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Prevalence is estimated at between 1/10,000 and 1/20,000.

Age at diagnosis depends on the severity of the disease. Five clinically distinct types of osteogenesis imperfecta (OI) have been identified. The most clinically relevant characteristic of all types of OI is bone fragility, which manifests as multiple spontaneous fractures. Type I is mild and nondeforming with normal height or short stature, blue sclera, and no dentinogenesis imperfecta (DI). Patients with type II present multiple rib and long bone fractures at birth, marked deformities, broad long bones, low density on skull X-rays, and dark sclera. These patients die at birth, or shortly after. Type III is severe and the main signs include severe short stature, a triangular face, severe scoliosis, grayish sclera, and DI. Type IV and 5 are moderate or severe forms. Patients with type IV have moderate short stature, variable severity of scoliosis, grayish or white sclera, and some have DI. Type V is characterized by mild to moderate short stature, metaphyseal dysplasia at birth, dislocation of the radial head, mineralized interosseous membranes of the forearm and lower leg, hyperplastic callus (particularly when growth is more rapid e.g. during infancy or puberty), white sclera, and no DI. They have variable severity of scoliosis.

In approximately 90% of cases, OI is caused by monoallelic variants in the COL1A1 and COL1A2 genes (17q21.33 and 7q21.3) encoding the alpha1 and alpha2 chains of type 1 collagen. These variants can cause types I-IV of OI. In Type V, the variant is in the promoter region of the IFITM5 gene (11p15.5). Over 15 causal genes have been identified and some geno-phenotypes are emerging: in children with BMP1 variants, high bone mass can be observed. Children with homozygous WNT1 variants have ptosis and neurodevelopmental delay; and craniosynostosis defects are associated with P4HB or SEC24D variants.

Diagnosis is based on skeletal and extra-skeletal clinical findings. Radiological studies reveal osteoporosis and the presence of Wormian bones. Bone densitometry confirms the low bone mass.

Differential diagnoses include in utero diagnosis of chondrodysplasia, idiopathic juvenile osteoporosis, osteoporosis-pseudoglioma syndrome, Cole-Carpenter and Bruck syndromes, hyper or hypophosphatasia, panostotic form of polyostotic fibrous dysplasia, non-accidental injury (multiple fractures without osteoporosis), and osteoporosis due to medication, nutritional deficiency, metabolic disease, or leukemia.

Antenatal diagnosis may be suspected through ultrasonography and/or confirmed through molecular analysis of amniocytes or chorionic villus cells if the causative mutation in the family has been identified.

Transmission is autosomal dominant for both Type I Collagen and IFITM5 variants. Autosomal recessive forms are also observed and are caused by variants in at least 15 other genes, and are typically severe; however, variability in severity has been noted especially for Type VI due to SERPINF1 variants; and for OI due to BMP1 or PPIB variants. Transmission is X-linked for MBTPS2 variants. Genetic counselling is recommended for affected families.

Management should be multidisciplinary involving experienced medical, orthopedic, physiotherapy and rehabilitation specialists. Bisphosphonates with potent antiresorptive properties are now considered as the standard of care for severe forms but do not constitute a cure. Prevention of vitamin D and calcium deficiency is essential throughout life. Surgical management is essential for the correction of bone and spinal deformities and the prevention of long bone fractures (insertion of intramedullary rods in long bones; spinal rods when growth is complete, or nearly complete). Early physiotherapy may improve autonomy by helping to evaluate any motor deficits, reducing the risk of falls and encouraging patients to take up a sporting activity. Occupational therapy and attendance to fine motor activities has strong relevance for school performance. Many families need psychological and social care support.

Functional prognosis depends on the severity of the disease and on the quality of management. Vital prognosis depends on the severity of any respiratory complications associated with spinal deformities.

Last update: May 2021 - Expert reviewer(s): Pr Nick BISHOP