Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder with bone fragility, caused mainly by variants in COL1A1 or COL1A2, which encode the chains of type I collagen (about 85 to 90%), in an autosomal dominant manner. Quantitative defects (haploinsufficiency of COL1A1) cause milder disease (type I), while structural defects (glycine substitutions) cause moderate to severe disease. Recessive forms involve CRTAP, P3H1, PPIB, SERPINH1, FKBP10, SP7, WNT1, BMP1, TMEM38B and others. Prevalence is about 1 in 15,000 to 20,000.

Sillence classification:

• Type I: mild, blue sclerae, normal stature or mildly short, fractures at preschool age, and hearing loss in adulthood
• Type II: perinatally lethal
• Type III: progressively deforming, severe, short stature, triangular facies and dentinogenesis imperfecta
• Type IV: moderate, normal sclerae, bowing and variable fractures
• Type V (IFITM5 variant): hyperplastic callus, interosseous membrane calcification, and radial head dislocation
• Types VI onwards: recessive forms

• Recurrent low trauma fractures, including long bone and vertebral compression fractures, bowing deformities, pseudarthrosis, and scoliosis; severe types may have fractures at birth
• Blue grey sclerae (type I), dentinogenesis imperfecta (opalescent, discoloured, brittle teeth), and hearing loss (conductive, sensorineural or mixed in 50% by age 50; otosclerosis like)
• Ligamentous laxity, hypermobility, short stature, basilar invagination (risk of brainstem compression), kyphoscoliosis, thoracic deformity with restrictive lung disease, easy bruising, and cardiac valve disease (aortic root dilatation, mitral and aortic regurgitation)
• Differential diagnosis includes non-accidental injury, hypophosphatasia, juvenile osteoporosis, rickets, Ehlers-Danlos and Bruck syndrome

• Clinical features, family history, radiographs (osteopenia, thin gracile bones, multiple fractures, wormian bones in the skull, platyspondyly), and DXA scan (low bone mineral density Z-score below -2). Confirmation by genetic testing (COL1A1, COL1A2 and OI gene panel; bone related gene panels). Biochemistry: normal calcium, phosphate, PTH and 25-hydroxyvitamin D (to exclude rickets) and alkaline phosphatase (low in hypophosphatasia). Collagen biochemical analysis on cultured fibroblasts is used if genetic testing is negative. Prenatal ultrasound shows fractures in severe types.

• Bisphosphonates (the mainstay for moderate to severe OI): pamidronate IV for 3 consecutive days per cycle (0 to 2 years: 0.5 mg/kg/day every 2 months; 2 to 3 years: 0.75 mg/kg/day every 3 months; above 3 years: 1 mg/kg/day every 4 months), with calcium and vitamin D; or zoledronic acid 0.025 to 0.05 mg/kg IV every 6 months; oral alendronate 5 to 10 mg daily or 35 to 70 mg weekly or risedronate in milder disease. They increase bone density, reduce vertebral fractures, reduce pain, and improve mobility, but evidence for long bone fracture reduction is mixed. First dose acute phase reaction (fever, myalgia) is common; give paracetamol and avoid in infants with hypocalcaemia. Treat vitamin D deficiency before starting.
• Denosumab is used in selected patients under specialist care (rebound hypercalcaemia on stopping).
• Calcium (1,000 mg/day, diet), vitamin D (800 to 2,000 IU/day to keep 25-OH vitamin D above 30 ng/mL (75 nmol/L)), and weight bearing exercise.
• Orthopaedics: fracture care with minimal immobilisation, intramedullary rodding with telescoping rods (Fassier-Duval) for recurrent long bone fractures and deformities, spinal surgery for scoliosis above 40 to 50 degrees, and surgery for basilar invagination if symptomatic.
• Rehabilitation: physiotherapy, hydrotherapy, safe handling, and orthoses.
• Hearing: annual audiometry from age 10; hearing aids, stapedectomy or cochlear implant.
• Dental care: protective crowns, orthodontic care.
• Respiratory and cardiac: pulmonary function testing, echocardiography in adult life and at diagnosis (valvular disease).
• Growth hormone is used in selected children with type I, III or IV; romosozumab and teriparatide for adults.
• Pregnancy: caesarean for severe types and for risk of fetal fracture or maternal pelvic deformity.
• Genetic counselling: 50% recurrence risk in dominant forms (germline mosaicism leads to a 5 to 7% recurrence risk even when parents are unaffected).