Background

Osteogenesis imperfecta (OI) is disorder of congenital bone fragility caused by mutations in the
genes that codify for type I procollagen (ie, COL1A1 and COL1A2).

The following 4 types of osteogenesis imperfecta have been reported:[1]

 Type I - Mild forms

 Type II - Extremely severe
 Type III - Severe
 Type IV - Undefined

Precise typing is often difficult. Severity ranges from mild forms to lethal forms in the perinatal
period. In addition, several syndromes resemble osteogenesis imperfecta, with congenital bone
fragility in association with other distinctive clinical or histologic features. Examples of these
findings are shown in the images below.

Pathophysiology
Type I collagen fibers are found in the bones, organ capsules, fascia, cornea, sclera, tendons,
meninges, and dermis. Type I collagen, which constitutes approximately 30% of the human body
by weight, is the defective protein in osteogenesis imperfecta.

In structural terms, type I collagen fibers are composed of a left-handed helix formed by
intertwining of pro-alpha 1 and pro-alpha 2 chains. Mutations in the loci that encode these chains
cause osteogenesis imperfecta (ie, COL1A1 on band 17q21 and COL1A2 on band 7q22.1,
respectively). Other mutations may cause congenital bone fragility associated with distinctive
clinical or histologic features (eg, redundant callus formation, pseudoglioma, defective
mineralization of bone). These conditions have been grouped as syndromes resembling
osteogenesis imperfecta.

Qualitative defects (eg, an abnormal collagen I molecule) and quantitative defects (eg, decreased
production of normal collagen I molecules) are described. Of note, recent studies have reported
that quantitative defects can cause very severe (even lethal) syndromes resembling osteogenesis
imperfecta through posttranslational modifications of collagen.[2]

Cartilage-associated protein (CRTAP) is a protein required for prolyl 3-hydroxylation. Loss of

CRTAP in mice causes an osteochondrodysplasia characterized by severe osteoporosis and
decreased osteoid production. In humans, CRTAP mutations cause excess posttranslational
modification of collagen, and may be associated with syndromes resembling osteogenesis
imperfecta, including recessive forms of lethal syndromes resembling OI and syndromes
resembling osteogenesis imperfecta with redundant callus formation.

The most widely used classification of osteogenesis imperfecta published by Sillence et al in

1989 does not include an expanding group of conditions with congenital brittle bones that are not
caused by mutations in the collagen genes. In many cases, these disorders are diagnosed as
osteogenesis imperfecta; however, increasing evidence suggests that they represent a separate
nosologic entity.[1] Some syndromes resembling osteogenesis imperfecta (SROI) have been
described in the literature as osteogenesis imperfecta types V-VII, but further research
demonstrated that some of these so-called forms are not caused by mutations in the type I
procollagen genes. Syndromes resembling osteogenesis imperfecta are caused by mutations in
genes other than the type I procollagen genes. They present with congenital brittle bones and,
often, with other distinctive characteristics (eg, blindness, congenital contractures, redundant
callus formation). In most cases, these are recessive conditions.

Congenital brittle bones with rhizomelia

This particular form with short humerus and femora and recessive inheritance was only
described in a First Nations community of Quebec. Mutations in either of two components of the
collagen prolyl 3-hydroxylation complex (cartilage-associated protein [CRTAP] and prolyl 3-
hydroxylase 1 [P3H1]) cause this autosomal recessive syndromes resembling osteogenesis
imperfecta with delayed collagen folding. The severity in terms of fractures and disability is
moderate to severe. Fractures may be present at birth. In linkage studies, the genetic defect has
been mapped to the short arm of chromosome 3, where no genes codify type I procollagen.

Congenital brittle bones with redundant callus formation

These patients develop hyperplastic calluses in long bones after having a fracture or orthopedic
surgery that involves osteotomies. Mutations in the type I procollagen genes have not been found
in these patients. This form of syndrome resembling osteogenesis imperfecta is the result of
mutations of the CRTAP gene. Inheritance appears to be autosomal dominant.

The initial presentation often resembles that of osteogenesis imperfecta with bone fragility and
deformity, but these patients develop hard, painful, and warm swellings over long bones that
may initially suggest inflammation or osteosarcoma. Patients with this condition have white
sclera and normal teeth.

