Basics
Description
Osteogenesis imperfecta (OI) is a genetic connective tissue disorder affecting primarily bones and soft tissues, characterized by bone fragility and susceptibility to bone fractures.
- Clinical severity is widely varied and dependent in part on the genetic etiology.
- Typical symptoms can include recurrent fractures, bone and/or spine deformities, short stature, blue or grey sclerae (occurring in approximately 80% of cases), dentinogenesis imperfecta (DI; occurring in approximately 40% of cases), and joint hypermobility.
Epidemiology
Incidence
1 in 10,000 births
Prevalence
6 " 7:100,000 persons
Risk Factors
Genetics
- The majority of cases ( ’ Ό85%) are due to autosomal dominant mutations in the genes encoding type I collagen, COL1A1 and COL1A2.
- Traditionally, OI has been classified due to clinical presentation, as initially described by Sillence. However, in the last decade, new dominant and recessive forms caused by mutations in several different genes have been described, which has altered the classification of OI. Modified classification typing is noted in parentheses below:
- Type I (classic nondeforming OI with blue sclerae): usually normal stature, fractures infrequent, and usually in prepubertal years. No bowing of long bones. Blue sclerae. Early hypoacusia common.
- Type II (perinatally lethal OI): death usually in perinatal period due to pulmonary hypoplasia. Intrauterine fractures, shortened long bones, and blue sclerae are common.
- Type III (progressively deforming OI): severely shortened stature, severe deformities of long bones, prevalent vertebral fractures, scoliosis, chest deformities. Characteristic triangular face.
- Type IV (common variable OI with normal sclerae): DI common, short stature, bowing of long bones, vertebral fractures, scoliosis, and joint laxity. Patients are usually ambulatory. Sclerae are usually normal hue.
- Other clinical forms of OI
- OI with calcification in interosseous membranes (type V): autosomal dominant mutations of IFITM5 gene. Patients can develop hyperplastic calluses in long bones after fracture causing tender, firm swellings over bones. Blue sclerae and DI not common.
- Type VI: rare form of recessive OI due to mutations in SERPINF1 gene causing severe matrix mineralization defect. No blue sclerae, DI, or wormian bones. Rhizomelic shortening of extremities.
- Type VII: recessive mutation of CRTAP gene causing rhizomelia, early fractures, and osteopenia
- Type VIII: absence or severe deficiency of prolyl 3-hydroxylase activity due to mutations in the LEPRE1 gene
- Type IX: moderate to severe OI caused by defects in the PPIB gene
- Type X and XI: chaperone defects caused by SERPINH1 or FKBP10 mutations. Type XI due to FKBP10 mutations can cause progressively deforming OI or Bruck syndrome.
Pathophysiology
- Mutations in COL1A1 or COL1A2 cause altered triple-helical collagen structure leading to abnormal collagen fibrils.
- Procollagen molecules more susceptible to proteolytic degradation
- Collagen fibrils are disorganized
- Abnormal osteoid formation
- Decrease in osteoid seams
- Recessive OI is caused by defects in genes whose products interact with type I collagen leading to many of the same cellular features, although the precise pathomechanisms are as yet incompletely understood.
- Osteoblasts: increased osteoblast cellularity; however, reduction in differentiated cells capable of making mineralized matrix
- Decreased bone formation during remodeling
- Osteoclasts: increased osteoclast number to remove defective matrix
- Growth retardation: Disruption of balance between bone formation and resorption is more pronounced during periods of rapid linear growth (i.e., childhood, puberty).
