Osteogenesis imperfecta type III

Alternate names

OI type 3; Osteogenesis imperfecta, progressively deforming with normal sclerae; OI type III; Progressive deforming osteogenesis imperfecta; Severe osteogenesis imperfecta; Progressively deforming OI

Definition

Osteogenesis imperfecta type III (OI type III) is a form of osteogenesis imperfecta, a group of genetic conditions that primarily affect the bones.

Cause

• OI type III is caused by changes (mutations) in the COL1A1 or COL1A2 genes. These genes provide instructions for making proteins that are used to assemble type I collagen.
• This type of collagen is the most abundant protein in bone, skin, and other connective tissues that provide structure and strength to the body.
• These mutations typically alter the structure of type I collagen molecules, resulting in abnormal type I collagen.
• A defect in the structure of type I collagen weakens connective tissues, particularly bone, resulting in the characteristic features of these more severe types of osteogenesis imperfecta.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

It is inherited in an autosomal dominant manner.

Signs and symptoms

In OI type III, specifically, a diagnosis can often be made shortly after birth as fractures (broken bones) during the newborn period simply from handling the infant are common. Other signs and symptoms vary significantly from person to person but may include severe bone fragility, bone malformations, short stature, dental problems (dentinogenesis imperfect), macrocephaly (unusually large head), hearing loss, and blue sclerae (whites of the eyes). Most affected people are unable to walk without assistance.

Diagnosis

COL1A1/2 osteogenesis imperfecta (OI) should be suspected in individuals with the following clinical, radiographic, and laboratory features.[1].

Clinical features

• Fractures with minimal or no trauma in the absence of other factors, such as non-accidental trauma (NAT) or other known disorders of bone
• Short stature or stature shorter than predicted based on stature of unaffected family members, often with bone deformity
• Blue/gray scleral hue
• Dentinogenesis imperfecta (DI)
• Progressive, postpubertal hearing loss
• Ligamentous laxity and other signs of connective tissue abnormality
• Family history of OI, usually consistent with autosomal dominant inheritance

Radiographic features of OI change with age. The major findings include the following :

• Fractures of varying ages and stages of healing, often of the long bones but may also rarely involve ribs and skull. Metaphyseal fractures can be seen in a very small number of children with OI. Rib fractures are much more common in NAT than in OI.
• "Codfish" vertebrae, which are the consequence of spinal compression fractures, seen more commonly in adults
• Wormian bones, defined as "sutural bones which are 6 mm by 4 mm (in diameter) or larger, in excess of ten in number, with a tendency to arrangement in a mosaic pattern" . Wormian bones are suggestive of but not pathognomonic for OI.
• Protrusio acetabuli, in which the socket of the hip joint is too deep and the acetabulum bulges into the cavity of the pelvis causing intrapelvic protrusion of the acetabulum
• Low bone mass or osteoporosis detected by dual energy x-ray absorptiometry (DEXA). Bone density can be normal, especially in individuals with OI type I, as DEXA measures mineral content rather than collagen

Laboratory features

• Serum concentrations of vitamin D, calcium, phosphorous, and alkaline phosphatase are typically normal; however, alkaline phosphatase may be elevated acutely in response to fracture and rare instances of abnormally low alkaline phosphatase levels have been noted anecdotally in severe OI.
• Analysis of type 1 collagen synthesized in vitro by culturing dermal fibroblasts obtained from a small skin biopsy reflects the structure and quantity of the collagen. The sensitivity of biochemical testing is approximately 90% in individuals with clinically confirmed OI

Establishing the Diagnosis The diagnosis of COL1A1/2-OI is established in a proband by identification of a heterozygous pathogenic or likely pathogenic variant in COL1A1 or COL1A2 by molecular genetic testing.

Treatment

• Ideally, management is by a multidisciplinary team including specialists in medical management of OI, clinical genetics, orthopedics, rehabilitation medicine, pediatric dentistry, otology/otolaryngology, and mental health.
• Parents / other caregivers must practice safe handling techniques.
• Mainstays of treatment include: bracing of limbs depending on OI severity; orthotics to stabilize lax joints; physical activity; physical and occupational therapy to maximize bone stability, improve mobility, prevent contractures, prevent head and spine deformity, and improve muscle strengthening; mobility devices as needed; and pain management.
• Fractures are treated with: as short a period of immobility as is practical; small and lightweight casts; physical therapy as soon as casts are removed; and intramedullary rodding when indicated to provide anatomic positioning of limbs.
• Progressive scoliosis in severe OI may not respond well to conservative or surgical management.
• Bisphosphonates continue to be used most extensively in severely affected children with OI.
• Surgical treatment for basilar impression should be done in a center experienced in the necessary procedures. Dental care strives to maintain both primary and permanent dentition, a functional bite or occlusion, optimal gingival health, and overall appearance.
• Conductive hearing loss may be improved with middle ear surgery; later-onset sensorineural hearing loss is treated in the same manner as when caused by other conditions.
• Mental health support through psychiatry/psychology and appropriate social worker intervention can improve quality of life.

[2].

NIH genetic and rare disease info

• NIH info on Osteogenesis imperfecta type III

Osteogenesis imperfecta type III is a rare disease.

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