Osteogenesis Imperfecta: Classification And Variants.

Francis H. Glorieux, M.D., Ph.D.
Genetics Unit, Shriners Hospital for Children, and McGill University, Montreal, Qc, Canada.

Osteogenesis imperfecta (OI), often referred to as "brittle bone disease", is a heritable disorder characterized in most instances by either qualitative or quantitative abnormalities in the synthesis of the most important component of the bone matrix, type I collagen. There are, however, forms of OI where links with the type I collagen genes are not readily apparent. Even in those cases where a mutation in either the COL1A1 or the COL1A2 gene has been established, there is not evident correlation between the type and molecule position of the mutation, and the severity of the clinical phenotype. Thus molecular diagnosis is, at present, of little help to characterize clinical severity and prognosticate evolution. Careful clinical evaluation remains of utmost importance to delineate the wide range of expression of the basic abnormalities underlying OI.

Sillence in 1979 proposed a classification based on clinical, radiographic and genetic criteria, that quickly was adopted worldwide: Type I is the mildest form, with occasional fractures before puberty, minimal deformity and normal stature. Large families from that group were used to demonstrate linkage with COLlAl and COLlA2. In type II, the most severe (lethal) form, fractures in utero lead to pulmonary insufficiency and perinatal death. In type III, frequent fractures causing progressive deformities, short stature, and triangular face are characteristic. In type IV, deformities and dwarfism are present, but are less severe. This latter group is heterogeneous, and is generally viewed to include all OI cases who do not fit clearly into one of the first three types. One such example are the two cases described by Cole and Carpenter (J. Pediatr. l10: 756, 1987) where bone fragility was accompanied by craniosynostosis, ocular proptosis, hydrocephaly and distinctive facial features.

Another level of characterization of OI is based on detailed bone histology and histomorphometry (see Rauch et al.). This approach has allowed to clearly separate from type IV, a group of patients now referred to as type V [Glorieux et al., J. Bone Min. Res. 12(l), 5389, 1997]. Its unique features are a high incidence of hypertrophic calluses and early ossification of the interosseous membrane of the forearms and legs. It is transmitted as a dominant trait, and there is no alteration in the sequence of either the COLlAl or the COL1A2 gene.

Three other variants, all transmitted as recessive traits, have been identified. In population isolates of South Africa (Wallis et al., J. Med. Genet. 30: 492, 1993) and North America (see Travers et al., P-44) large pedigrees have been studied by linkage analysis, and co-localization of the disease locus with those of COLlAl and COLlA2 has been excluded. In the North American population, the disease locus was mapped to 3p21-24. The second variant is the ocular form of OI also referred to as "osteoporosis-pseudoglioma syndrome" (OPG) where bone fragility and blindness segregate together. The locus for OPG was mapped to 11q12-13. The third variant is the Bruck syndrome, a recessive trait mapped to 17p12, characterized by bone fragility and congenital joint contractures. Although not linked to the type I collagen genes, it has been shown to be the expression of a mutation in the bone specific collagen type I telopeptide lysyl hydroxylase, (Bank et al., PNAS 96: l054, 1999).

Since genotype-phenotype correlations are not straightforward in the various forms of OI, such careful evaluation at different levels of the OI spectrum will continue to shed light on the basic mechanisms at play, with the ultimate goal to define efficient therapeutic approaches.

Reference: Proceedings of the 7th International Conference on Osteogenesis Imperfecta. Montreal, Canada, 1999.