Etiology
- Failure of normal maturation of procollagen to type 1 collagen and failure of normal collagen cross-linking
- Abnormality of collagen production and organization
Diagnosis
History
- Widely varied; may include recurrent fractures including fractures with little or no predisposing trauma
- May have positive family history, particularly if condition is due to an autosomal dominant mutation
Physical Exam
- Severe congenital forms:
- Intrauterine and perinatal fractures
- Limbs deformed and short
- Skull soft
- Rib deformities and pulmonary hypoplasia leading to respiratory insufficiency
- Mild and moderate forms:
- General: short stature
- Head: triangular facies in type III OI
- Eyes: blue or grey sclerae
- Ears: hypoacusia (generally develops in adulthood)
- Teeth: ’ Ό50% with DI: deciduous teeth more severely affected than permanent teeth, enamel normal, teeth easily broken but no increase in cavities; malocclusion
- Spine: kyphoscoliosis; often associated with pectus carinatum or pectus excavatum. Barrel chest deformity common.
- Pelvis: trefoil pelvis, protrusio acetabuli
- Extremities: bowing of long bones, coxa vara deformity, cubitus varus, joint hypermobility
Diagnostic Tests & Interpretation
Lab
- Serum calcium and phosphorus levels
- Alkaline phosphatase
- May be elevated after a fracture
- Type I collagen N-telopeptide normalized to urinary creatinine (NTx/uCr) highest in type III OI patients
- Diagnosis typically by DNA sequencing of genes implicated in OI from peripheral blood or cultured fibroblasts or analysis of collagen synthesis, structure, and electrophoretic mobility in cultured skin fibroblasts from skin biopsy.
Imaging
- Skull
- Wormian bones: detached portions of primary ossification centers in adjacent membranous bones; can be seen in other conditions
- Long bones
- Fractures: varying stages of healing
- Osteopenia
- Bowing deformity
- Metaphyseal ends: honeycomb appearance
- Acetabular protrusion
- Popcorn calcifications
- Spine
- Scoliosis
- "Codfish vertebrae " due to compression fractures
- Atlantoaxial subluxation
- Spondylolisthesis
Diagnostic Procedures/Other
- Once diagnosis is established
- Formal audiology assessment
- Dental evaluation if DI
- Consider screening for basilar impression with CT or MRI in more severe forms.
- Bone densitometry may be helpful.
Differential Diagnosis
- In utero
- Hypophosphatasia
- Thanatophoric dysplasia
- Campomelic dysplasia
- Achondrogenesis
- Infancy and childhood
- Child abuse
- Idiopathic juvenile osteoporosis
- Osteoporosis-pseudoglioma syndrome
- Cole-carpenter syndrome
- Hajdu-Cheney syndrome
- Bruck syndrome
- Hypophosphatasia
- Leukemia
- Osteopenia related to prematurity
- Glucocorticoid-induced osteopenia
- Cushing disease
- Homocystinuria
- Immobilization
- Anticonvulsant therapy
- Hyperplastic callus formation in OI type V may be confused with osteogenic sarcoma.
Treatment
Medication
- Antiresorptive agents (bisphosphonates)
- Currently used in clinical trials and more widely in clinical practice in recent years
- May improve bone mineral density, pain, and mobility
- May lessen fracture risk
- Most common side effects: flulike syndrome during initial treatment; hypocalcemia; delayed osteotomy healing
- Long-term side effects unknown
- Theoretically could be associated with atypical fractures and jaw osteonecrosis
- Adequate calcium (varies with age) and vitamin D intake (400 " 1,000 IU daily)
- Anabolic agents (growth hormone, insulin-like growth factor 1 [IGF-1], parathyroid hormone [PTH]): not considered routine treatment options, note PTH has black box warning now for pediatric indications
- Gene therapy: currently being developed; not yet available
Additional Therapies
General Measures
- Intramedullary rodding with or without osteotomies: mainstay of care in severe cases
- Often performed as early as 18 months of age
- Should weight-bear as soon as possible after surgery
- Many nonambulatory patients are able to walk after osteotomies.
- Spinal deformities
- Seen in ’ Ό90%
- Orthoses do not stop progression.
- Treatment: spinal fusion or halo gravity traction and posterior spondylodesis
- Fracture treatment
- Bone mineral density can decline after fracture while immobilized.
