hypophosphatasia resembles OI
with blue sclerae, bowing of legs,
and osteopenia; it can be differentiated
from OI by abnormal laboratory
findings such as the urine excretion
product phosphoethanolamine
and markedly decreased serum
alkaline phosphatase levels. Homocystinuria
is characterized by
osteoporosis, biconcave vertebrae,
and susceptibility to fracture; it can
be differentiated from OI by a marfanoid
habitus, ectopia lentis, and
abnormal urinary metabolites.
The distinction between mild
forms of OI and child abuse can be
difficult, but is crucial to consider.9
Both may present with a propensity
to fracture without a clear history
of definite trauma. Classically,
abuse presents with multiple fractures
in different stages of healing,
posterior rib fractures, metaphyseal
corner fractures, and skull fractures.
Other signs of abuse include
bruises, burns, and retinal hemorrhages.
Prenatal diagnosis of OI can be
made on the basis of structural
characteristics noted on fetal ultrasound,
collagen molecular studies
of cultured chorionic villus cells, or
genetic linkage studies with the use
of collagen markers.10 Prenatal
detection in pregnancies at risk for
OI can provide valuable information
for genetic counseling and
obstetric management. Ideally,
genetic counseling would provide
information concerning the likely
outcome of future pregnancies and
the prognosis for individual affected
children. In actuality, however,
this is difficult because of the high
incidence of spontaneous mutations
and sporadic cases, the lack of diagnostic
tests in the index case, and
the lack of an accurate carrier test.
Ultrasonography can effectively
screen fetuses for severe forms of
OI, but it remains difficult to detect
mild forms. Sillence type II OI can
be recognized on ultrasound scans
obtained before 20 weeksÕ gestation
by assessing femoral length adjusted
for gestational age, extent of
mineralization, evidence of fractures,
skull echogenicity, and thoracic
abnormalities. Midtrimester
ultrasonography is usually useful
in detecting type III OI by depiction
of intrauterine fractures and
deformity. Advances in transvaginal
ultrasound may provide a
means of first-trimester prenatal
diagnosis of severe forms of OI.
If a certain biochemical defect of
collagen or a specific mutation has
been identified in an affected parent
or sibling, prenatal detection
can be accomplished by screening
fetal tissue for the presence of that
defect. This is performed by culturing
chorionic villus cells and
examining the electrophoretic
properties of the collagen they produce.
Amniotic fluid cells are, in
general, not useful because most
cells synthesize a variant of type I
procollagen. Linkage studies performed
with the use of collagen
markers are currently the diagnostic
investigation of choice for families
with autosomal dominant OI,
allowing genotyping of the fetus.11
Classifications
Clinical, radiographic, molecular,
and genetic studies support the
concept that OI is a syndrome with
several variants related to classes of
type I collagen mutations, each
with a reasonably well-defined phenotypic
pattern. As a result of the
extensive phenotypic heterogeneity
of OI, numerous classifications
have been proposed to categorize
clinical subtypes, provide a framework
for understanding the natural
history, and guide management.
Looser, in 1906, classified OI into
two types on the basis of when
the first fractures occurred: congenita
(fractures at birth) and tarda
(fractures after the perinatal period).
He noted that the prognosis in
the congenita type was poor, with a
high mortality rate. Seedorff, in
1949, further subclassified OI tarda
into gravis (fracture occurs within
the first year of life) and levis (fracture
occurs after the first year of
life), noting that tarda gravis was
associated with the development of
severe deformities and disability.
Shapiro,12 in 1985, revisited this
concept, defining natural history and
musculoskeletal prognosis on the
basis of the time of initial fracture
and the radiographic appearance of
the bones at the time of initial fracture.
Patients with the congenita
form have intrauterine or birth
fractures. Patients with the tarda
form sustain fractures initially after
birth. The congenita form of OI
was subdivided into type A (crumpled
femurs and ribs) and type B
(normal bone contours with intrauterine/
birth fractures). The tarda
form was subdivided into type A
(fractures before walking) and type
B (fractures after walking). At follow-
up in that study, patients in
the congenita type A group had a
mortality rate of 94%. Patients in
the congenita type B group had a
mortality rate of only 8%, with 59%
eventually becoming wheelchairbound
and 33% being ambulatory.
