The four types of osteogenesis imperfecta are type I (mild), type II (perinatal, lethal), type III (progressive, deforming), and type IV (deforming with normal scleras). All forms of osteogenesis imperfecta are characterized by increased susceptibility to fractures (“brittle bones”), but there is considerable phenotypic heterogeneity, even within individual subtypes. Approximately one fourth of the cases of type I or type IV osteogenesis imperfecta represent new mutations; in the remainder, the history and examination of other family members reveal findings consistent with autosomal dominant inheritance. Type III is also transmitted as an autosomal dominant trait, although type III can occasionally be transmitted in an autosomal recessive manner. Type II, the most severe form, generally occurs as a result of a sporadic dominant mutation.
Type II osteogenesis imperfecta presents at birth (or even in utero) with multiple fractures and bony deformities, resulting in death in infancy and, therefore, not likely to be seen in a child 4 years of age. Type III presents at birth or in early infancy with multiple fractures—often prenatal—and progressive bony deformities. The absence of prenatal fractures and early deformities in this patient’s history is most suggestive of type I or type IV osteogenesis imperfecta. These individuals generally present in early childhood with one or a few fractures of long bones in response to minimal or no trauma, as seen in this case. Type I and type IV osteogenesis imperfecta are differentiated by their clinical severity and scleral hue. Type I tends to be less severe, with 10–20 fractures during childhood plus short stature but few or no deformities. These patients tend to have blue scleras. Patients with type IV osteogenesis imperfecta tend to have more fractures, resulting in significant short stature and mild to moderate deformities. Their scleras are normal or gray.
In patients with type I osteogenesis imperfecta, the fracture incidence decreases after puberty and the main features in adult life are mild short stature, conductive hearing loss, and occasionally dentinogenesis imperfecta (defective dentin formation in tooth development).
Advances in the last two decades demonstrate two genetically different groups: the “classical” group, in which more than 90% of cases are caused by a mutation of the COL1A1 or COL1A2 genes, which encode the subunits of type I collagen, proα1(I) and proα2(I), respectively, and a newer group, caused by loss-of-function mutations in proteins required for proper folding, processing, and secretion of collagen. The fundamental defect in most individuals with type I osteogenesis imperfecta is reduced synthesis of type I collagen resulting from loss-of-function mutations in COL1A1. Several potential molecular defects are responsible for COL1A1 mutations in type I osteogenesis imperfecta, including alterations in a regulatory region leading to reduced transcription, splicing abnormalities leading to reduced steady-state levels of RNA, and deletion of the entire COL1A1 gene. However, in many cases, the underlying defect is a single base pair change that creates a premature stop codon (also known as ...