Osteogenesis Imperfecta

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Original Editors - Barrett Mattingly from Bellarmine University's Pathophysiology of Complex Patient Problems project.

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Definition/Description

Osteogenesis imperfecta (OI) is a rare genetic disorder of the synthesis of collagen that affects bone and connective tissue. Osteogenesis imperfecta can also be referred to as brittle bone disease. OI can occur by both inheritence and spontaneous genetic mutation. Osteogenesis imperfecta has been linked to over 150 genetic mutations that all take affect on the genes COL1A1 and COL1A2, which are the genes that make up type I collagen. The mutation can either cause collagen production that is too low, or cause abnormal polypeptide chains that is unable to properly form type I collagen. There are four primary types of osteogenesis imperfecta that are described by the Sillence Classification of Osteogenesis Imperfecta.

"Sillence Classification of Osteogenesis Imperfecta

Type I (most common form)

• Mildest form of OI
• Mild to moderate fragility without deformity
• Most fractures occur before puberty
• Associated with blue sclerae, triangular face, hearing loss (beginning in twenties or thirties), easy bruising

Type II

• Most severe form of OI (perinatla lethal)
• Stillbirth or death during infancy or early childhood
• Extreme fragility of connective tissue
• Multiple in utero fractures
• Usually intrauterine growth retardation
• Severe bone deformity
• Soft, large cranium
• Micromelia: long bones crumpled and bowed; ribs beaded

Type III

• Moderately Severe
• Progressive deformities
• Scoliosis
• Triangular face, large skull
• Severe osteoporosis
• Severe fragility of bones; usually in utero fractures
• Factures heal with deformity and bowing
• Associated with tinted sclerae (blue, purple, or grey)
• Extremely short stature
• Usually wheelchair bound by teenage years

Type IV

• Variable but usually milder course; normal or near-normal lifespan
• Mild to moderate skeletal fragility and osteoporosis (more severe than type I)
• Associated with bowing of long bones
• Barrel-shaped rib cage
• Bones fracture easily before puberty; some children improve at puberty
• Light or normal sclerae; may or may not have moderately short stature and joint hyperextensibility"

Prevalence

Currently it is estimated that there are around 30,000 to 50,000 people in the United States living with osteogenesis imperfecta.The majority of kids with osteogenesis imperfecta inherit the genetic mutation from one of their parents. A parent that carries the OI genetic mutation has a 50% chance of passing this defect to their children. Around 25% fall in the category of children who have had spontaneous gene mutation leading to the diagnosis of OI. Osteogenesis imperfecta type I is the most common and has been found to be the type for around 50% of the people that have OI. The incidence for OI in the United States is about 1 in 20,000 people and around 6 to 7 in 100,000 people worldwide.

Characteristics/Clinical Presentation

Due to the different classifications, a patient with osteogenesis imperfecta can present anywhere from appearing normal with fractures that occur occasionally, to someone very small in stature with deformities to both the spine and long bones throughout the body. The clinical presentation of patients with OI is easier to picture when broken down into the four primary classifications.

Type I

• Due to only 50% of the collagen being produced, the patient's bones are predisposed to fracture. Most fractures in this classification occur before the child reaches puberty.
  
• Lax Joints
  
• Low muscle tone
  
• Tinted sclerae that may appear to be slightly blue, grey, or purple
  
• Possible scoliosis
  
• Stature should not be affected much, if at all
  
• Possible hearing loss that usually occurs in the third or fourth decade of life
  
• Triangular shaped face
  
• Very mild to no bony deformities
  
• Teeth may be brittle and easily broken
  

Type II

• Due to only 20% of the normal amount of collagen being produced due to malformation, this is the most severe type of OI.
• Usually results in stillbirth or death occuring in the early years of childhood. There have been a few people with type II OI that have survived into young adulthood.
• Respiratory problems that can lead to death
• Severe bone deformities
• Multiple in utero fractures
• Soft, large cranium
• Micromelia: long bones that are crumpled and bowed; ribs beaded"

