• OSTEOGENESIS IMPERFECTA

Earliest known case of osteogenesis imperfecta in a partially mummified infant’s skeleton from ancient Egypt now housed in the British Museum in London.

In 1835, Lobstein coined the term osteogenesis imperfecta

Other names for OI: Lobstein disease, brittle-bone disease, blue-sclera syndrome, and fragile-bone disease

Manifest itself with 1 or more of the following findings:

Blue sclerae Triangular facies Macrocephaly Hearing loss Defective dentition Barrel chest Scoliosis Limb deformities Fractures Joint laxity Growth retardation Constipation and sweating

Pathologic changes seen in all tissues in which type 1 collagen is an important constituent (eg, bone, ligament, dentin, and sclera)

Basic defect : qualitative or quantitative reduction in type 1 collagen

Mutations in genes encoding type 1 collagen affect the coding of 1 of the 2 genes

Mutations are either genetically inherited or new Inherited mutations : recurrence risk in subsequent

pregnancies of 50% if a parent is affected New mutations unpredictable recurrence risk

Quantitative defects of type 1 collagen : mutations on COL1A gene, production of premature stop codon or a microsense frame shift, which leads to mutant messenger RNA (mRNA) in the nucleus

Cytoplasm contains normal alpha1 mRNA; reduced amounts of structurally normal collagen produced

Mild form of disease

Qualitative defects of type 1 collagen: autosomal dominant mutations on either the COL1A or the COL1B gene, production of mixture of normal and mutant collagen chainstype 1 collagen thus formed is functionally impaired because of mutant chain

In bone :both endochondral and intramembranous ossification affected

Epiphysis and physis :broad and irregular, with disorganization of proliferative and hypertrophic zones ,loss of typical columnar arrangement, thinning of zone of calcified cartilage, deficiency of primary spongiosa of the metaphysis and delay of the secondary centers of ossification in the epiphysis.

Scoliosis and kyphosis Vertebral

bodies :wedged, translucent, and shallow

Thinning of the skull and multiple ossification centers (wormian bones) are present, particularly in the occiput

Epidemiology

Incidence : 1 case for every 20,000 live births

Equally common in males and females

Described in every human population in which skeletal dysplasias have been studied

No predilection for a particular race

History

Family history , but most cases due to new mutations

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 OI cannot be diagnosed with certainty in utero

Physical Examination

Clinical presentation depends on phenotype

Sillence classificatiom : 4 types on basis of clinical and radiologic features

Dentinogenesis imperfecta denoted as subtype B, whereas OI without dentinogenesis imperfecta is denoted as subtype A

Many cases of OI do not fit into the aforementioned categories; osteoporosis-pseudoglioma, Bruck syndrome, and Cole-Carpenter syndrome.

Osteoporosis-pseudoglioma syndrome : caused by mutations in gene encoding for low-density-lipoprotein receptor-related protein 5 (LRP5), with clinical features including blindness and bone fragility

Bruck syndrome: autosomal recessive condition caused by mutations in bone-specific collagen type 1 telopeptide lysyl hydroxylase enzyme, with clinical features that include congenital joint contractures and bone fragility

Cole-Carpenter syndrome : severe progressive form of OI, with associated multisutural craniosynostosis and growth failure

Complications

Repeated respiratory infections

Basilar impression caused by a large head, which causes brainstem compression

Cerebral hemorrhage caused by birth trauma

High risk for complications of anesthesia

Diagnostic Considerations

Differential diagnoses categorized into 3 stages of life:

Prenatal/neonatalPreschool/childhoodAdolescence/

adulthood

Conditions that should be considered in prenatal/neonatal stage include:

Jeune dystrophy Camptomelic dysplasia Chondrodysplasia punctata Chondroectodermal

dysplasia (Ellis–van Creveld syndrome)

Nonaccidental injury Hypophosphatasia

Preschool/childhood stage include:

