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Osteogenesis Imperfecta

What is Osteogenesis Imperfecta?

Osteogenesis imperfecta (OI) is a group of rare genetic disorders that affect the bones and its connective tissues. Affected individuals have extremely brittle bones that break easily, either from little trauma or no cause. The severity of OI ranges from having a few factures to hundreds of fractures over a lifetime. Multiple fractures can occur even before birth, complicating infancy. There are many types of OI. The mildest form is type I and the most severe is type II.

 

Synonyms

  • Brittle Bone disease
  • Ekman-Lobstein Disease
  • Lobstein Disease
  • Vrolik Disease
  • Fragilitas ossium

Osteogenesis imperfecta (OI) is a group of rare genetic disorders that affect the bones and its connective tissues. Affected individuals have extremely brittle bones that break easily, either from little trauma or no cause. The severity of OI ranges from having a few factures to hundreds of fractures over a lifetime. Multiple fractures can occur even before birth, complicating infancy. There are many types of OI. The mildest form is type I and the most severe is type II.

Acknowledgement of Osteogenesis Imperfecta has not been added yet.

OI affects approximately 6 to 7 per 100,000 people worldwide, and approximately 20,000 to 50,000 individuals in the United States. Types I and IV are the most common and affects approximately 1 in 30,000 people. Type II affects approximately 1 in 60,000 people.

Name Abbreviation
Brittle Bone disease OI
Ekman-Lobstein Disease OI
Lobstein Disease OI
Vrolik Disease OI
Fragilitas ossium OI

OI can occur as a de novo (new) mutation, which is a mutation that occurs at the time of conception and is not inherited. There is no previous family history of the disorder. Other cases are autosomal dominant inheritance, meaning that only one copy from one parent of the altered gene is necessary for the disease to appear. It can also be inherited in an autosomal recessive way, which both parents are carriers of the mutations, but do not have the disease.

Most affected individuals have mutations on either the COL1A1 or COL1A2 gene. These genes carry instructions for the production of collagen. OI type I occurs mainly with mutations in the COL1A1 gene. These mutations causes collagen to decrease in production, which is a major source of protein for the bones and its connective tissues including the skin, tendons, and the whites of the eyes (sclera). Without collagen, bones become brittle and break. OI type II, III, and IV occur with mutations at either the COL1A1 or COL1A2 gene. These mutations affect the structure and molecules of collagen. The defected structures weaken connective tissues, leading to severe bone abnormalities and problems with growth.


Mutations in the IFITM5 gene (type V) occur less frequently and is inherited in an autosomal dominant way. On rare occasions, the mutations occur on either the SERPINF1 (type VI and X), CRTAP (type VII), LEPRE1 (type VIII), PPIB (type IX), or P3H1 (type XI) gene and are inherited as autosomal recessive. Many new genetic causes of been identified in the recent years.

Type I is the most common and mildest form. It is characterized by bone fractures during childhood and adolescence from minor trauma.  Fractures can occur less often in adulthood. Some children can have a few fractures, while others can experience multiple fractures and chronic pain. There is usually only a little bone deformity with normal to near normal height. Affected individuals often have bluish discoloration of the whites of the eyes (sclera) and hearing loss that develops as young adults. Some can experience flexible joints, muscle weakness, flat feet, dislocations, and sprains.

Type II is the most severe form. Before birth, bone fractures occur frequently, spontaneously, and from little to no trauma. They are born with multiple fractures, small chests, and soft skulls. They have short limbs causing the legs to be in a frog-leg position. Many experience breathing and swallowing problems. The abnormally small and fragile rib cage, and underdeveloped lungs are life threatening. Other features include blue sclera, short stature, low birth weight, brittle and discolored teeth, respiratory problems, and hearing loss. It is difficult to distinguish the symptoms of type II versus type III.

The other types have symptoms that fall in between the range of type I and type II. The sclera ranges from white, blue, purple, to gray. Many have multiple fractures, short stature, and slowed growth. Some have respiratory and breathing difficulties, which may require a respirator or supplemental oxygen. Some can have calcification at the joints that restricts movement.

A diagnosis of OI is based on a clinical evaluation, patient and family history of fractures, characteristic symptoms, and a variety of specialized diagnostic tests. A clear indication of OI is fractures that occur spontaneously or infants born with broken bones. Mild cases of OI are not diagnosed until teen to adult years. Ultrasounds can detect bone fractures before the infant is born.

A biopsy of the skin can determine if abnormalities of collagen are present. X-rays can detect characteristic changes to the bone. Molecular genetic testing can detect the presence of the genetic mutations.

