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Osteogenesis Imperfecta

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Last Update: February 3, 2019.

Introduction

Osteogenesis imperfecta (OI) is a genetic disorder of connective tissues caused by an abnormality in the synthesis or processing of type I collagen.[1][2] It is also called brittle bone disease. It is characterized by an increased susceptibility to bone fractures and decreased bone density. Other manifestations include blue sclerae, dentinogenesis imperfecta, short stature, as well as deafness in adulthood. There are also reports of valvular insufficiencies and aortic root dilation. Milder manifestations include generalized laxity, easy bruising, hernias, and excess sweating.[3] Clinical manifestations range from mild with a nearly asymptomatic form to most severe forms (involving infants presenting with crumpled ribs, fragile cranium, and long bone fractures incompatible with life) resulting in perinatal mortality.[4]

Etiology

Osteogenesis imperfecta is a rare genetic disease. In the majority of cases, it occurs secondary to mutations in the COL1A1 and COL1A2 genes. More recently, there has been the identification of diverse mutations related to OI.[5]

OI classification according to International Society of Skeletal Dysplasias on the basis of mode of inheritance and genes involved.[6]

Osteogenesis Imperfecta / Type / Inheritance / Genes

Nondeforming OI (Type I) / AD / COL1A1, COL1A2 / X-linked / PLS3

Perinatal (type II) / AD, AR / COL1A1, COL1A2, CRTAP, LEPRE1, PPIB, BMP1   

Progressively deforming (type III) / AD, AR / COL1A1, COL1A2, CRTAP, LEPRE1, PPIB, FKBP10, SERPINH1, SERINF1, WNT1

Moderate (type IV) / AD, AR / COL1A1, COL1A2, CRTAP, FKBP10, SP7, SERPINF1, WNT1, TMEM38B

Calcification of interosseous membrane or hypertrophic callus (type V) / AD / IFITM5

Epidemiology

Osteogenesis imperfecta is a rare disease occurring in 1 in 15,000 to 20,000 births.[4] The population frequencies of type I OI has been reported to range between 2.35 to 4.7 in 100000 worldwide. Reports of the incidence of type II OI range between 1 in 40,000 to 1.4 in 100000 live births. The exact incidence of types III and IV OI is not known, although the incidence is much less common than type I.[7][8][9] In Shapiro's study,[10][11] the incidence of types congenita A, congenita B, tarda A, and tarda B were approximately 19%, 31%, 25%, and 25%, respectively.

Pathophysiology

Two pro-alpha-1 chains and one pro-alpha-2 chain make up type I collagen, which forms the main protein of extracellular membrane of skin, bones, tendons, etc., which creates a rigid triple helix structure. Each alpha chain consists of an amino-terminal pro-peptide and carboxyl-terminal pro-peptide and a central pro-peptide consisting of 338 repeats of glycine. Glycine is the smallest residue that can occupy the axial position of the triple helix.[12] Triple helix structure of type I collagen is possible because of the presence of glycine at every third amino acid residue. 

At least 90% of OI patients have a genetic defect resulting in quantitative and qualitative (or both) abnormalities in type I collagen molecule. This disorder is inheritable in an autosomal dominant, autosomal recessive or a spontaneous mutation pattern.[12][13] The autosomal dominant forms are caused by direct defects in type 1 collagen, while autosomal recessive forms are caused by non-collagenous proteins, which take part in post-translational modifications or triple helix formation.[4]

Defects involving type 1 collagen molecules: 

Frameshift mutations (involving premature stop codon in the affected allele) can result in a quantitative decrease in the amount of structurally normal type 1 collagen. When a patient is heterozygous for this condition, he may secrete half the normal amount of type 1 collagen [haplo-insufficiency; as seen in type IA OI in Sillence Classification].[9] Alternatively, errors in substitution or deletion involving a glycine peptide residue along the polypeptide chain can result in the production of structurally or qualitatively abnormal or less effectual collagen. The phenotypic expression of these defects depends on the position of substitution whether glycine substitutes at carboxy-terminal (severe form) or amino terminal (milder form) of the polypeptide chains.[14] Substitutions at the carboxy end of the peptide are potentially more serious owing to cross-linking of the triple helix beginning at the carboxy terminus of polypeptide chains. These patients with mutations of glycine residues affecting the quality of collagen chains (commonly identified defect in Sillence types II, III and IV types) develop more severe skeletal manifestations than patients with haploinsufficiency defects.[15]

Other mutations: 

Apart from type I collagen mutations, other genetic mutations producing autosomal recessive types of OI (types VI, VII, VIII, IX, X and XI) have also been described. These mutations may involve components that encode collagen 3-hydroxylation complex, which helps in the assembling of the triple helix. These recessive mutational types account for less than 5% of the cases of OI collectively.[15]

