Osteogenesis Imperfecta - Types, Symptoms, Manifestations, Diagnosis and Treatment

What Is Osteogenesis Imperfecta?

Osteogenesis imperfecta is the name given to the group of disorders characterized by severe osteoporosis and multiple fractures in infancy and childhood. This disorder involves not only the skeleton but other extraskeletal tissues such as the sclera, eyes, joints, ligaments, teeth, and skin. It is a recessive disorder of type 1 collagen synthesis. Collagen constitutes 90 % to 95 % of the bone matrix that are fragile and easy to break. The skeletal manifestations of osteogenesis imperfecta are due to defective osteoblasts, which normally synthesize the type 1 collagen. This results in thin or non-existent cortices and irregular trabeculae, which means the bones are too little so the bones are very fragile and liable to multiple fractures.

Osteogenesis imperfecta means imperfectly formed bone and is also called,

• Brittle bone.

• Fragilitas ossium.

• Osteopsathyrosis.

• Lobstein's disease.

What Causes Osteogenesis Imperfecta?

Most osteogenesis imperfecta is caused by mutations in the COL1A1 gene located in chromosome 17q21 and the COL1A2 gene located in chromosome 7q22.1. As a result, both quantitative and qualitative defects of type 1 collagen biosynthesis occur. These genes are essential for the synthesis of type 1 collagen, which is a protein and the main component to create the bone.

The basic defect occurs in the organic matrix with the failure of fetal collagen to be transformed into mature collagen, leading to osteopenia, a tendency for bone fracture, and defective bone healing. Osteogenesis imperfecta can range from mild to severe.

In mild osteogenesis imperfecta, it results in reduced collagen production, and in severe osteogenesis imperfecta, it results in the formation of abnormal collagen chains that are rapidly degraded. Mutations in CRTAP and LEPRE genes show dominant inheritance where an abnormal gene from one parent can cause disease, which modifies the protein biosynthesis of collagen, resulting in weak bones.

What Are the Types of Osteogenesis Imperfecta?

Four well-documented types (type 1 to type 4) are recognized based on clinical and genetic findings. Recently, type 5, type 6, and type 7 were added to the existing types of osteogenesis imperfecta. However, the exact genetic defects in these newer types are yet to be established.

Type 1 -It is the most common and the mildest form of osteogenesis imperfecta. It is also called classic non-deforming osteogenesis imperfecta with blue sclerae. Around 10 % of the patients show prenatal fractures as it does not produce enough collagen.

The common, consistent features are:

• Blue sclera.

• Mild to moderate bone fragility.

• Kyphoscoliosis.

• Hearing loss.

• Bruising tendency.

However, the incidence of fractures considerably reduces when the patient attains puberty.

Type 2 -Type 2 is the most severe form of osteogenesis imperfecta, with extreme bone fragility and frequent fractures. It is also known as perinatal lethal osteogenesis imperfecta. Around 90 % of the cases are either stillborn or die before four weeks of postnatal life. Prenatal fractures are common in most patients and are mostly life-threatening. Children with osteogenesis imperfecta have,

• Narrow chest.

• Broken ribs.

• Misshapen ribs

• Underdeveloped lungs.

Type 3 -It is also called progressively deforming osteogenesis imperfecta. In utero, fractures occur in 50 % of the type 3 osteogenesis imperfecta patients. The rest of the cases acquire fractures in the neonatal period. It is the severe form of osteogenesis imperfecta where the bones break easily. Hearing loss has not been reported in this type, and the bone deformities get worse over time.

Type 3 osteogenesis imperfecta is associated with:

• Opalescent dentin.

• The sclera of variable hue.

• Limb shortening and progressive deformities.

• Triangular facies with frontal bossing.

• Pulmonary hypertension.

Type 4 -Type 4 osteogenesis imperfecta is a common variable osteogenesis imperfecta with normal sclerae and is further subdivided into subtype A and subtype B. Subtype A is not associated with opalescent dentin, and subtype B, which is associated with opalescent dentin.

The features of type 4 osteogenesis imperfecta include:

• Normal sclera.

• Normal hearing.

• Fractures that begin in infancy are rare.

• Mild angulation.

• Shortening of long bones.

What Are the Signs and Symptoms of Osteogenesis Imperfecta?

The age of onset of symptoms varies, and often, it leads to stillbirth, or the affected baby dies shortly after birth. The severity of clinical features of osteogenesis imperfecta at birth ranges from no clinical features to prenatally lethal skeletal abnormalities.

The condition may be evident at:

• Birth - Osteogenesis imperfecta congenita.

• Adolescence - Osteogenesis imperfecta tarda (more severe).

The age of onset of symptoms varies depending on the type of osteogenesis imperfecta as:

• Type 1 and 4 osteogenesis imperfecta - Infancy.

• Type 2 osteogenesis imperfecta - In utero.

• Type 3 osteogenesis imperfecta - In utero and neonatal period.

It is common for fractures to occur while an infant is crawling or walking, and there is no sex predilection. The fractures heal rapidly, but the new bone is of similar imperfect quality.

The clinical characteristics of osteogenesis imperfecta are:

• Multiple broken bones.

• Extreme fragility.

• Loose joints.

• Bowed legs and arms.

• The porosity of bones.

• Heart defects.