For severe cases, OI can be diagnosed before birth with ultrasounds, amniocentesis, and/or chorionic villus sampling (CVS). Ultrasounds can reveal fractures or bowing of the long bones. Amniocentesis fluid or tissue samples can determine if a genetic mutation is present.

Treatment depends on the symptom of the affected individual. The goal is to prevent symptoms, maintain mobility, and strengthen the bones and muscles.

Exercise and physical therapy programs help improve muscle strength, increase weight-bearing capacity, and reduce the tendency of bones to fracture. Exercise can help prevent delays in motor skill development. Occupational therapy is recommended to help with daily activities. As the affected individual grows older, regular exercise to maintain bone strength and muscle mass is recommended. Swimming and water therapy are good for all ages by allowing movement with low fracture risk. Walking is good exercise for those who can, with or without walking aids.

Surgery may be necessary to treat fractured bones. Metal rods are surgically inserted into the long bones to prevent fractures, a procedure called rodding. Severe deformities may require surgery to stabilize the spine. Dental procedures can help correct various dental abnormalities. Surgery to repair tiny bones in the middle ear can help improve hearing.

Lightweight casts, braces, and splints help with the healing process of fractures. It should only be used for a short period of time. Movement should begin as soon as possible after the fracture is healed. It is not recommended for long term because immobility can weaken the bones and muscles, causing weakness and more fractures.

Young adults should be monitored for hearing loss. Hearing aids may be necessary. Some may need supplemental oxygen to help with breathing. Mobility aids may be necessary to decrease the risk of falls and fractures. Genetic counselling is recommended for individuals and their families.

A variety of drugs have been studied for the treatment of OI including bisphosphonates, growth hormones, teriparatide, and denosumab. Further study is necessary to clarify what roles and benefits these drugs offer for affected individuals.

Prognosis depends on the severity of the disease and the quality of management of the disease. Affected individuals with severe type II often face life threatening complications with respiratory or cardiac issues. The life expectancy of affected individuals with severe type II is extremely low, type III is below average, and mild to moderate is average. Many affected individuals with mild to moderate symptoms go on to attend schools, have careers, and raise families.

When lifting a child with OI, fingers should be spread apart, with one hand between the legs and under the buttocks, and the other hand placed behind the shoulders, neck, and head. It is not recommended to lift a child under the armpits.

When changing a diaper, do not pull on the arms or the legs, instead lift the legs by the ankles. Select infant car seats that recline to easily place or remove the child from the seat. In addition, consider padding the seat with an extra layer of foam for extra protection. A stroller should be large enough to accommodate casts. Avoid purchasing a sling or umbrella-type strollers.

Living a healthy lifestyle with exercise and nutritious foods is important. Swimming and walking are often approved as safe exercises. Maintaining vitamin D and calcium levels helps with bone health. A healthy weight is important because extra weight adds stress to the bones, heart, and lungs. Affected individuals should avoid smoking, second hand smoke, alcohol, caffeine, and steroid medications. These all decrease bone density.

It is important to remember that fractures can occur despite all precautions and care. Strictly follow the instructions of healthcare providers, especially in regards to cast care and mobility exercises.

Marini J, Smith SM. Osteogenesis Imperfecta. In: Endotext.  National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/books/NBK279109/. Updated April 22, 2015.

Osteogenesis Imperfecta. National Organization for Rare Disorders (NORD) website. Available at: https://rarediseases.org/rare-diseases/osteogenesis-imperfecta/. Updated 2007. 

Osteogenesis Imperfecta. Osteogenesis Imperfecta (OI) Foundation website. Available at: http://www.oif.org/site/PageServer. August 2015.

Osteogenesis Imperfecta. Genetic Home Reference website. http://ghr.nlm.nih.gov/condition/osteogenesis-imperfecta.  Updated April 2013. 

Shaker JL, Albert C, Fritz J, Harris G. Recent developments in osteogenesis imperfecta. F1000Res. 2015;4:681.

Steiner RD, Adsit J, Basel D. COL1A1/2-Related Osteogenesis Imperfecta. Gene Reviews website. http://www.ncbi.nlm.nih.gov/books/NBK1295/.  Updated February 14, 2013. 

Valadares ER, Carneiro TB, Santos PM, Oliveira AC, Zabel B. What is new in genetics and osteogenesis imperfecta classification? J Pediatr (Rio J). 2014;90(6):536-541.


Van Dijk FS, Sillence DO. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A. 2014;164(6):1470-1481.

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Osteogenesis Imperfecta Foundation

The website for the Osteogenesis Imperfecta Foundation.

03/20/2017

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