On radiographs, a redundant callus can be observed around some fractures. The size and shape of
the callus may remain stable for many years after a rapid growth period. Histomorphometric
studies reveal that the bone lamella are arranged in meshlike fashion, as opposed to the typical
parallel arrangement in patients with osteogenesis imperfecta.

A variant of this syndrome is called aspirin-responsible expansile bone disease.

Osteoporosis pseudoglioma syndrome

This condition is inherited in an autosomal recessive fashion. Bone fragility is mild to moderate.
Blindness is due to hyperplasia of the vitreous, to corneal opacity, and to secondary glaucoma.
The genetic defect has been identified and mapped to chromosomal region 11q12-13. The defect
is specifically in the LRP5 gene that encodes for the low-density lipoprotein receptor-related
protein 5.
Other ocular forms

At least 2 other forms with ocular involvement are described in the literature. One variant
includes optic atrophy, retinopathy, and severe psychomotor retardation; another variant includes
microcephaly and cataracts.

Congenital brittle bones with craniosynostosis and ocular proptosis (Cole-Carpenter

syndrome)

Two boys and one girl have been described with this particular form. In the boys, diagnosis was
made after several months of life, and they were apparently healthy at birth. They developed
craniosynostosis, hydrocephalus, ocular proptosis, facial dysmorphism, and several metaphyseal
fractures associated with generalized low bone density.

By adulthood, both boys were nonambulatory, with short stature, severe osteopenia, and bone
deformity. They had normal intellectual and neurologic development.

No specific mutation has been identified as responsible for this syndrome. Neurologic
development is normal in this form.

Congenital brittle bones with joint contractures (Bruck syndrome)

Patients with Bruck syndrome have congenital brittle bones that lead to repeated fractures, as
well as joint contractures and pterygia (arthrogryposis multiplex congenita). Wormian bones are
present.

Inheritance appears to be recessive. No mutations in the COL1A1 or COL1A2 genes were found
in 3 patients with Bruck syndrome who underwent procollagen mutation testing. The basic defect
was mapped to locus 17p12 (18-cM interval), where a bone telopeptidyl hydroxylase is located.

Congenital brittle bones with mineralization defect

This rare form is clinically indistinguishable from moderate-to-severe osteogenesis imperfecta.

Diagnosis is possible only by means of bone biopsy findings, in which a mineralization defect
affecting the bone matrix and sparing growth cartilage is evident. Patients have normal teeth, and
they do not have wormian bones. They have no radiologic signs of growth-plate involvement
despite the mineralization defect evident on bone biopsy. This form shares several characteristics
with fibrogenesis imperfecta ossium, and a mild form may be observed.

The pattern of inheritance is not clear, but cases in 2 siblings from healthy consanguineous
parents suggest gonadal mosaicism or a somatic recessive trait. The structure of the collagen
molecule appears to be normal, and no mutations of COL1A1 and COL1A2 genes have been
found.
Other recessive syndromes resembling osteogenesis imperfecta

Genetic studies of recessive syndromes resembling osteogenesis imperfecta reported in South

African blacks showed mutations that involved both the CRTAP gene and the leucine proline-
enriched proteoglycan 1 (LEPRE1) gene, which are both involved in collagen proline-3
hydroxylation. Cases of recessive lethal syndromes resembling osteogenesis imperfecta have
been found to be caused by mutations in the CRTAP gene.

Several other syndromes with congenital brittle bones have been described in humans since the
original publication describing syndromes resembling osteogenesis imperfecta as a class,
including the association of elastosis perforans serpiginosa and congenital bone fragility[3] and
the association of severe hypertelorism, midface prominence, prominent/simple ears, severe
myopia, borderline intelligence, and bone fragility.[4]

A lack of cyclophilin B with normal collagen folding has been described in 2 siblings with
congenital brittle bone disease without ryzomielia. They had a homozygous start-codon mutation
in the peptidyl-prolyl isomerase B gene (PPIB), which results in a lack of cyclophilin B (CyPB),
the third component of the complex. The patients' collagen had normal collagen folding and
normal prolyl 3-hydroxylation, suggesting that CyPB is not the exclusive peptidyl-prolyl cis-
trans isomerase that catalyzes the rate-limiting step in collagen folding, as was previously
thought.[5] Deficiency of cyclophilin B causes congenital brittle bones in mice.[6]

The syndrome resembling osteogenesis imperfecta model was also applied to animal models of
bone fragility.[7]

Epidemiology
Frequency

United States

The prevalence of OI is estimated to be 1 per 20,000 live births; however, the mild form is
underdiagnosed, and the actual prevalence may be higher.