Histopathology

Generally, the defects involving decreased collagen type 1 secretion or secretion of abnormal collagen result in insufficient osteoid production.[16] Both enchondral and intramembranous ossification are affected. Thin, poorly organized bony trabeculae and collagen matrix, scanty spongiosa, a relative abundance of osteoblasts and osteoclasts, increased bone turnover; and broad, irregular physis with disorganized proliferative and hypertrophic zones, as well as thinned calcified zone are typical histological features.[17]

History and Physical

Two clinically useful classification systems of osteogenesis imperfecta have been described by Sillence et al.  and Shapiro et al.[7][18][10] In 1979, Sillence and Danks initially described four types of OI based on the clinical and genetic basis. They originally identified types I and IV as autosomal dominant and types II and III as autosomal recessive inheritance. More recent literature, however, has shown that true autosomal recessive inheritance is quite rare. Based on further research on the genetic defects involved, Cole further added types V to XI to the original Sillence Classification (type V with autosomal dominant and types VI to XI with autosomal recessive transmissions).[12][4]

Osteogenesis imperfecta classification based on phenotypic characteristics and mode of inheritance modified from Sillence et al. [9][6]:

Type I: Autosomal dominant (COL1A1 gene does not produce viable mRNA for procollagen); collagen amount is 50% reduced, however, the molecule is structurally normal. General manifestation shows generalized osteoporosis, abnormal bone fragility (fractures typically during the ambulatory years of child development and reduce bone maturity), blue sclera, conductive deafness, and mild stunting. IA (Normal Teeth), IB/IC(Dentinogenesis Imperfecta).

Type II: Originally classified as autosomal recessive; however recent work indicates that it follows a dominant negative inheritance (7% risk of disease in subsequent pregnancies), often as a result of spontaneous mutation. This form results in severe disruption in the qualitative function of the collagen molecule: perinatal lethal form. General manifestation demonstrates extreme bone fragility (accordion femur), delayed skull ossification, blue sclera, and perinatal death. Type IIA  has short and wide long bone with fractures, wide ribs with sparse fractures. II-B manifests with short and widened long bones with fractures, ribs with sparse fractures. II-C presents with thin long bones with fractures, thin ribs.[19][12]

Type III: Autosomal recessive or dominant negative inheritance; type I collagen alteration is both qualitative and quantitative. Most children with severe clinical manifestations belong to this category. General manifestation presents with blue sclera in infancy and returns to normal hue in adolescence. Moderate to severe bone fragility, coxa vara, multiple fractures and marked long bone deformities (more severe than type I with greater ambulation difficulties). These patients require intramedullary nailing prophylactically. Other specific features: Early onset scoliosis, triangular facies, frontal bossing, basilar invagination and extremely short stature.[3][20][13][21][22]

Type IV: Heterogenous group; autosomal dominant that also has qualitative and quantitative changes in type I collagen. More severe clinical manifestations than type I OI. General manifestation shows normal sclera, moderate to severe bone fragility and deformity of the long bones and spinal column, moderate to severe growth stunting. Type IV A presents with normal teeth while Type IV B shows dentinogenesis imperfecta.

Type V: Autosomal dominant; mutation in the gene encoding interferon-induced transmembrane protein-5 (IFITM5); histologically demonstrates a mesh-like appearance of the lamellar bone. It presents with mild to moderate degrees of severity. Specific features include normal sclera, the absence of dental involvement, calcification of interosseous membrane especially the forearm that can lead to secondary dislocation of radius, hypertrophic callus and a radiodense band near long bone physis are specific characteristics of this type.[23][24][25]

Type VI: Mutation involving SERPINF1 gene; characteristic histological presentation includes lamellar bone with fish scale pattern under a polarized light microscope and severe mineralization defects. This type presents with moderate to severe skeletal manifestations, normal sclera, and absence of dental involvement.

Types VII, VIII and IX[4][26][27]:

Common features: 1.A defect in prolyl 3-hydroxylation complex in the endoplasmic reticulum (ER) (which helps in the assembly of the triple helix). 2.Autosomal Recessive.

Specific defects include cartilage associated protein defects (CRTAP) - type VII, prolyl 3-hydroxylase (LEPRE1) - type VIII and peptidyl-prolyl cis-trans isomerase B (PPIB) - type IX.

General Manifestation: 

Type VII: Moderate to severe. Associated with rhizomelia and coxa vara.

Type VIII: Severe to lethal. It is associated with rhizomelia.

Type IX: Similar to types VII and VII; however no rhizomelia.

Types X and XI[27][28]

Common features: 1.A defect in collagen chaperones which accompany procollagen molecules from ER to Golgi apparatus. 2.Autosomal Recessive.

Specific defects: SERPINH1 - type X, FKBP10 - type XI.

