Genetics of Osteogenesis Imperfecta 

Osteogenesis imperfecta (OI) is disorder of congenital bone fragility caused by mutations in the genes that codify for type I procollagen (ie, COL1A1 and COL1A2).

The following 4 types of osteogenesis imperfecta have been reported:^[1]

• Type I - Mild forms
• Type II - Extremely severe
• Type III - Severe
• Type IV - Undefined

Precise typing is often difficult. Severity ranges from mild forms to lethal forms in the perinatal period. In addition, several syndromes resemble osteogenesis imperfecta, with congenital bone fragility in association with other distinctive clinical or histologic features. Examples of these findings are shown in the images below.

Type I collagen fibers are found in the bones, organ capsules, fascia, cornea, sclera, tendons, meninges, and dermis. Type I collagen, which constitutes approximately 30% of the human body by weight, is the defective protein in osteogenesis imperfecta.

In structural terms, type I collagen fibers are composed of a left-handed helix formed by intertwining of pro-alpha 1 and pro-alpha 2 chains. Mutations in the loci that encode these chains cause osteogenesis imperfecta (ie, COL1A1 on band 17q21 and COL1A2 on band 7q22.1, respectively). Other mutations may cause congenital bone fragility associated with distinctive clinical or histologic features (eg, redundant callus formation, pseudoglioma, defective mineralization of bone). These conditions have been grouped as syndromes resembling osteogenesis imperfecta.

Qualitative defects (eg, an abnormal collagen I molecule) and quantitative defects (eg, decreased production of normal collagen I molecules) are described. Of note, recent studies have reported that quantitative defects can cause very severe (even lethal) syndromes resembling osteogenesis imperfecta through posttranslational modifications of collagen.^[2]

Cartilage-associated protein (CRTAP) is a protein required for prolyl 3-hydroxylation. Loss of CRTAP in mice causes an osteochondrodysplasia characterized by severe osteoporosis and decreased osteoid production. In humans, CRTAP mutations cause excess posttranslational modification of collagen, and may be associated with syndromes resembling osteogenesis imperfecta, including recessive forms of lethal syndromes resembling OI and syndromes resembling osteogenesis imperfecta with redundant callus formation.

The most widely used classification of osteogenesis imperfecta published by Sillence et al in 1989 does not include an expanding group of conditions with congenital brittle bones that are not caused by mutations in the collagen genes. In many cases, these disorders are diagnosed as osteogenesis imperfecta; however, increasing evidence suggests that they represent a separate nosologic entity.^[1] Some syndromes resembling osteogenesis imperfecta (SROI) have been described in the literature as osteogenesis imperfecta types V-VII, but further research demonstrated that some of these so-called forms are not caused by mutations in the type I procollagen genes. Syndromes resembling osteogenesis imperfecta are caused by mutations in genes other than the type I procollagen genes. They present with congenital brittle bones and, often, with other distinctive characteristics (eg, blindness, congenital contractures, redundant callus formation). In most cases, these are recessive conditions.

Congenital brittle bones with rhizomelia

This particular form with short humerus and femora and recessive inheritance was only described in a First Nations community of Quebec. Mutations in either of two components of the collagen prolyl 3-hydroxylation complex (cartilage-associated protein [CRTAP] and prolyl 3-hydroxylase 1 [P3H1]) cause this autosomal recessive syndromes resembling osteogenesis imperfecta with delayed collagen folding. The severity in terms of fractures and disability is moderate to severe. Fractures may be present at birth. In linkage studies, the genetic defect has been mapped to the short arm of chromosome 3, where no genes codify type I procollagen.

Congenital brittle bones with redundant callus formation

These patients develop hyperplastic calluses in long bones after having a fracture or orthopedic surgery that involves osteotomies. Mutations in the type I procollagen genes have not been found in these patients. This form of syndrome resembling osteogenesis imperfecta is the result of mutations of the CRTAP gene. Inheritance appears to be autosomal dominant.

The initial presentation often resembles that of osteogenesis imperfecta with bone fragility and deformity, but these patients develop hard, painful, and warm swellings over long bones that may initially suggest inflammation or osteosarcoma. Patients with this condition have white sclera and normal teeth.

On radiographs, a redundant callus can be observed around some fractures. The size and shape of the callus may remain stable for many years after a rapid growth period. Histomorphometric studies reveal that the bone lamella are arranged in meshlike fashion, as opposed to the typical parallel arrangement in patients with osteogenesis imperfecta.

A variant of this syndrome is called aspirin-responsible expansile bone disease.