International

Prevalences appear to be similar worldwide, although an increased rate has been observed in 2
major tribal groups in Zimbabwe.

Race

No differences based on race are reported.

Sex

No differences based on sex are reported.

Age

The age when symptoms (ie, fractures) begin widely varies. Patients with mild forms may not
have fractures until adulthood, or they may present with fractures in infancy. Patients with severe
cases present with fractures in utero.

History
Patients often have a family history of osteogenesis imperfecta (OI), but most cases are due to
new mutations.

 Patients most commonly present with fractures after minor trauma.

 In severe cases, prenatal screening ultrasonography performed during the second
trimester may show bowing of long bones, fractures, limb shortening, and decreased skull
echogenicity. Lethal osteogenesis imperfecta cannot be diagnosed with certainty in utero.
 Patients may bruise easily.
 Patients may have repeated fractures after mild trauma. However, these fractures heal
readily.
 Deafness is another feature. About 50% of patients with type I osteogenesis imperfecta
have deafness by age 40 years

Physical
Physical examination can vary depending on the severity. Degrees of severity may vary among
different affected members of the same family.

 Type I - Mild forms

o Patients have no long-bone deformity.
o The sclera can be blue or white. Blue sclera may also occur in other disorders,
such as progeria, cleidocranial dysplasia, Menkes syndrome, cutis laxa, Cheney
syndrome, and pyknodysostosis.
o Dentinogenesis imperfecta may be present.
o Over a lifetime, numbers of fractures can range from 1-60 or more.
o Height is usually normal in individuals with mild forms of osteogenesis
imperfecta.
o People with osteogenesis imperfecta have a high tolerance for pain. Old fractures
can be discovered in infants only after radiographs are obtained for other reasons
other than an assessment of osteogenesis imperfecta, and they can occur without
any signs of pain.
o Exercise tolerance and muscle strength are significantly reduced in patients with
osteogenesis imperfecta, even in the mild forms.
o Fractures are most common during infancy but may occur at any age.
o Other possible findings include kyphoscoliosis, hearing loss (at any age),[8]
premature arcus senilis, and easy bruising.
 Type II - Extremely severe
 o Type II is often (but not always) lethal.
o Blue sclera may be present.
o Patients may have a small nose, micrognathia, or both.
o All patients have in utero fractures, which may involved the skull, long bones,
and/or vertebrae.
o The ribs are beaded, and the long bones are severely deformed.
o Causes of death include extreme fragility of the ribs, pulmonary hypoplasia, and
malformations or hemorrhages of the CNS.
 Type III - Severe
o Patients may have joint hyperlaxity, muscle weakness, chronic unremitting bone
pain, and skull deformities (eg, posterior flattening) due to bone fragility during
infancy.
o Deformities of upper limbs may compromise function and mobility.
o The presence of dentinogenesis imperfecta is independent of the severity of the
osteogenesis imperfecta.
o The sclera have variable hues.
o In utero fractures are common.
o Limb shortening and progressive deformities can occur.
o Patients may have a triangular face with frontal bossing. Malocclusion is
common.
o Basilar invagination is an uncommon but potentially fatal occurrence in
osteogenesis imperfecta.
o Vertigo is common in patients with severe osteogenesis imperfecta.
o The incidence of congenital malformations of the heart in children with
osteogenesis imperfecta is probably similar to that of the healthy population.
o Hypercalciuria may be present in about 36% of patients with osteogenesis
imperfecta but does not appear to affect renal function.
o Respiratory complications secondary to kyphoscoliosis are common in individuals
with severe osteogenesis imperfecta.
o Constipation and hernias are also common in people with osteogenesis
imperfecta.
 Type IV - Undefined
o This type of osteogenesis imperfecta is not clearly defined.
o Whether patient have normal height or whether scleral hue defines the type has
not been established in consensus.
o Dentinogenesis imperfecta may be present. Some have suggested that this sign
can be used to divide type IV osteogenesis imperfecta into subtypes a and b.
o Fractures usually begin in infancy, but in utero fractures may occur. The long
bones are usually bowed.