General Manifestation: 

Type X: Severe bone dysplasia, dentinogenesis imperfecta, transient skin bullae, blue sclera, pyloric stenosis, and renal stones.

Type XI: Bone dysplasia, ligamentous laxity, scoliosis, and platyspondyly. Normal sclera and absence of dental involvement.

The pitfall of Sillence Classification: Significant variability in the severity of deformities and fractures within different classification categories. Less prognostic relevance.

Looser et al. (1906):

Classified OI into two types - OI congenita (presence of numerous fractures at birth); and OI tarda (fractures occur after perinatal period).

Shapiro's modification of Looser classification (4 types): Excellent practical application regarding prognostication for survival and ambulation.[10]

Congenita A (Incompatible with life) - Sustain fractures in utero or at birth; Radiographically, present with crumpled long bones, crumpled ribs, rib cage deformity, fragile skull.

Congenita B (Compatible with survival) - Sustain fractures in utero or at birth; Radiographically, present with more tubular long bones with funnelization in the metaphysis, normally formed ribs and no rib cage deformity.

Tarda A - Fractures before walking; Age of onset of fractures - not prognostic for ambulation.

Tarda B - First fracture after walking age; All patients usually ambulate.

Evaluation

It is of foremost importance to rule out non-accidental trauma in these patients presenting with multiple fractures.[29][30]

Diagnosis: Based on clinical and family history, bone mineral density (lumbar vertebra), bone biochemistry and radiographic features.[31]

The most common clinical finding is bone fragility present in a majority of OI types. Most of them have specific features as described by Van Dijk and Sillence.[32]

Four Major Clinical Features:

  • Decreased bone mass, increased bone fragility
  • Blue Sclera
  • Dentinogenesis imperfecta (Normal enamel with dentin abnormality)
  • Hearing loss
  • Other features include ligament laxity and increased joint mobility, short stature, and easy bruising.

Fractures in OI: Earlier the onset of fractures, the prognosis is poor.[33] [34] There is a possibility of hypertrophic callus during fracture healing (which may resemble osteosarcoma); however, the fractures on most occasions heal at the usual rate. Bony deformities can occur secondary to fractures: protrusio acetabuli, proximal varus or anterolateral bowing (femur), anterior bow (tibia), cubitus varus and other proximal forearm deformities are known to occur.[35] 

Facies in OI: Elfin facies, helmet head appearance.

Manifestations depend on the type of OI.

Laboratory: No commercially available diagnostic test is available due to a wide variety of genetic mutations. Laboratory values are typically within normal range — mildly elevated alkaline phosphatase (ALP).

Plain Radiograph: 

  • Head, neck, and Spine: wormian bones, basilar invagination, kyphoscoliosis (39 to 100%), platyspondyly
  • Chest: pectus excavatum or carinatum
  • Pelvis: protusio acetabuli, coxa vara
  • General: osteoporosis, lack of funneling of long bones, cortical thinning, hypertrophic callus formation, popcorn calcifications involving metaphysis and epiphysis, pseudoarthrosis at the site of fractures

Prenatal ultrasound: decreased calvarial ossification, shortened and angulated long bones, multiple bone fractures, a beaded appearance of ribs, polyhydramnios.[36]

Computed Tomography (CT)[37]:

  • Wormian bone
  • Basilar invagination
  • Otosclerosis
  • Long bone fractures

Magnetic Resonance Imaging (MRI): to evaluate basilar invagination

Fibroblast culturing to analyze type I collagen (positive in 80% of type IV) is used for confirmation of diagnosis in equivocal cases

Biopsy: 

  • Collagen analysis of a punch biopsy
  • Iliac crest biopsy which demonstrates a decrease in cortical widths and the volume of cancellous bone, with increased bone remodeling

Treatment / Management

Management varies with age, severity and functional status of patients.[38][39]

  • Mild disease: subtle restriction, avoid contact sports, treated for any fractures
  • Moderate to Severe disease: rehabilitation and orthopedic interventions, management of acute fractures and scoliosis
  • Severe form: an intramedullary rod with osteotomy used to correct severe bowing of long bones

Medical Management[40][41][42][43][44][45][46]

  • Sex hormones, sodium fluoride, calcium, calcitonin, magnesium oxide, vitamins C and D - attempted in the past with no or mixed results 
  • Bisphosphonates (intravenous pamidronate, oral alendronate) - have been demonstrated to be useful (decrease fracture risk, improve bone mineral density, improved ambulatory status) through their ability to reduce the osteoclastic resorption of bone in children with OI
  • Gene therapy (to correct defective COL1A1, COL1A2 genes) - still not available

Orthopedic management:

Goals - 

To ameliorate patient functional status, prevent deformity and disability, correct deformities and monitor for complications.