- Postfracture physiotherapy critical
Inpatient Considerations
Initial Stabilization
Emergency care
- For unstable fractures, such as femur fractures, spine instability
- Depends on location of fracture and details of individual situation
Ongoing Care
Follow-up Recommendations
Patient Monitoring
Multidisciplinary approach
- Pediatric endocrinologist or geneticist
- Pediatric orthopedic surgeon
- Fracture repair, rodding, osteotomies, spinal fusion
- Physiotherapist
- Postoperative rehabilitation, orthotics, physical therapy to improve mobility and stability of bones and increase muscle strength
- Psychologist/social worker
- Adjustments and accommodations at school
- Issues regarding self-esteem
Patient Education
- Techniques for safe handling, protective positioning, and safe movement are taught to parents.
- Physical education at school should be strongly encouraged, but children should not participate in contact sports. An individualized program may be necessary depending on OI severity.
Prognosis
- Largely depends on severity of OI
- In general, the earlier the fractures occur, the more severe the disease.
- Tendency toward improvement after somatic growth is complete in adolescence with relatively lower bone removal and less frequent fractures.
- Future therapeutic options including gene therapy hold promise for improved treatment.
Complications
- Pathologic fractures
- Scoliosis
- Cardiorespiratory problems (restrictive lung disease in severe cases with severe kyphoscoliosis, aortic dilatation, mitral valve prolapse, aortic regurgitation)
- Hearing loss
- Short stature
- Basilar impression: descent of the skull on the cervical spine; may progress to brainstem compression or obstructive hydrocephalus
Additional Reading
- Bishop N, Adami S, Ahmed SF, et al. Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382(9902):1424 " 1432. [View Abstract]
- Byers PH, Pyott SM. Recessively inherited forms of osteogenesis imperfecta. Annu Rev Genet. 2012;46(1):475 " 497. [View Abstract]
- Glorieux FH, Moffatt P. Osteogenesis imperfecta, an every-expanding conundrum. J Bone Miner Res. 2013;28(7):1519 " 1522. [View Abstract]
- Marini JC, Blissett AR. New genes in bone development: what 's new in osteogenesis imperfecta. J Clin Endocrinol Metab. 2013;98(8):3095 " 3103. [View Abstract]
- Morello R, Bertin TK, Chen Y, et al. CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006; 127(2):291 " 304. [View Abstract]
- Sillence DO. Osteogenesis imperfecta: an expanded panorama of variants. Clin Orthop Relat Res. 1981;1(159):11 " 25. [View Abstract]
- Steiner RD, Adsit J, Basel D. COL1A1/2-related osteogenesis imperfecta. GeneTests Web site. http://www.genetests.org. Accessed March 11, 2015.
Codes
ICD09
- 756.51 Osteogenesis imperfecta
ICD10
- Q78.0 Osteogenesis imperfecta
SNOMED
- 78314001 Osteogenesis imperfecta (disorder)
- 385482004 osteogenesis imperfecta type I (disorder)
- 205496008 osteogenesis imperfecta type II (disorder)
- 385483009 osteogenesis imperfecta type III (disorder)
- 63890001 Osteogenesis imperfecta with blue sclerae AND dentinogenesis imperfecta (disorder)
FAQ
- Q: What is the typical life expectancy for persons with OI?
- A: Infants with perinatal/lethal (type II) OI do not survive the perinatal period and often die within the first 48 hours of life. For mild and moderate OI, life expectancy is normal. Life expectancy for patients with severe (type III) OI is widely variable and can be shortened by kyphoscoliosis contributing to restricted lung disease.
- Q: How is OI inherited?
- A: OI is often inherited in an autosomal dominant manner. New mutations are not uncommon, and this often provides the explanation for lethal cases of OI in families with no history of OI. More recently, autosomal recessive forms of OI (mainly severe and lethal) have been described.
- Q: How is OI differentiated from child abuse?
- A: Differentiation of OI from child abuse is usually straightforward once the history, physical examination, radiographic findings, and family history are carefully considered. However, in difficult cases, genetic and/or biochemical testing may be useful.