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Osteogenesis Imperfecta, Pediatric

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Osteogenesis Imperfecta, Pediatric

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.

1 in 10,000 births

6 " 7:100,000 persons

- Serum calcium and phosphorus levels - Alkaline phosphatase - May be elevated after a fracture

- Pediatric endocrinologist or geneticist - Pediatric orthopedic surgeon - Fracture repair, rodding, osteotomies, spinal fusion

  • 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

Risk Factors

  • The majority of cases ( ’ ˆ 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 OIOI 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 osteopeniaType VIII: absence or severe deficiency of prolyl 3-hydroxylase activity due to mutations in the LEPRE1 geneType IX: moderate to severe OI caused by defects in the PPIB geneType 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.
  • 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 degradationCollagen fibrils are disorganizedAbnormal osteoid formationDecrease 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 matrixDecreased 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).
  • Procollagen molecules more susceptible to proteolytic degradation
  • Collagen fibrils are disorganized
  • Abnormal osteoid formation
  • Decrease in osteoid seams
  • Decreased bone formation during remodeling

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 fracturesLimbs deformed and shortSkull softRib deformities and pulmonary hypoplasia leading to respiratory insufficiency
  • Mild and moderate forms:General: short statureHead: triangular facies in type III OIEyes: blue or grey scleraeEars: hypoacusia (generally develops in adulthood)Teeth: ’ ˆ Ό50% with DI: deciduous teeth more severely affected than permanent teeth, enamel normal, teeth easily broken but no increase in cavities; malocclusionSpine: kyphoscoliosis; often associated with pectus carinatum or pectus excavatum. Barrel chest deformity common.Pelvis: trefoil pelvis, protrusio acetabuliExtremities: bowing of long bones, coxa vara deformity, cubitus varus, joint hypermobility
  • Intrauterine and perinatal fractures
  • Limbs deformed and short
  • Skull soft
  • Rib deformities and pulmonary hypoplasia leading to respiratory insufficiency
  • General: short stature
  • Head: triangular facies in type III OI
  • Eyes: blue or grey sclerae
  • Ears: hypoacusia (generally develops in adulthood)
  • Teeth: ’ ˆ 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

  • Serum calcium and phosphorus levelsNormal
  • Alkaline phosphataseMay 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.
  • Normal
  • May be elevated after a fracture
  • SkullWormian bones: detached portions of primary ossification centers in adjacent membranous bones; can be seen in other conditions
  • Long bonesFractures: varying stages of healingOsteopeniaBowing deformityMetaphyseal ends: honeycomb appearanceAcetabular protrusionPopcorn calcifications
  • SpineScoliosis "Codfish vertebrae "  due to compression fracturesAtlantoaxial subluxationSpondylolisthesis
  • Wormian bones: detached portions of primary ossification centers in adjacent membranous bones; can be seen in other conditions
  • Fractures: varying stages of healing
  • Osteopenia
  • Bowing deformity
  • Metaphyseal ends: honeycomb appearance
  • Acetabular protrusion
  • Popcorn calcifications
  • Scoliosis
  • "Codfish vertebrae "  due to compression fractures
  • Atlantoaxial subluxation
  • Spondylolisthesis
  • Once diagnosis is establishedFormal audiology assessmentDental evaluation if DIConsider screening for basilar impression with CT or MRI in more severe forms.Bone densitometry may be helpful.
  • 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 uteroHypophosphatasiaThanatophoric dysplasiaCampomelic dysplasiaAchondrogenesis
  • Infancy and childhoodChild abuseIdiopathic juvenile osteoporosisOsteoporosis-pseudoglioma syndromeCole-carpenter syndromeHajdu-Cheney syndromeBruck syndromeHypophosphatasiaLeukemiaOsteopenia related to prematurityGlucocorticoid-induced osteopeniaCushing diseaseHomocystinuriaImmobilizationAnticonvulsant therapy
  • Hyperplastic callus formation in OI type V may be confused with osteogenic sarcoma.
  • Hypophosphatasia
  • Thanatophoric dysplasia
  • Campomelic dysplasia
  • Achondrogenesis
  • 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

Treatment

Medication

  • Antiresorptive agents (bisphosphonates)Currently used in clinical trials and more widely in clinical practice in recent yearsMay improve bone mineral density, pain, and mobilityMay lessen fracture riskMost common side effects: flulike syndrome during initial treatment; hypocalcemia; delayed osteotomy healingLong-term side effects unknownTheoretically 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
  • 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

Additional Therapies

  • Intramedullary rodding with or without osteotomies: mainstay of care in severe casesOften performed as early as 18 months of ageShould weight-bear as soon as possible after surgeryMany nonambulatory patients are able to walk after osteotomies.
  • Spinal deformitiesSeen in ’ ˆ Ό90%Orthoses do not stop progression.Treatment: spinal fusion or halo gravity traction and posterior spondylodesis
  • Fracture treatmentBone mineral density can decline after fracture while immobilized.Postfracture physiotherapy critical
  • 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.
  • Seen in ’ ˆ Ό90%
  • Orthoses do not stop progression.
  • Treatment: spinal fusion or halo gravity traction and posterior spondylodesis
  • Bone mineral density can decline after fracture while immobilized.
  • Postfracture physiotherapy critical

Inpatient Considerations

  • For unstable fractures, such as femur fractures, spine instability
  • Depends on location of fracture and details of individual situation

Ongoing Care

Follow-up Recommendations

  • Pediatric endocrinologist or geneticistMedical management of OI
  • Pediatric orthopedic surgeonFracture repair, rodding, osteotomies, spinal fusion
  • PhysiotherapistPostoperative rehabilitation, orthotics, physical therapy to improve mobility and stability of bones and increase muscle strength
  • Psychologist/social workerAdjustments and accommodations at schoolIssues regarding self-esteem
  • Medical management of OI
  • Fracture repair, rodding, osteotomies, spinal fusion
  • Postoperative rehabilitation, orthotics, physical therapy to improve mobility and stability of bones and increase muscle strength
  • 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.