Osteoporosis pseudoglioma syndrome

This condition is inherited in an autosomal recessive fashion. Bone fragility is mild to moderate. Blindness is due to hyperplasia of the vitreous, to corneal opacity, and to secondary glaucoma. The genetic defect has been identified and mapped to chromosomal region 11q12-13. The defect is specifically in the LRP5 gene that encodes for the low-density lipoprotein receptor-related protein 5.

Other ocular forms

At least 2 other forms with ocular involvement are described in the literature. One variant includes optic atrophy, retinopathy, and severe psychomotor retardation; another variant includes microcephaly and cataracts.

Congenital brittle bones with craniosynostosis and ocular proptosis (Cole-Carpenter syndrome)

Two boys and one girl have been described with this particular form. In the boys, diagnosis was made after several months of life, and they were apparently healthy at birth. They developed craniosynostosis, hydrocephalus, ocular proptosis, facial dysmorphism, and several metaphyseal fractures associated with generalized low bone density.

By adulthood, both boys were nonambulatory, with short stature, severe osteopenia, and bone deformity. They had normal intellectual and neurologic development.

No specific mutation has been identified as responsible for this syndrome. Neurologic development is normal in this form.

Congenital brittle bones with joint contractures (Bruck syndrome)

Patients with Bruck syndrome have congenital brittle bones that lead to repeated fractures, as well as joint contractures and pterygia (arthrogryposis multiplex congenita). Wormian bones are present.

Inheritance appears to be recessive. No mutations in the COL1A1 or COL1A2 genes were found in 3 patients with Bruck syndrome who underwent procollagen mutation testing. The basic defect was mapped to locus 17p12 (18-cM interval), where a bone telopeptidyl hydroxylase is located.

Congenital brittle bones with mineralization defect

This rare form is clinically indistinguishable from moderate-to-severe osteogenesis imperfecta. Diagnosis is possible only by means of bone biopsy findings, in which a mineralization defect affecting the bone matrix and sparing growth cartilage is evident. Patients have normal teeth, and they do not have wormian bones. They have no radiologic signs of growth-plate involvement despite the mineralization defect evident on bone biopsy. This form shares several characteristics with fibrogenesis imperfecta ossium, and a mild form may be observed.

The pattern of inheritance is not clear, but cases in 2 siblings from healthy consanguineous parents suggest gonadal mosaicism or a somatic recessive trait. The structure of the collagen molecule appears to be normal, and no mutations of COL1A1 and COL1A2 genes have been found.

Other recessive syndromes resembling osteogenesis imperfecta

Genetic studies of recessive syndromes resembling osteogenesis imperfecta reported in South African blacks showed mutations that involved both the CRTAP gene and the leucine proline-enriched proteoglycan 1 (LEPRE1) gene, which are both involved in collagen proline-3 hydroxylation. Cases of recessive lethal syndromes resembling osteogenesis imperfecta have been found to be caused by mutations in the CRTAP gene.

Several other syndromes with congenital brittle bones have been described in humans since the original publication describing syndromes resembling osteogenesis imperfecta as a class, including the association of elastosis perforans serpiginosa and congenital bone fragility^[3] and the association of severe hypertelorism, midface prominence, prominent/simple ears, severe myopia, borderline intelligence, and bone fragility.^[4]

A lack of cyclophilin B with normal collagen folding has been described in 2 siblings with congenital brittle bone disease without ryzomielia. They had a homozygous start-codon mutation in the peptidyl-prolyl isomerase B gene (PPIB), which results in a lack of cyclophilin B (CyPB), the third component of the complex. The patients' collagen had normal collagen folding and normal prolyl 3-hydroxylation, suggesting that CyPB is not the exclusive peptidyl-prolyl cis-trans isomerase that catalyzes the rate-limiting step in collagen folding, as was previously thought.^[5] Deficiency of cyclophilin B causes congenital brittle bones in mice.^[6]

The syndrome resembling osteogenesis imperfecta model was also applied to animal models of bone fragility.^[7]

Frequency

United States

The prevalence of OI is estimated to be 1 per 20,000 live births; however, the mild form is underdiagnosed, and the actual prevalence may be higher.

International

Prevalences appear to be similar worldwide, although an increased rate has been observed in 2 major tribal groups in Zimbabwe.

Race

No differences based on race are reported.

Sex

No differences based on sex are reported.

Age

The age when symptoms (ie, fractures) begin widely varies. Patients with mild forms may not have fractures until adulthood, or they may present with fractures in infancy. Patients with severe cases present with fractures in utero.