Osteogenesis imperfecta

Abstract

| Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17052 | 1 PRIMER © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .In this Primer, we provide an overview of epidemio logy, genetics and pathophysiology of osteogenesis imperfecta, as well as diagnosis and management. EpidemiologyStudies from Europe and the United States have found a birth prevalence of osteogenesis imperfecta of 0.3-0.7 per 10,000 births 5,6 . These birth cohort analyses reflect more severe types of osteogenesis imperfecta and do not include more subtle types that become apparent after birth. A population based study that used the Danish National Patient Register found an annual incidence of osteogenesis imperfecta of 1.5 per 10,000 births between 1997 and 2013 (REF. 7). Population surveys in countries with comprehensive medical databases, such as Finland, estimated a prevalence of about 0.5 per 10,000 individ uals 8 , with most having phenotypically milder osteo genesis imperfecta type I and type IV (BOX 1; TABLE 1). Because these birth cohort and population surveys are based on clinical findings and tend to find mutu ally exclusive populations, a reasonable estimate of the incidence of osteogenesis imperfecta is about 1 per 10,000 individuals. Most patients are heterozygous for mutations in COL1A1 or COL1A2. No difference in the prevalence between sexes was reported.Approximately 90% of the 3,000 individuals whose mutations ha...

Compromised Exercise Capacity and Mitochondrial Dysfunction in the Osteogenesis Imperfecta Murine (oim) Mouse Model

“…Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized most often by bone fragility, short stature, blue‐gray sclera, and muscle weakness . OI is a heterogeneous disease, both in phenotype and genotype that ranges in severity and can be classified into four main types: I to IV, and at least nine subtypes .…”

“…Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized most often by bone fragility, short stature, blue‐gray sclera, and muscle weakness . OI is a heterogeneous disease, both in phenotype and genotype that ranges in severity and can be classified into four main types: I to IV, and at least nine subtypes . Type II is perinatal lethal; type III is the most severe viable form with patients often nonambulatory, whereas patients with types I and IV experience more mild and moderate manifestations, respectively .…”

Osteogenesis Imperfecta: New Perspectives From Clinical and Translational Research

“…In addition, abnormal bone shape and restricted mobility can lead to secondary problems in extraskeletal tissues. Thus, it is not surprising that many organ systems can be directly or indirectly affected in individuals with OI . Here we focus on a few topics that have been highlighted by recent studies.…”

“…This defect is caused by dominant or recessive mutations that lead to bone fragility and other skeletal manifestations, such as short stature and bone deformities. Extraskeletal tissues and organs can also be involved . Apart from bone fragility, the classical description of the OI phenotype includes blue or grey discoloration of the sclera and abnormalities of tooth structure called dentinogenesis imperfecta.…”

Management of atypical femoral fracture in a patient with osteogenesis imperfecta

“…Type I collagen is largely involved in the formation of the extracellular matrix in bones, these mutations thus cause diminished bone mass, impaired bone mineralisation and bone deformities. Recent studies also report that defects in osteoblast differentiation and function further contribute to decreased bone quality 1. As a result, the primary concern in patients with OI is their susceptibility to multiple fractures with little or no trauma and variable deformities of long bones.…”