Osteogenesis Imperfecta

Synonyms: brittle bone syndrome, Adair-Dighton syndrome, Van der Hoeve syndrome, Ekman-Lobstein syndrome

This is an inherited condition causing increased fragility of bone. It principally affects those tissues containing the main fibrilla collagen, type I, e.g. bone and teeth. It also affects sclerae, joints, tendons, heart valves and skin.
There are seven different types:

• Type I - mildest form, autosomal dominant inheritance causing reduction in the amount of bone and defective bone formation. Due to abnormal or decreased pro-alpha 1 or pro-alpha 2 collagen polypeptides.The osteoblasts make approx. the usual amount of bone collagen. This causes osteoporotic bone with an excess of osteoblasts and osteocytes seen. Also causes thin sclerae, slender weak tendons, thin heart valves and dilated aortic root.
• Type II - lethal form, mostly autosomal dominant. Cases arising due to new dominant mutations result in multiple fractures, frequently occurring in-utero, and short limbs due to faulty conversion of normal mineralised cartilage to defective bone matrix. The result is completely disorganised and structurally incompetent bone structure.
• Type III - Severely progressive, deforming subtype. Autosomal recessive transfer with variable amounts of woven immature bone, disorganised trabeculae and multiple islands of cartilage in the epiphyses and metaphyses. The child may be born with fractures. Characterised by deformity of bones increasing with age and extreme short stature due to repeated childhood fractures. There is commonly impaired dentition, 'dentinogenesis imperfecta', with blue-yellow, small mis-shapen teeth, secondary to the type 1 collagen defect.
• Type IV - moderately severe form. Differentiated from type 1 by having white sclerae, and from type III by autosomal dominant inheritance.

Several other types have recently been described (types V, VI, VII). The same genetic mutations are not present as in types I-IV.

• Type V . Is a mild to moderately severe autosomal dominant osteogenesis imperfecta (OI), which does not appear to be associated with collagen type I mutations¹. There are normal coloured sclerae and ligament laxity. There is no dentinogenesis imperfecta. Typically patients have ossification of interosseous membrane of the forearm with radial head dislocation, hyperplastic callus formation and an abnormal histopathological pattern.
• Type VI . This is a moderate to severe form of brittle bone disease with accumulation of osteoid due to a mineralisation defect, in the absence of a disturbance of mineral metabolism². Patients with OI type VI sustain more frequent fractures than patients with OI type IV. Fractures are first documented between 4 and 18 months of age. Sclerae are white or faintly blue and dentinogenesis imperfecta is uniformly absent. All patients have vertebral compression fractures. The underlying genetic defect is not yet known.
• Type VII. This is a moderate to severe autosomal recessive form, characterised by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopaenia³. Rhizomelia (proximal limb shortening) is a prominent clinical feature. The disease has been localised to chromosome 3p22-24.1, which is outside the loci for type I collagen genes.

Incidence approx. 1/20,000 -1/50,000 live births, but this may be underestimated as milder forms can evade diagnosis. Leading cause of lethal short-limbed dwarfism and crippling skeletal dysplasia.

Type I - accounts for 60% of all cases.

• Fractures can occur at any time from the perinatal period to the early menopause.
• There is a 7x greater incidence of overall fracture rate than normal, with only 70% vertebral bone mineral content in adults.
• In childhood, fractures may be numerous but rarely lead to deformity.
• Any type of fracture can occur and these become less frequent with age, most commonly affected are the lower limbs.
• The skull shows multiple wormian bones and the vault may overhang the base, causing basilar compression needing surgical correction.
• When teeth are affected, some may be more affected than others. There is discolouration with enamel fracturing easily from the dentine, causing rapid erosion in both sets.
• Blue sclerae is an important sign caused by scleral thinness allowing the pigmented coat of the choroid to become visible.
• Frequently there is early arcus unrelated to hypercholesterolaemia.
• Cardiac effects are important, they include: aortic incompetence, aortic root widening and mitral valve prolapse.
• Often there is hypermobility of joints with flat feet, hyperextensible large joints and dislocations.
• Hearing can be affected by changes in the middle ear.