In the tarda type A group, 33% of
patients were wheelchair-bound,
and 67% were ambulatory. All
patients in the tarda type B group
were ambulatory.
The classification system currently
used most widely was developed
by Sillence in 1979 from a comprehensive
survey of patients in Australia.
The Sillence classification
divides OI patients into four types
on the basis of multiple clinical,
genetic, and radiologic features
Type I OI is the
mildest and most common form.
Inheritance is autosomal dominant,
although new mutations are frequent.
Type I is subclassified into
the more common type A (without
dentinogenesis imperfecta) and the
less common type B (with dentinogenesis
imperfecta). The sclerae are
blue, and the first fractures usually
occur in the preschool years, after
walking has begun. There is commonly
absence of significant deformity;
kyphoscoliosis is comparatively
mild and uncommon; and stature
is generally normal. Life expectancy
is normal for patients with type IA
OI and only marginally impaired for
those with type IB. Socially, type I
OI patients are scarcely distinguishable
from the normal population,
with most fully employed and living
independently.
Type II OI is the lethal
perinatal form.

Six-week-old neonate with lethal perinatal type II OI who died at 12 weeks due
to respiratory failure. Features included blue sclerae, short stature, and short, deformed
extremities. B, Lateral lower-extremity radiograph of another child with type II OI shows
osteopenia, short crumpled femurs, multiple fractures, and deformity.
stillborn, and survivors are often
born prematurely. The disorder is
usually lethal within the first few
weeks of life, but some affected
infants survive for several months,
and a few live for one or more
years. Death is generally due to
respiratory failure, intracranial
hemorrhage, or brainstem compression.
The sclerae tend to be blue or
grayish. There are multiple intrauterine
fractures, and the femurs,
tibias, and ribs are short, broad,
crumpled, and deformed. Inheritance
was thought to be autosomal
recessive; however, most cases
appear to result from new dominant
mutations in a proband of
unaffected parents. Occasionally,
unaffected parents have multiple
affected children; this is thought to
result from parental mosaicism or
to be due to a rare autosomal recessive
form.
Type III OI is the severe deforming
form, with fractures generally
present at birth (Fig. 4). The sclerae
are generally normal in color.
Frequent fractures and deformity
are common, stature is typically
severely shortened, and the spine is
often deformed (Fig. 5). Respiratory
complications and dentinogenesis
imperfecta are common. Inheritance
is thought to be autosomal
recessive; however, new dominant
mutations are common, and a rare
autosomal dominant variety exists.
Life expectancy is decreased, but
affected individuals live into adulthood.
Early mortality is due to respiratory
illness, injury with intracranial
hemorrhage, and basilar
invagination.
Type IV OI is a moderately
severe form with great phenotypic
variation, but is usually intermediate
in severity between type III and
type I. This variant is infrequent,
accounting for approximately 5% of
cases. Sclerae are normal, short
stature is variable, dentinogenesis
imperfecta is common, and fractures
and deformity are relatively
common. Inheritance is autosomal
dominant. Life expectancy can be
decreased depending on disease
severity; however, a large percentage
of patients function independently
well into adulthood.
The Sillence classification correlates
with the congenita/tarda temporal-
radiographic Shapiro groups.
The congenita A group encompasses
Sillence type II lethal perinatal
patients; congenita B and tarda A
are generally Sillence type III
patients with progressive deformity;
and tarda B represents the
Sillence type I benign autosomal
dominant patients.
Molecular Basis
Studies examining the skin of
patients with OI in the 1960s and
1970s gave the first clear indication
of collagen abnormalities. Subsequently,
skin fibroblast cell culture
studies have confirmed that the
cells of affected individuals produce
either decreased amounts of
collagen or defective collagen.
Detailed biochemical investigations
have demonstrated heterogeneity
of type I collagen defects.
Radiograph of a newborn with type III OI. Features include osteopenia and a fracture
of the left femur.
Four-year-old child with type III
OI. Features include a broad flattened
forehead, short arms, and short stature.
She has undergone osteotomies with
intramedullary rodding of her lower
extremities and ambulates with braces and
a walker.