Pyknodysostosis Hajdu-Cheney

syndrome Osteochondromatosis Nonaccidental injury

Differentiate between OI and child abuse

Keys to distinguishing OI from child : Metaphyseal corner fractures, which

are common in child abuse, rare in OI

In children with OI, fractures may continue to occur while they are in protective custody

Child abuse has nonskeletal manifestations (eg, retinal hemorrhage, visceral intramural hematomas, intracranial bleeds of various ages, pancreatitis, and splenic trauma)

Differential Diagnoses

Achondroplasia Menkes Kinky Hair Disease Glucocorticoid Therapy Cushing Syndrome Homocysteinemia McCune-Albright Syndrome Osteopetrosis Osteoporosis Pediatric Acute Lymphoblastic

Leukemia Rickets Scurvy Thanatophoric Dysplasia Wilson Disease

Laboratory Studies

Within reference ranges, and useful in ruling out other metabolic bone diseases

An analysis of type I, III, and V collagens synthesized by fibroblasts helpful

Collagen synthesis analysis : culturing dermal fibroblasts obtained during skin biopsy

Results are negative in syndromes resembling OI.

Tests

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS- PAGE)

2-Dimensional SDS-PAGE Cyanogen bromide

(CNBr) mapping Thermal stability studies An analysis of amino acid

composition of collagens

DNA blood testing for gene defects has an accuracy of 60-94%.

Prenatal DNA mutation analysis can be performed in pregnancies with risk of OI 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

Prenatal ultrasonography : Useful in evaluating OI types II

and III Detects limb-length

abnormalities at 15-18 weeks 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

Radiographic skeletal survey after birth Plain radiographs :3 radiologic categories of

OIA. Category I – Thin and gracile bonesB. Category II – Short and thick limbsC. Category III – Cystic changes

Radiologic features Fractures – Commonly, transverse fractures and those affecting

the lower limbs Excessive callus formation and popcorn bones - Multiple

scalloped, radiolucent areas with radiodense rims Skull changes - Wormian bones enlargement of frontal and

mastoid sinuses, and platybasia with or without basilar impression

Deformities of the thoracic cage - Fractured and beaded ribs and pectus carinatum

Pelvic and proximal femoral changes - Narrow pelvis, compression fractures, protrusio acetabuli, and shepherd’s-crook deformities of the femurs

Mild OI (type I) : thinning of the long bones with thin cortices,wormian bones,no deformity of long bones

Extremely severe OI (type II) : beaded ribs, broad bones, and numerous fractures with deformities of long bones

Moderate and severe OI (types III and IV) :cystic metaphyses, or a popcorn appearance of growth cartilage, deformities of long bones, old rib fractures, vertebral fractures

Dual x-ray absorptiometry (DEXA)

To assess bone mineral density in children with milder forms

Bone mineral density low in children and adults regardless of severity.

Bone mineral densities can be normal in infants with OI, even in severe cases

In pediatric patients, DEXA results not useful for predicting risk of fracture

No reliable published reference data regarding DEXA in infants available

Polarized light microscopy or microradiography used in combination with scanning electron microscopy to assess dentinogenesis imperfecta

With skin biopsy, collagen can be isolated from cultured fibroblasts and assessed for defects, with an accuracy of 85-87%

Bone biopsy : show changes in concentrations of noncollagenous bone proteins, such as osteonectin, sialoprotein, and decorin

Histologic Findings

• Width of biopsy cores, width of cortex, and volume of cancellous bone decreased in all types of OI

• Number and thickness of trabeculae reduced• Evidence of defects in modeling of external

bone in terms of size and shape production of secondary trabeculae by endochondral ossification, thickening of secondary trabeculae by remodeling

Treatment

No cureOrthotics: limited role, to stabilize lax joints

(eg, ankle and subtalar joints with ankle-foot orthoses) and to prevent progressive deformities and fractures.