Causes
 Osteogenesis is an inherited disorder.
 In almost all cases, mode of inheritance in osteogenesis imperfecta is dominant or
involves a new dominant mutation, regardless of the clinical form of osteogenesis
imperfecta observed.
  A recessive pattern of inheritance has been demonstrated in some families from South
Africa.
 Some have proposed possible germ-cell mosaicism as an explanation for cases occurring
in families with healthy parents that have more than one child with osteogenesis
imperfecta.
 Syndromes resembling osteogenesis imperfecta (SROI) are usually inherited in recessive
fashion.

Laboratory Studies
 Results from routine laboratory studies in patients with osteogenesis imperfecta (OI) are
usually within reference ranges and they are useful in ruling out other metabolic bone
diseases.
 Collagen synthesis analysis is performed by culturing dermal fibroblasts obtained during
skin biopsy. The occurrence of false-negative results is not clear, although the rate may
be about 15%. Results are negative in syndromes resembling osteogenesis imperfecta.
 Prenatal DNA mutation analysis can be performed in pregnancies with risk of
osteogenesis imperfecta to analyze uncultured chorionic villus cells. Samples are
obtained during chorionic villus sampling performed under ultrasonographic guidance
when a mutation in another member of the family is already known.
 Bone mineral density, as measured with dual-energy x-ray absorptiometry (DEXA), is
low in children and adults with osteogenesis imperfecta despite the severity. Bone
mineral densities can be normal in infants with osteogenesis imperfecta, even in severe
cases. In pediatric patients, DEXA results are not useful for predicting the risk of
fracture. No reliable published reference data regarding DEXA in infants is available.

Imaging Studies
 Obtain a radiographic skeletal survey after birth.
o In mild (type I) osteogenesis imperfecta, images may reveal thinning of the long
bones with thin cortices. Several wormian bones may be present. No deformity of
long bones is observed.
o In extremely severe (type II) osteogenesis imperfecta, the survey may reveal
beaded ribs, broad bones, and numerous fractures with deformities of the long
bones. Platyspondylia may also be revealed.
o Moderate and severe (types III and IV) osteogenesis imperfecta, Imaging may
reveal 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 can be used to detect limb-length abnormalities at 15-18 weeks'
gestation.
o Mild forms may result in normal sonogram findings.
 o Features include supervisualization of intracranial contents caused by decreased
mineralization of calvaria (also calvarial compressibility), bowing of the long
bones, decreased bone length (especially of the femur), and multiple rib fractures.

Histologic Findings
 The width of biopsy cores, the width of the cortex, and the volume of cancellous bone are
decreased in all types of osteogenesis imperfecta. The number and thickness of trabeculae
are reduced.
 Samples may show evidence of defects in modeling of external bone in terms of the size
and shape, the production of secondary trabeculae by endochondral ossification, and the
thickening of secondary trabeculae by remodeling. Therefore, osteogenesis imperfecta
might be regarded as a disease of the osteoblast.[9]
 Bone formation is quantitatively decreased, but the quality of the bone material is
probably most important in the pathogenesis of the diseas

Medical Care
Because osteogenesis imperfecta (OI) is a genetic condition, it has no cure.

 Cyclic administration of intravenous pamidronate reduces the incidence of fracture and

increases bone mineral density, while reducing pain and increasing energy levels.[10]
Doses vary from 4.5-9 mg/kg/y, depending on the protocol used.
 Current evidence does not support the use of oral bisphosphonates in patients with
osteogenesis imperfecta. Alendronate decreases predicted material properties and has
detrimental effects on osteoblasts and bone formation in mice with osteogenesis
imperfecta. Risedronate may have some effect in reducing fractures in patients with
osteogenesis imperfecta.[11]
 A preclinical study demonstrated that RANKL inhibition improves density and some
geometric and biomechanical properties of the oim/oim mouse bone but does not
decrease fracture incidence when compared with placebo.[12]
 Nutritional evaluation and intervention are paramount to ensure appropriate intake of
calcium and vitamin D. Caloric management is important, particularly in adolescents and
adults with severe forms of osteogenesis imperfecta.
 In utero transplantation of adult bone marrow has been shown to decrease perinatal
lethality in a murine model of osteogenesis imperfecta.

Surgical Care
Orthopedic surgery is one of the pillars of treatment for patients with osteogenesis imperfecta.[13]
Surgical interventions include intramedullary rod placement, surgery to manage basilar
impression, and correction of scoliosis.

