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CHAPTER
2
Clinical and Genetic Classification
of Osteogenesis Imperfecta and
Epidemiology
Jay R. Shapiro
Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA
INTRODUCTION
differences including the adequacy of population sam-
pling as well as epigenetic factors that may change gene
expression in different populations.
The clinical classification of OI is a source of confusion
for physicians and patients and their families. Patients and
parents with young children consider the current schema
for classification, i.e., the Sillence classification, as having
predictive significance as to the future course of the disor-
der. Emphasis may be placed on classifying based on the
results of genetic testing where such predictive value does
not currently exist. Clinical decisions by physicians may
be based on the assumption that OI of a certain OI “type”
implies an eventual medical outcome where that may not
be the case. One example involves predictions of potential
fetal lethality based on the findings of uterine ultrasound
suggesting type II OI where such conclusions have been
shown to be unwarranted in several cases.
This discussion presents examples of where the
genetic classification of OI is a “work in progress.” First,
because of the expanding number of genes associated
with an OI phenotype, and second, because of marked
variability in gene expression that is characteristic of OI.
We are currently in the most dynamic period yet expe-
rienced for the understanding of the molecular basis of
osteogenesis imperfecta (OI), the recognition of the causes
of clinical variation, and the potential for the identification
of new and more effective therapies. In this chapter we
discuss three topics: the clinical heterogeneity of OI, the
genetic bases of that heterogeneity and the epidemiology
of OI. The objective of this chapter is to provide a platform
on which to understand the complexity that underlies the
clinical diagnosis of OI, the implications for treatment, and
the ability to provide clear counseling about the natural
history and recurrence risks in each family.
A current assessment of the epidemiology of OI,
that is, the prevalence of genotypes in any one popula-
tion, cannot be accurately described because of the sev-
eral mutations that have recently been defined in genes
directly and indirectly related to bone matrix synthesis.
With regard to specific OI phenotypes, again, limited
prevalence numbers are available for many populations.
As an example of the population data yet to be inves-
tigated, Cabral et al. identified an LEPRE1 mutation
exclusively in African Americans and contemporary
West Africans.
1
The mutation (
LEPRE1
c.1080 + 1 G>T)
is perinatal lethal when homozygous but heterozygous
carriers are clinically unaffected. The study revealed that
approximately 0.4% of Mid-Atlantic African Americans
carry this mutation, estimating recessive OI in 1/260,000
births in this population, compared to an estimate of
1/18,260 births affected with recessive OI in Nigeria
and Ghana.
1
There are many potential reasons for these
CLINICAL AND GENETIC
CLASSIFICATIONS OF OI
OI has been recognized as a discreet familial disorder
for almost three centuries. Parent to child inheritance was
appreciated in many families and while very marked
clinical heterogeneity was identified the genetic or
molecular bases of this variation were not known. Prior