• Bone pain.

• Lateral curving of the upper spine (scoliosis).

• Triangular-shaped face.

• Pale blue sclera.

• Respiratory problems.

• Brittle teeth.

• Hearing loss (hypoacusis).

• Hypermobility of joints.

• Capillary bleeding.

• Abnormal outward curving of the upper spine (kyphosis).

What Are the Oral Manifestations of Osteogenesis Imperfecta?

Osteogenesis imperfecta is a disturbance of mesodermal tissues, particularly the calcified tissues. When a widespread congenital disturbance in bone formation exists, a disturbance in dentin formation occurs. Osteogenesis imperfecta causes abnormal dentin formation affecting both dentitions, resulting in a condition similar to dentinogenesis imperfecta, which is known by the term opalescent dentin.

The large head size, frontal and temporal bossing create a greater percentage of:

• Class 3 malocclusions.

• Crossbite.

• Open bite.

Osteogenesis imperfecta is more reported with maxillary hypoplasia, impactions, and ectopic teeth. In permanent dentition, patients often have unerupted first and second molars, a condition that is rare in the general population. Thus, the clinical and radiological evaluations of the dentition may be the only important component in the diagnosis of a questionable case of osteogenesis imperfecta.

How Is Osteogenesis Imperfecta Diagnosed?

The diagnosis of osteogenesis imperfecta is usually obvious clinically. In childhood, the disease can be mistaken for non-accidental injury and in adulthood for osteoporosis. In such cases, genetic testing can be of diagnostic value. They can also be diagnosed with family history and tests such as x-rays (shows the fractures), DNA tests (identifies the mutation), blood tests (if they are associated with any other symptoms), urine tests, biochemical testing (uses a sample from the skin to examine the collagen).

Prenatal ultrasonography may be helpful for the early diagnosis of prenatal fractures in types 1, 2, 3, and 4. Prenatal diagnosis may be confirmed by performing a chorion villus biopsy and demonstrating the production of abnormal collagen type 1 by culturing the chorionic villi cells or obtaining DNA for molecular analysis of the genes involved. Periapical radiographs reveal premature pulpal obliteration of affected teeth.

The characteristic radiographic findings are:

• Osteopenia.

• Deformity of the long bones.

• Multiple fractures.

• Wormian bones in the skull.

How Is Osteogenesis Imperfecta Treated?

No known treatment exists for osteogenesis imperfecta. Genetic counseling plays a major role in managing patients with osteogenesis imperfecta. Medical therapy is not involved, other than the treatment of infections when they occur. The aim is to reduce the occurrence of fractures, minimize the pain, maximize the functions, and prevent further deformities.

The treatment is multidisciplinary, involving:

1. Bisphosphonates.

2. Intravenous Pamidronate.

3. Pretreatment evaluation and monitoring.

4. Surgical reduction and fixation of fractures.

5. Physical and occupational therapy.

6. Primary care considerations.

1) Bisphosphonates Therapy:

Bisphosphonates are an important prevention therapy for fractures that are widely used in the treatment of osteogenesis imperfecta. Bisphosphonates reduce fracture frequency in children by up to 100 %. The long-term outcomes for the treatment of osteogenesis imperfecta are unclear. The dosing range and interval, duration of treatment, and safety profile are yet to be established.

2) Intravenous Pamidronate:

For all forms of osteogenesis imperfecta, Pamidronate is advised except for type 6. It is administered intravenously for three consecutive days at two to four months intervals. The dose ranges from 0.5 to 1 mg/mg/kg/day, depending on the age, and the corresponding annual dose is 9 mg/kg. It should be started with a minimal dose before initiating a new cycle of treatment. Especially intravenous Pamidronate is given in children, but there is limited evidence that this prevents the fracture or deformity.

3) Pretreatment Evaluation and Monitoring:

If the dietary intake is inadequate, calcium and vitamin D should be supplemented before the treatment. The calcium, phosphorus, and parathyroid hormone levels should be checked before the initiation of the treatment and should be followed for a year. To know that the child is not hypocalcemic, check the calcium levels before every intravenous bisphosphonate infusion.

4) Surgical Reduction and Fixation of Fractures:

Fixation of fractures by placing the intramedullary rods helps with long bone deformities (like the femur, tibia, and humerus). When the child is more than two years of age, telescoping rods are advisable. Surgery is done if there is a lateral curve of the upper spine.

5) Physical and Occupational Therapy:

Occupational therapy helps in the rehabilitation of patients with bone deformities. It helps drastically reduce the deformities that can occur in day-to-day activities. Physical therapy helps to minimize the fracture and prevents bone loss.

6) Primary Care Considerations:

Children with osteogenesis imperfecta have special routine care and immunizations. At nine months of age, hearing aids are advised at regular intervals. Pneumococcal and influenza vaccination is required, the visual examination should be done every three years, and also dental care is also of utmost importance.

Conclusion:

Osteogenesis imperfecta is a disorder of bone growth and development where the prognosis varies from relatively good to very poor. This brittle bone disease is life-threatening as it can be seen in approximately 1 per 20000 births. So taking good care during pregnancy, diagnosing the condition at an earlier stage, and preventing and managing the familial history of osteogenesis imperfecta helps to reduce the incidence and complications of this condition.