Recently, molecular biology studies
have defined more than 150
specific gene mutations that result
in OI, and investigations to characterize
the mechanisms that translate
these mutations into the various
observed phenotypes are
ongoing.2,15-18
Osteogenesis imperfecta is
caused by mutations in the
COL1A1 (18-kilobase [kb] size,
located on the long arm of chromosome
17) and COL1A2 (38-kb size,
located on the long arm of chromosome
7) genes that encode the two
pro-a1(I) and one pro-a2(I) chains
of the type I procollagen trimer,
respectively. These genes contain
more than 50 exons to generate
about 1,450 amino acids of each
chain. The formation of the essential
triple helical structure of procollagen
I from these three pro-a(I)
chains depends on the presence of
glycine in every third position in
the 1,014-residue triple helical
domain and is stabilized by the
presence of hydroxyproline. The
triple helix is propagated from the
carboxyl-terminal end toward the
amino-terminal end of the molecule.
The mature molecule is then
secreted from the cell into the extracellular
matrix, where the aminoterminal
and carboxyl-terminal
propeptides are removed enzymatically
and type I collagen fibrillogenesis
occurs by self-assembly.2,15-18
More than 150 mutations of the
COL1A1 and COL1A2 genes, including
single base-pair changes,
deletions, insertions, premature
stop codons, and splicing mutations,
have been described, causing
forms of OI ranging in phenotype
from mild to lethal. The most frequent
mutation types are single
base-pair substitutions in either of
the two alleles that alter a codon
for glycine in the triple helical
domain of the chain.
The molecular basis of Sillence
type I OI remains poorly understood.
Cells from affected individuals
largely demonstrate a quantitative
defect of type I collagen; they
synthesize and secrete about half
the normal amount of type I procollagen.
This is due to decreased
synthesis of pro-a1(I) chains; in
general, the pro-a2(I) chain is normal.
The mutation often occurs in
one allele, resulting in about half
the normal amount of the molecule,
as type I procollagen must
contain two pro-a1(I) chains.
The vast majority of infants with
type II OI appear to be heterozygous
for mutations that result in
substitutions for glycine residues
within the triple helical domain of
either the pro-a1(I) or the pro-a2(I)
chain. In some instances, exonskipping
mutations in either gene
can result in this phenotype. Type
III and type IV phenotypes can also
result from heterozygosity for point
mutations of glycine residues within
the triple helical domains of
either chain of type I procollagen or
from exon-skipping mutations.2,15-18
There are several basic concepts
concerning the nature of mutations
and their phenotypic consequences.
Quantitative mutations
that decrease expression and synthesis
of normal type I procollagen
molecules result in milder phenotypes,
such as type I OI. Qualitative
mutations that lead to structural
aberrations and abnormal
type I procollagen result in more
severe phenotypes, such as types II
and III. The severity of the phenotype
reflects the location of the
mutation within the chain, the
nature of the mutation, and the
chain in which the mutation occurs.
In general, with point mutations,
the phenotype becomes
milder as the mutation is shifted
toward the amino-terminal end of
the chain, because the essential
triple helical structure is formed
from the carboxyl-terminal end
toward the amino-terminal end in
a zipperlike helical-coiling manner.
With glycine substitution mutations,
amino acid replacements
with bulkier side chains, such as
arginine, result in more severe
phenotypes than those with smaller
side chains, such as serine and
cysteine. Mutations in the
COL1A2 gene have milder consequences
than similar mutations in
the COL1A1 gene, as the type I
procollagen molecule has two proa1(
I) chains and one pro-a2(I)
chain.2,15-18
The expression of these mutations
into the observed phenotypic
patterns is poorly understood. On
the molecular level, these mutations
can decrease the rate of synthesis,
decrease the thermal stability
of the triple helical molecules,
delay the rate of folding of the precursor
procollagen molecule,
increase the level of aberrant posttranslation
modification of procollagen
chains, and impair the rate of
export of molecules from cell to
matrix. Mutated chains are more
slowly incorporated into fibrils
than normal collagen molecules;
demonstrate an abnormal configuration,
with more branching, shortening,
or thickening; and impair
mineralization by providing a
mutated structural template for
incorporation of hydroxyapatite
crystals. The end result of these
molecular changes eventually
translates into the microscopic and
gross pathologic features characteristic
of OI.2,15-19
The identification of a vast array
of genetic mutations associated
with OI is commensurate with the
observed phenotypic heterogeneity
of this disease. This supports the
concept that OI represents a continuum
of mutational events translating
into a continuum of phenotypic
involvement from perinatal lethal
forms to moderate deforming forms
to mild, nondeforming forms.