Provide walking aids, specialized wheelchairs, and home adaptation devices to help improve patient’s mobility and function

Surgery

Pillar of treatment Only if it is likely to improve function and

treatment goals are clearIntramedullary rod placement, surgery to

manage basilar impression, and correction of scoliosis

Soft tissue surgery : lower-limb contractures, particularly those of the Achilles tendon

Painful bony deformities and recurrent fractures are typically treated with intramedullary stabilization with or without corrective osteotomies.

In children with severe forms of OI (eg, type III), rodding of lower extremities is performed to correct deformities and provide preventive protection around the time of first attempts at standing

Because bone is soft in OI, rods (eg, extendable Sheffield rods or Bailey-Dubow rods), pins (eg, Rush pins), and wires (eg, Kirschner wires) are used rather than solid nails, plates, and screws; the latter are associated with increased fracture risk above and below the device and with poor fixation

Rod placement use in femur and less commonly used in tibia, humerus, and forearm

In the prebisphosphonate era, extendable rods preferred to nonextendable ones in order to prevent bone bowing and bone growth beyond end of rod

Bailey-Dubow rods : high incidence of mechanical failures (eg, migration and disconnection of T-parts)

Sheffield rods and the Fassier-Duval modification commonly used

With decreased fragility of bone exposed to bisphosphonate, future role of extendable rods unclear

In long bones (eg, tibiae and radii), nonextendable rods such as Rush pins and Kirschner wires most often used

Complications of rod placement include breakage, rotational deformities, and migration

Extendable and nonextendable rods associated with similar complications

Rate of repeat surgical intervention is lower with extendable rods than with nonextendable rods

Surgery for basilar impressionBasilar invagination: result in long tract signs

and respiratory depression from direct compression of brainstem and upper cervical and cranial nerves

Treated with decompression and stabilization of the craniocervical junction; reserved for cases with neurologic deficiencies

Surgery for spinal deformities Bracing not effective in treating spinal deformities such

as scoliosis and kyphosis, because the rib cage is fragile to transfer brace pressure to vertebral column.

External pressure may worsen the chest deformities. Surgery is indicated when the following 2 conditions

are present:Acceptable bone qualityProgressive scoliosis with curvature of more than 45° if

OI is mild or more than 30-35° if OI is severe

Posterior spinal arthrodesis is the treatment of choice and is best performed with segmental instrumentation. Often, significant correction and stable fixation are not achieved. Pretreatment with pamidronate appears to improve the surgical outcome

Skilled administration of anesthetics and awareness of the limitations of surgery are essential prerequisites.

Anesthetic-related problems : Patients with relatively large heads and tongues and in

those with short necks Chest deformities may cause respiratory complications On the operating table, fractures may arise as a result

of the application of a blood pressure cuff or tourniquet, or they may occur during transfers

Watch for hyperthermia and increased sweating

Bisphosphonates Synthetic analogues of

pyrophosphate that inhibit osteoclast-mediated bone resorption on the endosteal surface of bone by binding to hydroxyapatite.

Unopposed osteoblastic new bone formation on the periosteal surface results in an increase in cortical thickness.

Cyclic intravenous (IV) pamidronate : Dosage of 7.5 mg/kg/y at 4- to 6-month intervals Dosages have ranged from 4.5 to 9 mg/kg/y, depending on the

protocol used Cyclic administration of IV pamidronate reduces the incidence of

fracture and increases bone mineral density Current evidence does not support the use of oral bisphosphonates in

patients with OI. IV pamidronate effective in babies and can be used to relieve pain in

severe cases Adverse effects of pamidronate : acute febrile reaction, mild

hypocalcemia, leukopenia, a transient increase in bone pain, and scleritis with or without anterior uveitis

Risedronate, alendronate, and zoledronic acid being assessed

Growth hormone: act on growth plate,stimulate osteoblast function, possibly via IGF-1 ,IGFBP-3

Teriparatide : Recombinant human form of parathyroid hormone

that increases number and activity of osteoblasts Potential use of teriparatide for the treatment of

OI remains to be defined

Cellular and Genetic Therapy

Bone marrow transplantation: potential future therapeutic modality for OI

Because there are very few MSCs in the average human bone marrow graft, approaches involving expansion of the number of MSCs in ex vivo cultures with subsequent infusion into the recipient needed

Such cell therapies usually result in somatic mosaicism, where normal and abnormal osteoblasts exist in the same body

Unfortunately, higher proportion of engrafted normal cells required to achieve the level of normal osteoblasts necessary to functionally correct the OI phenotype.