1. Orthotic treatment: orthosis, walking aids, wheelchairs

2. Management of long bone fractures

3. Management of long bone deformities: 

A. Infants and children[47][48][49][50]:  

  • Closed osteoclasis without intramedullary fixation
  • Closed osteoclasis with percutaneous intramedullary fixation
  • Open osteotomy with internal fixation (Sofield and Millar procedure) - Rush nail, Williams rod

B. Young adult patients

  • External fixation with circular or uniplanar constructs with osteotomy.

4. Prophylactic intramedullary rod for children who repeatedly fracture their long bones. Different types of rods according to bone size and skeletal maturity:

  • Osteotomy and fixation with telescoping rod (Bailey-Dubow rod, Sheffield rod, Fassier-Duval rod)
  • Osteotomy and fixation with a non-telescoping rod (Kirschner wire, Steinmann pin, Williams rod, push rod, other fixed-length rods)

5. Management of spinal deformities: basilar invagination, kyphoscoliosis, spinal fractures

Differential Diagnosis

Major differentials[29][30][51][52]

1. Congenital hypophosphatasia

2. Achondroplasia

3. Pyknodysostosis

4. Diffuse osteopenia in early stages of leukemia

5. Idiopathic juvenile osteoporosis

6. Child abuse or battered child syndrome

Prognosis

Varied across the diverse spectrum of the disease (previously discussed).[10]

Shapiro's classification (more than Sillence classification) is a good prognostic indicator (previously discussed). 

Age of onset of long bone fractures has been demonstrated as an important prognostic indicator for ambulatory ability (previously discussed).

Survival: The most significant indicators include the location of fractures, the severity of fractures and general radiographic appearance of the skeleton.

Engelbert et al. demonstrated that children who achieved independent sitting or standing or both by 12 years of age, were finally able to ambulate. 

Engelbert and co-workers also found that children who could achieve independent sitting or standing, or both, by the age of 12 months were likely to be able to walk.[53]

Complications

The following complication may present with osteogenesis imperfecta[54][55][56][57]

  1. Hyperplastic callus formation: Rare; differential diagnosis: osteogenic sarcoma - Management: conservative, palliative radiotherapy (caution: secondary malignancy), bisphosphonates
  2. Tumors: Osteogenic sarcoma
  3. Basilar invagination: Cranial nerve involvement, direct brain stem compression, altered cerebrospinal fluid (CSF) dynamics
  4. Malignant hyperthermia: Both the surgeon and anesthesiologist should keep in mind the possibility of malignant hyperthermia during anesthesia

Deterrence and Patient Education

It is of vital importance to educate the parent regarding the likelihood of survival; and what to expect regarding deformity, disability, and ambulatory capacity. Genetic counseling and prenatal screening (including ultrasonography) may be necessary during future pregnancies.  The parents should also receive counsel that the children, despite their orthopedic impairments, have normal intelligence and social abilities. Parents should also receive information regarding the need for caution against falls, to obviate recurrent fragility fractures.[58]

Antenatal diagnosis[3]:

Antenatal ultrasound - can demonstrate OI Sillence type II by 16 weeks of fetal age. Based on the severity of disease expression, Sillence types I, III and IV can also be diagnosable on imaging. 

Parents with a history of a fetus affected by OI type II carry a 2% to 7% risk of a similarly affected fetus in future pregnancies. Antenatal diagnosis can be made in such scenarios by DNA analysis of chorionic villus samples obtained by ultrasonographic imaging.

Enhancing Healthcare Team Outcomes

The management of osteogenesis imperfecta is challenging and complex.[58] The primary reason underlying the complexity of management is the wide variation in the phenotypic expression across the different spectra of the disease. The significant role of early diagnosis (clinical, imaging, biochemical, and genetic evaluation) and early risk stratification in the long-term management of the child can never be understated. The importance of multidisciplinary interventions over long term involving a family physician, pediatrician, endocrinologist, radiologist, orthopedic surgeon, neurosurgeon, anesthesiologist, orthotic expert, occupational therapist, physiotherapist, and nurse practitioner over different stages of management needs to be understood. The orthopedic surgeon gets involved in the prevention and management of fractures and deformities of extremities. Medical management with bisphosphonates can prevent fractures in children with recurrent fractures. A neurosurgeon may be involved in the management of upper cervical spine/craniocervical junction compressive pathologies or spinal deformities. The role of parent education on what to expect at different stages of disease management is also extremely significant. Nurse practitioners can play a vital role in imparting of holistic care to the patient, as well as provide needed support to the caregivers. Such interdisciplinary care can aid in meeting basic goals in the management of OI including melioration of patient's functional status, prevention of deformity and disability, correction of existing deformities and monitoring for possible complications.

Most of the current knowledge on the subject of OI has its basis in available level 3 to 5 evidence.

Questions

To access free multiple choice questions on this topic, click here.

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