Included in this continuum would
be type VII Ehlers-Danlos syndrome
and some variants of osteoporosis.
In type VIIA and type VIIB

Ehlers-Danlos syndrome, the molecular
abnormality is impaired
cleavage of the N-terminal propeptides
from procollagen secondary to
mutations in the COL1A1 and
COL1A2 genes. Phenotypically,
this results in joint hypermobility,
skin changes, and other signs of
connective tissue involvement.
Thus, any classification system of
OI must impose arbitrary boundaries
within this continuum. However,
for purposes of facilitating
communication, predicting natural
history, and planning management
strategies, it seems reasonable to
continue classifying into clinical
subtypes, such as the Sillence classification
or the congenita-tarda
schemes. These groupings represent
a series of syndromes related
to classes of molecular defects, each
with a reasonably well-defined phenotypic
pattern.
Management
Systemic Therapy
Several systemic treatments for
OI have been attempted, but all
have been ineffective or inconclusive
or are still experimental. Two
features of OI make evaluation of
the efficacy of therapeutic interventions
difficult. First, the large
genetic and biochemical heterogeneity
in OI results in trials that
combine patients with different
mutations. Thus, a treatment that
may benefit individuals with specific
mutations and biochemical
defects may be ineffective for other
patients with different mutations
and biochemical defects. Second,
the frequency of fractures within
the same patient can differ dramatically
from one time period to
another. Thus, studies that use
fracture frequency or linear growth
to evaluate efficacy without wellmatched
controls may show
improvement unrelated to drug
effect.2
Calcitonin has been used because
of its osteoclastic inhibitory
effects and resultant increase in
bone density in osteoporosis. Results
in patients with OI have been
mixed, with some studies finding
decreased fracture frequency and
increased bone density, and other
studies finding no effect and high
side-effect profiles. Similarly,
sodium fluoride, calcium, anabolic
steroids, growth hormone, magnesium
oxide, vitamin C, and vitamin
D have been tried in OI patients
with mixed results and failure
to demonstrate definite treatment
value. The efficacy of bisphosphonates
in increasing bone mineral
content and density while reducing
bone resorption in patients
with OI has not yet been established.
1,2
Although still strictly theoretical,
conceivably the most dramatic and
efficacious form of treatment for OI
and related disorders would be gene
therapy. In Sillence type I OI, this
could involve stimulation of type I
collagen synthesis. In the more
severe types, this could involve
replacement of the defective gene.
In one series of experiments, researchers
developed a modified
oligonucleotide that specifically
inhibited expression of a mutated
gene for the pro-a1(I) chain of type I
procollagen by 50% to 80% in cell
culture studies. There are considerable
technical barriers involved in an
oligonucleotide design and delivery
system in vivo; however, the potential
optimal effect may be to convert
a severely debilitating phenotype to
a milder form of the disease through
inhibition of expression.2,15 In another
series of experiments, researchers
developed a transgenic
mouse line that expressed an antisense
RNA for the pro-a1(I) chain.
When bred to mice that expressed a
phenotype of severe brittle bones,
offspring that expressed both genes
had a marked decrease in lethality
and an increase in the incidence of
brittle bones, presumably because
they had a rescue phenotype.2,15
Orthopaedic Management
The overall goals of treatment of
OI are to maximize function, minimize
disability, achieve relative independence
in activities of daily living,
attain the greatest possible degree of
mobility, allow social integration,
and maintain overall health. This
requires a team approach from the
health-care providers, including the
pediatrician, orthopaedic surgeon,
geneticist, neurologist, neurosurgeon,
dentist, ophthalmologist,
physical therapist, social worker,
and nurse-clinician. Care must be
individualized, depending primarily
on the severity of the disease and the
age of the patient. Sillence type I OI,
in its milder forms, may have only a
minimal impact on the patient, and
the role of the orthopaedic surgeon is
limited to conventional fracture care.