Use of immunosuppressive agents to prevent graft rejection and graft versus host reaction can itself damage bone

• Future approaches: autografting of genetically modified mutant osteoblasts, whereby mutant collagen gene is inactivated

• Gene therapy: being explored in animal models, but major obstacles remain, both because of intrinsic difficulties and because of dominant negative mechanism of disease

Diet and Activity

Nutritional evaluation and intervention paramount to ensure appropriate intake of calcium, phosphorus, and vitamin D

Caloric management important, particularly in adolescents and adults with severe forms of OI

Physical therapy, in form of comprehensive rehabilitation programs, directed toward improving joint mobility and developing muscle strength

In early infancy, gentle handling of babies by parents to prevent fractures, with frequent positional changes advised to prevent occipital flattening, torticollis, and frog-leg positioning of hips

When infant is crawling: upper-limb mobility, propelling a wheelchair or ambulating with walking aids

When child starts to stand: walking encouraged, both as exercise and as primary or secondary means of mobility

Weightbearing promoted in pool, on tricycles, and with walkers

Prone positioning to prevent hip flexion contractures; aided by strengthening of hip extensors and quadriceps.

Bisphosphonates have significantly improved the walking ability of children with severe forms of OI

Care of patients with OI multidisciplinary: occupational therapist, physical therapist, nutritionist, audiologist, orthopedic surgeon, neurosurgeon, pneumologist, and nephrologist, among others

Genetic counseling to parents of child with OI who plan to have more children

Prognosis

Morbidity and mortality vary widely, depending on genotype

Variability occurs between individuals with different mutations

Life expectancy of subjects with nonlethal OI appears same as that for the healthy population, except for those with severe respiratory or neurologic complications.

Although patients with lethal OI may die in perinatal period, individuals with extremely severe OI can survive until adulthood

Patient Education

Patients with OI: well motivated and keen to achieve as much as possible despite their physical limitations

Education extremely importantEducation of parents and families :to know

how to position child in crib and how to hold child so as to minimize risk of fractures while maintaining bonding and physical stimulation

Living with ostogenesis imperfecta

The tips reproduced below have been developed by the Osteogenesis Imperfecta Foundation for taking care of children with osteogenesis imperfecta.

Do not be afraid to touch or hold an infant with osteogenesis imperfecta, but be careful. To lift an infant with osteogenesis imperfecta, spread your fingers apart and put one hand between the legs and under the buttocks, and place the other hand behind the shoulders, neck, and head.

Never lift a child with osteogenesis imperfecta by holding him or her under the armpits.

Do not pull on arms or legs or, in those with severe osteogenesis imperfecta, lift the legs by the ankles to change a diaper.

Select an infant car seat that reclines. It should be easy to place or remove your child in the seat. Consider padding the seat with foam and using a layer of foam between your child and the harness.

Be sure your stroller is large enough to accommodate casts. Do not use a sling- or umbrella-type stroller

Follow your doctor's instructions carefully, especially with regard to cast care and mobility exercises. Swimming and walking are often recommended as safe exercises.

Adults with osteogenesis imperfecta should avoid activities such as smoking, drinking, and taking steroids because they have a negative impact on bone density.

Increasing awareness of child abuse and a lack of awareness about osteogenesis imperfecta may lead to inaccurate conclusions about a family situation. Always have a letter from your family doctor and a copy of your child's medical records handy.