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Árvai, Kristóf, Péter Horváth, Bernadett Balla, Bálint Tobiás, Karina Kató, Gyöngyi Kirschner, Valéria Klujber, Péter Lakatos, and János P. Kósa. “Next-generation sequencing of common osteogenesis imperfecta-related genes in clinical practice.” Scientific reports 6 (2016): 28417.


What is Osteogenesis Imperfecta?

Osteogenesis Imperfecta (OI) or commonly known as Brittle Bone disorder is a group of disorders affecting the connective tissue and leading to weak, fragile bones and frequent fractures without any apparent impact like a fall. Like the name implies, OI refers to imperfect bone formation and structure. Babies/children with OI present with multiple fractures and in most cases, babies are born with fractures or bone dislocations. In India, OI affects 10 per 100,000 people. The condition affects both males and females and it is estimated that at least 3000-5000 individuals are affected in India.

The severity of the condition varies among individuals though multiple fractures are common for all types of OI.

While there are at least eight types of OI based on severity and symptoms, we discuss the following four types:
  • Type I – is the most common and mildest. Usually the child experiences repeated fractures during childhood and the frequency lessens after puberty. Repeated fractures may lead to slight deformation in the upper limbs and lower limbs. In many case of OI Type I, individuals have a blue sclera (bluish tint in the whites of the eye). Type I is also associated with hearing impairment and hearing loss usually begins in the 30s. Most individuals with Type I have a triangular shaped face, short stature and sometimes go on to develop curvature of the spine (scoliosis or kyphosis).
  • Type II – is the most severe form of OI with infants presenting with fractures at birth. Infants with Type II have low birth weight and in some cases respiratory complications. They also present with short arms and legs and blue sclera. Infants with Type II also have underdeveloped lungs and small upper thorax often leading to congestive heart failure. Type II also presents with low muscle tone, short stature, multiple fractures throughout childhood and adulthood and fragile skin. Type II is further subdivided into A, B and C based on differences in bone formation as seen in x-rays.
  • Type III and IV – are also characterized by fragile bones and multiple fractures. Fractures may be present at birth and bone malformations are often progressive right from childhood through adulthood. Short stature, malformed spine, respiratory insufficiency are also common features. Progressive malformation of bones due to repeated fractures may often require the individual to use a wheelchair. Individuals with Type III have a triangular shaped face, blue sclera, hearing impairment and repeated dental issues (dentinogenesis imperfecta).
Other types of OI are not so frequently seen in populations.

Around 85% of all OI cases are the result of an autosomal dominant gene inherited from one of the parents. Only one copy of the gene is enough to express the disease. In cases where the parent does not have the dominant mutation, OI is a result of a spontaneous mutation. In families which carry the autosomal dominant version of the OI gene, there is a 50% chance of each child inheriting the mutated gene.

Around 15% of OI cases are the result of autosomal recessive genes inherited from both parents. In this case, the parents do not have the disease but are carriers of the disease causing gene. The child inherits two mutated copies of the gene. In families where both parents are carriers of the mutated gene, each child has a 25% chance of inheriting the disease (where two mutated copies of the disease gene are passed on to the child).

Genetic counselling is important for families where OI is passed on to the children. Prevention is possible with carrier genotyping and CVS to determine the disease status of the fetus.

Mutations in the COL1A1, COL1A2, CRTAP and P3H1 genes lead to OI. These genes provide instructions for making the protein collagen. Collagen is present in the bone, skin and all other connective tissues in the body. Collagen is the protein responsible for bone strength. Either insufficient production of collagen or a mutated form of collagen is the cause of OI. In 90% of all OI cases, mutations in the COL1A1 and COL1A2 are the chief cause. In rare and severe cases of OI, CRTAP and P3H1 are the main cause. Currently researchers are working to identify if other mutations are responsible for OI.

An infant who is born with a limb fracture or a dislocation must immediately be checked for OI. Some of the signs and symptoms which occur in babies and children include:
  • fractures while trying to stand up or walk
  • fractures with no known cause
  • bluish tint in the whites of the eye
  • repeated respiratory episodes with breathing difficulty
  • continuous crying indicative of pain due to fractures
If the pediatrician or orthopedician suspects OI, he/she may refer the patient and family to a clinical geneticist. Clinical geneticists diagnose OI with:
  • biochemical test – collagen biopsy test
  • molecular test – DNA tests
The collagen test and DNA test (genotyping to detect one of the disease mutations) usually detect 90% of all Type I mutations. A positive collagen biopsy test for Type I confirms dominant OI. If the test is negative, it can mean that the patient has a mutation which is not associated with Type I. This could be a recessive mutation and further DNA studies can confirm the exact mutation.

Currently, no permanent cure is available for OI. Treatment is aimed at preventing fractures, strengthening bone and muscle mass and preserving mobility. Fractures are usually treated with total rest, screw/rod fixation surgeries or casts with plaster of paris. Children and adults with OI may require frequent dental and other surgical procedures. A surgical procedure called “rodding” is often required for children/adults with OI. Rodding involves inserting titanium rods into the long bones to prevent fractures, strengthen the bone and prevent deformities.
Individuals with OI are also given other medications and treatments like growth hormone therapies, oral and intravenous drugs like bisphosphonates and drugs like teriparatide and zoledronic acid. The objective of these interventions are to prevent fractures and preserve bone strength.

Children/adults with OI must be encouraged to participate in non-impact sports like swimming which strengthens core muscles. Safe exercises like light yoga, Tai-chi, pilates or water exercises are permitted. Diet and nutrition are important for preserving bone strength and a diet rich in calcium is recommended. Calcium and D3 supplements are also given to children and adults and quarterly tests like serum calcium and 25(OH)D are recommended. Smoking, alcohol and steroids are to be avoided as these can deplete minerals from the bones. All individuals with OI must be monitored for hearing loss at least once a year.

Many children and adults with OI may use supportive measures like crutches, braces and wheelchair.

Gene therapy has the potential for a permanent cure for OI. In some of the more severe forms, editing and silencing the mutant allele is a possibility. The suppression of the allele can convert a severe phenotype to a more milder form of OI. Several methods are in the experimental stage including antisense oligodeoxyribonucleotides (ODNs), ribozymes, short interfering RNA (siRNA) and short hairpin RNA (shRNA).

Another promising intervention to treat OI is the transplantation of normal stem cells with osteoblast differentiation potential. Some of the potential sources of donor stem cells for OI cell therapy are:

  • iPSCs – induced pluripotent stem cells
  • MSCs – mesenchymal stem cells
  • BM – bone marrow
  • hf-MSCs – human fetal mesenchymal stem cells
  • hf-CSCs – human fetal chorionic stem cells

Gene and cell-based therapies are currently being investigated for safety, efficacy and toxicity.

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Children and adults with OI can participate in all life activities and must be encouraged to go to regular schools, colleges and participate in social activities. Genetic counselling and psychosocial counselling must be made available whenever required with other supportive measures. While one needs to be careful and avoid unnecessary falls, it does not mean that individuals cannot participate in most life activities.

If there is a known case of OI in the family, it is absolutely essential for closest relatives like siblings, uncles, aunts and cousins to test for carrier status.

If a woman with a carrier status is pregnant, prenatal test is essential to determine if the fetus has the disease mutation.