Early death often occurs in type II OI
before any orthopaedic intervention
is indicated. Type III and type IV
present the greatest management
challenges for the orthopaedist in
terms of fracture prevention, fracture
management, limitation of deformity,
and optimization of function.20-22
The management of OI begins
with early detection in utero for
pregnancies at risk to guide in family
planning and obstetric management.
In the neonate with deforming
OI (type III and some type IV),
immediate life-threatening problems
of respiratory insufficiency
and intracranial hemorrhage are
managed by the neonatologist. In
utero fractures have usually healed,
and recent fractures often do not
require special treatment other than
splinting. The parents should be
educated about handling of the
infant and about the natural history
of the disease. Lay organizations,
such as the OI Foundation, are
helpful with parental education.
In infancy and childhood, physical
therapists can be instrumental
Mininder S. Kocher, MD, and Frederic Shapiro, MD
Vol 6, No 4, July/August 1998 233
in optimizing normal development
patterns as the infant develops
trunk control and functional limb
use. The orthopaedist is involved
in helping to obtain the greatest
degree of mobility possible and in
the treatment of fractures, which
can be frequent. When fractures
occur, one should use as little
immobilization as possible to prevent
overall deconditioning, worsening
the extent of osteopenia, and
increasing the risk of further fracture.
In severe OI, the multiplicity
of fractures, the underlying osteoporotic
bone, and the abnormal
mechanical stresses on malaligned
bones can lead to further fractures
and deformity, interfering with the
ability to stand and walk. External
support from orthoses or splints
may be necessary to optimize function.
Deformity that is impairing
function can be addressed surgically
by multiple osteotomies and
intramedullary fixation.
Fracture rates almost always decrease
dramatically after puberty,
but increases have been documented
in women after menopause and
in men after age 60. Pregnancy in
women with OI requires special
obstetric management due to
increased fracture risk, pelvic dysplasia,
and metabolic abnormalities.
Nonoperative treatment is the
mainstay of orthopaedic management
of OI. Depending on disease
severity, a comprehensive and progressive
program of mobilization
and bracing is pursued for patients
with ambulatory potential, and a
program of appropriate seating and
wheelchair locomotion is pursued
for nonambulatory patients. The
goal is to emphasize ultimate independent
function and to maximize
social integration.20-22 Lightweight
bracing can be helpful for external
structural support to promote
stance and locomotion and for the
prevention and treatment of fractures.
Pneumatic trouser splints
and vacuum pants have been introduced
to support fragile bones,
improve mobility, and maintain
alignment after fracture or closed
osteoclasis.23
Closed treatment methods are
the mainstay of fracture management.
Fractures generally heal,
often with exuberant callus but
with the same abnormal bone quality.
The difficulty in fracture management
lies in the prevention of
deformity and the vicious circle
associated with immobilizationÑ
deconditioning, osteoporosis, and
increased fracture risk. Lightweight
splints and braces are most
often used, with the emphasis on
early mobilization.
Operative intervention is indicated
for recurrent fractures or
deformity that impairs function.
The optimal age for surgical intervention
is controversial; some recommend
early intervention with
elongating rods, but traditional
management involves accepting
deformity from closed treatment
until the patient is about 5 years
old and then proceeding to corrective
osteotomies.
Various techniques for deformity
correction have been espoused,
including closed osteoclasis with
traction followed by pneumatic
splints (Morel technique), closed
osteoclasis with percutaneous
intramedullary nailing,24 multiple
corrective osteotomies with
intramedullary nailing (Sofield-
Millar technique)25,26 , and
osteotomies with elongating intramedullary
(Bailey-Dubow) rods.27,28

Leg deformity in a patient with type III OI. A, Preoperative AP radiograph
obtained at age 6 years demonstrates deformity. B, Postoperative film with leg in cast
shows multiple osteotomies (arrows) with intramedullary fixation. C, Film obtained after
healing of osteotomies.