 Intramedullary rod placement

 o In patients with bowed long bones, intramedullary rod placement may improve
weight bearing and, thus, enable the child to walk at an earlier age that he or she
might otherwise. Use of the new extensible Fassier-Duval rods has shown
promising results in these patients.
o In children appropriately treated with bisphosphonates, the percutaneous
technique of multiple osteotomy with intramedullary fixation is safe and effective.
o An experienced team can perform as many as 4 rod procedures in the long bones
of the lower extremities in one surgical session.
o Fractures heal normally in about 85% of patients with osteogenesis imperfecta.
o Postoperative immobilization is significantly shortened with this technique.
Prolonged immobilization after a fracture must be avoided.
 Surgery for basilar impression: This procedure is reserved for cases with neurologic
deficiencies, especially those caused by compression of brainstem and high cervical cord.
A team of orthopedic surgeons and neurosurgeons is required.
 Correction of scoliosis: Correction of scoliosis may be difficult because of bone fragility.
Spinal fusion may be helpful. Pretreatment with pamidronate appears to improve the
surgical outcome.

Consultations
 Care of patients with osteogenesis imperfecta is multidisciplinary. Team members may
include an occupational therapist (OT), a physical therapist (PT), nutritionist, an
audiologist, an orthopedic surgeon, neurosurgeon, pneumologist, and nephrologist,
among others.
 Offer genetic counseling to the parents of a child with osteogenesis imperfecta who plan
to have more children. During genetic counseling, the possibility of germline mosaicism
must be discussed.

Diet
 Adequate calcium, vitamin D, and phosphorus intake are paramount.
 Caloric management is necessary in nonambulatory patients with severe osteogenesis
imperfecta.

Activity
 Parents need special instructions in handling affected children.
 Parents need to know how to position the child in the crib and how hold the child to avoid
causing fractures while maintaining bonding and physical stimulation.

Further Outpatient Care

 Physical therapy in osteogenesis imperfecta (OI)
 o Therapy should be directed toward improving joint mobility and developing
muscle strength
o Overall, emphasize the achievement of functional ability.
o Independence is the main objective of therapy.
 Periodic nutritional evaluation and intervention
 Periodic evaluation and intervention by an occupational therapist (OT) and/or a physical
therapist (PT)

Complications
 Repeated respiratory infections are complications of severe osteogenesis imperfecta.
 Basilar impression caused by a large head, which causes brainstem compression, is the
major neurologic complication in a child with osteogenesis imperfecta. This is most
commonly observed in children with very severe osteogenesis imperfecta.
 Cerebral hemorrhage caused by birth trauma is another possible complication.
 Patients with osteogenesis imperfecta should be considered to be at high risk for
complications of anesthesia, although they are not particularly prone to have malignant
hyperthermia. Patients with osteogenesis imperfecta have a high basal metabolism that
may cause hyperthermia during anesthesia but is almost never malignant. In fact, only
one case of malignant hyperthermia in a child with osteogenesis imperfecta is described
in the literature, and that particular patient had a family history of malignant
hyperthermia.

Prognosis
 The life expectancy of subjects with nonlethal osteogenesis imperfecta appears to be the
same as that for the healthy population, except for those with severe osteogenesis
imperfecta with respiratory or neurologic complications.
 Patients with lethal osteogenesis imperfecta may die in the perinatal period, but
individuals with extremely severe osteogenesis imperfecta can survive until adulthood.

 CONTRIBUTOR INFORMATION AND DISCLOSURES

 Author
 Horacio Plotkin, MD, FAAP Adjunct Associate Professor of Pediatrics and Orthopedic
Surgery, University of Nebraska School of Medicine

Horacio Plotkin, MD, FAAP is a member of the following medical societies: American
Academy of Pediatrics and American Society of Human Genetics

Disclosure: Enobia Pharma Salary Management position

 Chief Editor
 Bruce Buehler, MD Professor, Department of Pediatrics and Genetics, Director RSA,
University of Nebraska Medical Center
 Bruce Buehler, MD is a member of the following medical societies: American Academy
for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics,
American Association on Mental Retardation, American College of Medical Genetics,
American College of Physician Executives, American Medical Association, and
Nebraska Medical Association

Disclosure: Nothing to disclose.

 Additional Contributors
 Erawati V Bawle, MD, FAAP, FACMG Retired Professor, Department of Pediatrics,
Wayne State University School of Medicine

http://emedicine.medscape.com/article/947588-overview