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CHAPTER
1
Evolution of the Present Understanding
of the Clinical and Genetic
Heterogeneity and Molecular and
Biochemical Basis of Osteogenesis
Imperfecta
David Owen Sillence
1
and Shireen R. Lamandé
2
1
Sydney Children's Hospital Network (Westmead), Westmead, New South Wales, Australia,
2
Murdoch Children's Research Institute, The Royal Children's Hospital, Flemington Road Parkville,
Victoria, Australia
The nomenclature and classification as well as the
pathogenesis of the brittle bone syndromes, now com-
monly known as osteogenesis imperfecta (OI), has
evolved considerably since the publication by Ekman
in 1788 of a thesis describing a fragile-boned family
Figure 1.1
).
1
From the very outset the familial nature of
an increased predisposition to fractures, distinct from
acquired causes of osteoporosis, has been an impor-
tant feature in directing avenues for research. Similarly,
since the description by Vrolik
2
that this bone fragil-
ity arose “
ex Imperfecta osteogenesis
,” an underlying
pathogenesis resulting from defects in the formation
and integrity of bone has been sought.
3
As with many
other disorders of the skeleton at the time there was a
tendency to apply eponyms to the various presenta-
tions of the brittle bone disorders, e.g., Ekman, Lobstein
or Vrolik disease and van der Hoeve syndrome etc.
4
Furthermore, the age at presentation coupled with a
notion of severity of the disorder was used to distin-
guish different “types” of OI into
congenital
, meaning
fractures at birth, and
tarda
, with later onset of fractures,
whereas in fact these were clinical descriptions which
had only a broad relationship to the pathogeneses of
individual brittle bone disorders. At that time the true
complexity of collagen protein biology and molecu-
lar genetics of matrix components could not have been
envisaged.
When Victor McKusick (1921-2008) published his
classic work
Heritable Disorders of Connective Tissue 4th
edition
in 1972, he could only state that “the exception-
ally wide range of expressivity” in OI “may be but dif-
ferent expressions of a single type of connective tissue
disorder, inherited as a Mendelian autosomal dominant
disorder. However the existence of an infrequent auto-
somal recessive form…is quite certain.”
5
A few authors
had published pedigrees which in addition to autoso-
mal dominant inheritance also supported the possibil-
ity that some types of OI showed autosomal recessive
inheritance. Once admitted that there were both auto-
somal recessively inherited forms of OI as well as
dominantly inherited types of OI, the conclusion was
reached that OI had to be a genetically heterogeneous
group of disorders. The question then was: how much
genetic heterogeneity was there? Recent studies have
characterized 14 gene loci in which mutations result
in various types of OI.
6,7,77-80
The relative prevalence