A B C
Management must be highly individualized,
taking into account
personal experience, the severity of
the patientÕs deformity, the diameter
of the long bones, and the
advantages and complications of
each technique. Elongating rods
have a decreased replacement rate
when compared with nonelongating
rods; however, they are weaker;
traverse the physis; are technically
more demanding, as they
require a larger medullary canal
and central placement; and are
associated with complications
related to disassembly and nonelongation.
27,28
General principles in the surgical
management of OI include avoiding
surgery in patients under age 2
years, avoiding plate-and-screw fixation
in favor of intramedullary fixation,
and use of gentle technique
for muscle preservation and minimization
of soft-tissue bleeding.
Bone-holding clamps should be
avoided, as they can crush fragile
bone. Radiographic control is
essential, as the deformities are
often three-dimensionally complex,
necessitating different views.
When multiple osteotomies are
performed, the individual fragments
should be as long and
straight as possible. Placement of
osteotomies in diaphyseal regions
enhances stability with intramedullary
rods. Some bone shortening
may be necessary when there
are severe deformities, as the taut
soft-tissue structures on the concave
side can be stretched excessively
when deformity is corrected.
Reaming may occasionally be necessary
for rod placement. Violation
of the growth plate should be
avoided when possible. Immobilization
with casting or braces until
bone union is almost always necessary.
The anesthesiologist should be
aware of the increased risk of
malignant hyperthermia in patients
with OI. Anesthetic principles
include avoiding the use of atropine,
careful metabolic monitoring,
not insulating the patient with
large numbers of drapes, and
aborting the operation at the earliest
signs of hyperthermia.8 Patients
with OI may have platelet
and coagulation abnormalities, and
perivascular fragility due to collagen
abnormalities may predispose
to bleeding. Blood loss and insensible
losses due to hypermetabolism
should be carefully monitored.
Spinal deformity in patients with
OI is difficult to manage. Truncal
shortening of thoracolumbar spinal
segments can occur secondary to
collapse of osteopenic vertebrae. If
the patient is symptomatic, a soft
spinal orthosis is helpful. Scoliotic
and kyphoscoliotic curves often
progress rapidly. The soft, deformed
rib cage and truncal shortening
combine to render bracing
relatively ineffective, but it can be
helpful in mild forms of OI and as a
sitting aid for the nonambulator.
In milder forms of OI, bracing
can be utilized for curves of 20 to
40 degrees or kyphosis greater than
40 degrees. Spinal fusion has been
recommended for scoliotic curves
greater than 45 degrees to halt progression
(Fig. 7). For patients with
more severe involvement, bracing
is ineffective and can produce thoracic
cage deformity; fusion is recommended
for curves over 35
degrees, as these curves are most
often progressive and potentially
severe. There is a high incidence of
complications from spinal fusion in
OI, because internal fixation is limited
by poor bone quality, autogenous
iliac-crest bone graft is limited,
and patients have a propensity
to bleeding.3,29
Summary
Osteogenesis imperfecta is a remarkable
disorder. Recent clinical,
genetic, and molecular investiga-
Rapidly progressive spinal deformity in a 12-year-old child with type III OI. A,
Preoperative AP radiograph shows a 90-degree right thoracic curve with severe rib deformities
at the curve concavity. B, AP film obtained after spinal fusion with Luque instrumentation.
tions have characterized its heterogeneous
phenotypic and genotypic
features. In addition, insight has
been gained from investigations
into the altered collagen chemistry
and its effect on the structure and
function of bone.
Ongoing research holds great
promise for the treatment of OI. The
potential for gene therapy to increase
the synthesis of type I collagen
in mild variants and to correct
mutations in severe variants lies
ahead, but there are a great number
of technical difficulties to overcome.
Further understanding of how genotypic
mutations lead to abnormal
molecular structure and then abnormal
bone structure is essential.
As long as the potential for gene
therapy remains distant, welldesigned
controlled trials with systemic
treatment modalities are
needed. Ideally, these would direct
specific interventions to patients
with particular biochemical abnormalities,
recognizing the underlying
heterogeneity of the disorder.
The development of registries
including both phenotype and
genotype would catalog this new
classification of patients and would
facilitate defect-specific trials.
Development of comprehensive
treatment teams to address the
multiple health-care needs of OI
patients will ultimately help them
achieve goals of relative independence
and social integration.

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