• These are often diagnosed prenatally at the 20 week ultrasound.
• Not all infants die immediately with multiple fractures.
• Infant is short, limbs are short and deformed , skull is soft and deformed and sclerae are deep grey-blue .
• There are crumpled long bones and beaded ribs.

• The child may be born with fractures and the skull is well ossified.
• There is progressive deformity of the skull, long bones, spine, chest and pelvis during early years.
• Face appears triangular with large vault, prominent eyes and small jaw.
• Sclera is blue in infancy but normal colour in childhood.
• Patients rarely walk even after multiple surgical procedures, and have very short stature.
• Early death can occur from respiratory infections predisposed to by reduction in vital capacity associated with severe kyphoscoliosis.

Other forms of lethal, short-limbed dwarfism including:

• Achondrogenesis.
• Thanatophoric dwarfism.
• The asphyxiating thoracic dystrophies.

Non-accidental injury is the main differential diagnosis in childhood.
During late childhood and adolescence, idiopathic juvenile osteoporosis.

Prenatal diagnosis in second trimester by ultrasound in the most severe forms. Routine scanning shows shortness and deformity of limbs and abnormal skull shape. There is also absence of mineralisation and deformity of ribs causing 'champagne cork' appearance on AP projection.
There is currently no method of biochemical screening .

• Type III requires lifelong and specialised care.
• Patients are of normal intelligence and prolonged admission to hospital should not affect their education.
• Multidisciplinary care including physiotherapy, rehabilitation, bracing and splinting is good practice.
• Intramedullary rodding and osteoclasis needs to be used very selectively.
• A specialised course of rehabilitation may be needed.
• Recent advances have shown the use of growth hormone and bisphosphonate to be beneficial^4,5,6,7.
• Bisphosphonate therapy is used under specialist centre guidance and is particularly useful for pain and recurrent fractures in type 3. (Bisphosphoantes bind to, and stabilise bone by inhibiting osteoclast activity, whilst stimulating osteoblast activity.)
• Cyclical intravenous pamidronate administration can reduce bone pain and fracture incidence, and increase bone density and level of mobility, with minimal side effects⁸.
• Effects on bone include increase in size of vertebral bodies and thickening of cortical bone. This also allows for better corrective surgery, e.g. intramedullary rodding of the long bones.
• However, substantial variability in individuals response to treatment has been noted⁹.
• Research continues into use of transplanted normal stromal cells from bone marrow.

Normal life expectancy in type I, and only slightly reduced in type IV.
Where deformity is severe e.g. type III, the patient may lose mobility and become wheelchair bound.

• In families with known collagen mutations, fetal DNA analysis from chorionic villus biopsy, in the first trimester, may be possible.
• It can be difficult to give genetic advice:
• In type I and type IV, there is a 50% probability of affected child, where one parent is affected.
• However, where neither parent is affected with the lethal and progressively deforming type II and III, it may be impossible to give chance of further offspring being affected, because of germline and somatic-cell mosaicism.
• However, general guidelines are, in child with type I or IV with clinically unaffected parents, likely to be new dominant mutation and risk of further affected offspring is probably no greater than normal (50% of any offspring of child will be affected). Following diagnosis of type II infant, general advice is that there is a 7% chance of further offspring being affected.
• The design of potential gene therapy is complicated by the genetic heterogeneity of the disease and by the fact that most of the osteogenesis imperfecta mutations are dominant negative, where the mutant allele product interferes with the function of the normal allele¹⁰.

Charles Adair-Dighton was an English Otorhinolaryngologist, born in Liverpool in 1885. It was he who, in 1912, first described the autosomal dominant transmission of blue sclerae and its association with adult-onset deafness.
In 1918, van der Hoeve and de Kleyn of Utrecht, described a syndrome where brittle bones were associated with blue sclerae and deafness, in osteogenesis tarda. This was also noted by the Swedish physician, Ekman-Lobstein.