Type III

• Very short stature
• Triangular face
• Easily fractured bones
• Scoliosis
• Tinted sclerae that may appear to be slightly blue, grey, or purple
• Barrel-shaped chest
• Teeth may be brittle and easily broken
• Possibility of problems with respiration
• Possible hearing loss
• Increased joint laxity
• "Severe osteoporosis
• Fractures heal with deformity and bowing
• Large skull
• Usually in utero fractures
• Usually wheelchair bound by teenage years"

Type IV

• More severe than type I and less severe than type III
• Short stature that is not as extreme as type III
• Barrel shaped chest
• Scoliosis
• Sclera are normal
• Triangular shaped face
• Teeth may be brittle and fracture easily
• Skin may be thin and smooth
• Possible hearing loss
• Bruises easily
• High pitched voice
• May perspire excessively
• "Mild to moderate skeletal fragility and osteoporosis
• Associated bowing of long bones
• Bones fracture easily before puberty; some children improve at puberty
• Joint Hyperextensibility"

Associated Co-morbidities

• Joint hypermobility
  
• Hearing impairment/Loss
• Excessive diaphoresis
• Cardiovascular complications
• Scoliosis
• Pectus deformity
• Metabolic defects
• Atrophy of muscles
• Multiple fractures
• Delayed developmental motor skills
• Spinal and lond bone deformities
• Shortened stature

Medications

Past Pharmacological Treatment Options

The following medications have been not been proven be effective for OI in controlled trials.

• Anabolic Steroids
• Vitamin D
• Vitamin C
• Sodium Fluoride
• Magnesium Oxide
• Flavanoids
• Calcitonin

Current Pharmalogical Treatment

• Growth Hormone - This is used to improve bone metabolism and to improve growth for statural purposes.
  
• Bisphosphonates - These are used to "promote bone mineral accretion while at the same time reducing bone turnover."
  

Diagnostic Tests/Lab Tests/Lab Values

The diagnosis of osteogenesis imperfecta generally begins with the physician's findings during an examination. Physicians may find evidence of skeletal deformities accompanied by multiple past fractures that have healed using x-rays or bone scans. Wormian bodies, which are irregularly shaped islands of bone found in the wide sutures on skull radiographs of patients with OI, may also be present. Other ways to help confirm the diagnosis of OI include a history of osteogenesis imperfecta in the family, a skin biopsy, DNA testing, and ultrasound imaging before the child is born. Although OI is not always passed down from the parents, this would help the physician come to a conclusion because if one of the parents have OI, they have a 50% chance of passing this along to their child. A skin biopsy is used to determine if there is enough type I collagen or if the collagen is abnormal. DNA testing is accomplished by means of a blood test that is examined to locate the genetic mutation. Ultrasound imaging can be used to help diagnose OI before the child is born. The more severe the type of OI, the earlier ultrasound imaging can detect the fractures and deformities. By 14-16 weeks, type II OI is usually possible to diagnose. Type III OI is possible to diagnose around 16-18 weeks gestation. Types I and IV are generally not diagnosed with ultrasound.

Causes

Osteogenesis imperfecta is a genetic disorder that can be caused by inheritance from a parent with OI, or a random genetic mutation. The genetic disorder in most cases is passed from one of the parents to the child through autosomal dominant inheritance. This means that one copy of the mutated gene in each cell is enough to cause the osteogenesis imperfecta. This type of inheritence is usually the cause for most people with type I or type IV OI. Random mutation of the COL1A1 or COL1A2 gene may also occur. These children have no family history of OI and tend to have either type II or type III osteogenesis imperfecta, which are more serious. The least common way that osteogenesis imperfecta is caused is by autosomal reccessive inheritance. This is when each cell has two copies of the mutated gene. This cause occurs by two people that are carriers of the mutated gene passing one copy each to a child. This cause usually results in a child with type III OI.

Systemic Involvement

Gastrointestinal

• Constipation that may be caused due to pelvic assymetry in more serious forms of OI.
• Diffuculties swallowing solid foods in more serious forms of OI.[1]

Cardiac

• Heart valve problems such as aortic valve insufficiency, aortic aneurysm, mitral valve regurgitation, and mitral valve prolapse.

Respiratory

• Restrictive pulmonary disorder is common in people with severe forms of OI.
• Pulmonary complications due to rib fractures, weakness of the muscles in the chest wall, chronic bronchitis, pneumonia, asthma and heart valve disorders.

Neurological

• Basilar invagination of the base of the skull may occur in OI patients in the adult years and cause complications with the brain stem.

Renal

• Kidney stones have at times been associated with osteogenesis imperfecta.
  

Integumentary

• Patients with OI may have thin skin.
• Excessive diaphoresis may be apparent.

Metablolic

• Elevated serum pyrophoshate
• Decreased platelet aggregation

Auditory

• Hearing loss/impairment is a common occurance in patients with OI. This can occur from deformity of the bony auditory structures. This can also be caused by a fracture of the stapes bone.

Vision

• Sclera may be blue, purple, or grey tinted.
• Vision loss can occur.

Musculoskeletal

• Muscular atrophy
  
• Joint hypermobility
  
• Multiple fractures
  

Pain

• "It is a myth that patients with osteogenesis imperfecta feel less pain than patients without OI."

Medical Management (current best evidence)

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Physical Therapy Management (current best evidence)

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Alternative/Holistic Management (current best evidence)

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Differential Diagnosis

The differential diagnosis for osteogenesis imperfecta can be grouped into stages of life that the differential diagnoses occur.

Prenatal/Neonatal

• "Thanatophoric dysplasia
• Jeune dystrophy
• Achondroplasia
• Camptomelic dysplasia
• Chondrodysplasia punctata
• Chondroectodermal dysplasia (Ellis–van Creveld syndrome)
• Nonaccidental injury
• Menkes kinky-hair syndrome
• Menkes Kinky Hair Disease
  
• Hypophosphatasia"
  

Preschool/Childhood

• "Pyknodysostosis
• Hajdu-Cheney syndrome
• Osteopetrosis
• Vitamin D–resistant rickets
• Osteochondromatosis
  
• Secondary osteoporosis (immobilization)
• Rickets
• Scurvy
• Leukemia
• Cushing syndrome
• Nonaccidental injury"

Adolescence/Adulthood

• "Mafucci syndrome
• Homocystinuria
• Albright hereditary osteodystrophy
• Wilson disease"

Milder forms of osteogenesis imperfecta may not be diagnosed early and can often be mistaken for child abuse by physicians.

Case Reports

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• Yochum TR, Kulbaba S, Seibert RE. Osteogenesis Imperfecta in a Weightlifter. Journal of Manipulative and Physiological Therapeutics; 25: 334-339. 2002.
  
• Nishimura A, Hasegawa M, Kato K, Fukuda A, Sudo A, Uchida A. Total knee arthroplasty in osteogenesis imperfecta: case report. The Knee; 15(6):494-496. 2008.
  
• Modi HN, Suh SW, Song HR, Hazra S, Lee SH. Pelvic fracture after scoliosis surgery in osteogenesis imperfecta: a case report. Journal of Pediatric Orthopedics; 17(5):225-229.2008.

Resources

• http://www.oif.org
  
• http://www.genome.gov/25521839
• http://www.osteogenesisimperfecta.org
• http://www.nlm.nih.gov/medlineplus/osteogenesisimperfecta.html
• http://ghr.nlm.nih.gov/condition=osteogenesisimperfecta
  
• http://www.brittlebone.org
  

Recent Related Research (from Pubmed)

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References

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