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with normal parents and, in some families, evidence of
parental consanguinity. It was soon recognized that sib
recurrence was better explained by parental mosaicism
for dominant mutations in type I collagen genes and, as a
result, the search for the recessive causes of OI was unex-
pectedly delayed for more than a decade.
5
Like OI type
II, a progressive and deforming type of OI, type III, was
thought to result from recessive mutations. These children
usually did not die in the perinatal period but did have
marked bone deformity, severe scoliosis, white sclerae
and usually were mobile only with assistance. Again,
biochemical and genetic studies soon demonstrated that
most of these individuals had dominant mutations in type
I collagen genes. It is important to point out, however, that
the first mutation identified in a type I collagen gene was
a homozygous frameshift in
COL1A2
in a child thought
to have a milder form of OI type III.
6
This was followed
shortly by clear evidence that dominant mutations in type
I collagen genes were more frequent causes of OI type III.
OI type IV was characterized by dominant inheritance,
non-blue sclera, usually shorter than those with OI type I,
and had dentinogenesis imperfecta (DI) and moderate
bone deformity. It was recognized from the outset that
these numerical descriptions transformed a clinical con-
tinuum into a more rigid classification in an attempt to
provide a basis for counseling about the risk for future
pregnancies.
It did not take long for additional heterogeneity to
be recognized as new investigational tools were used.
On clinical grounds, it was recognized that some indi-
viduals initially considered to be in the OI type IV group
developed dramatic hypertrophic callus. This condition
was dominantly inherited and separated out as OI type
V.
7
When new laboratory studies were applied, some
individuals thought to have OI type IV were found to
have unusual histological changes in bone when it was
examined under polarizing light. They were reclassified
into a group called OI type VI, in which inheritance was
thought to be autosomal recessive, on the basis of sibling
recurrence with unaffected parents.
8
Also, earlier there
has been recognition of a group of individuals who had
joint contractures at birth and went on to develop frac-
tures. This combination of fractures and contractures
was called Bruck syndrome in recognition of the German
physician who had described a young man with frac-
tures and contractures in the late 1800s.
9
Although often
sporadic, sibling recurrence to unaffected parents was
consistent with recessive inheritance. The era of clinical
differentiation of OI types culminated with the descrip-
tion of an apparently recessively inherited form of OI
among a First Nations Canadian population in which
clinical features included striking rhizomelia with frac-
tures, designated as OI type VII.
10
Type VIII OI has been
separated from the above based on clinical features
which include lethal to severe phenotype, white sclerae,
undertubulation of the long bones, gracile ribs without
beading and a small to normal head circumference.
11
It is now appreciated that the identification of muta-
tions in the type I collagen genes and in genes involved
in type I collagen intracellular processing has not per-
mitted a clear separation of individual types of OI: e.g.,
genotype/phenotype relationships are not established
for any of the dominantly inherited Sillence OI types
I-IV (see Dalgleish, Chapter 10). An element of clinical
ambiguity also exists for the recently described OI types
that are recessively inherited. An example is that Sillence
type II OI, associated with COL1A1 or COL1A2 muta-
tions, presents a severe phenotype and is lethal in the
perinatal period: a few infants will, however, survive.
Recessively inherited mutations in CRTAP and LEPRE1
genes (
Table 2.1
) are also associated with a lethal or
severe phenotype termed OI type VIII, which at birth is
clinically indistinguishable from autosomal dominant
Sillence type II disease.
12
However, Marini et al. sug-
gest differentiation of type VIII OI in that neonates with
this severe OI type due to CRTAP/LEPRE1 mutations
have white sclerae, broad long bones, gracile ribs with-
out beading and a small to normal head circumference.
11
In contrast to this designation, Van Dijk et al. have pro-
posed a revised classification of OI with the exclusion of
OI type VII and VIII since these types have been added
solely because of genetic criteria (autosomal recessive
inheritance) while the clinical and radiological features
are indistinguishable from OI types II-IV.
13
Table 2.1
lists the 12 genes which are, to date, associ-
ated with the OI phenotype including Bruck syndrome.
Mutations affecting PPIB, FKBP10, SP7 and SERPINH1
have been listed as associated with moderate to severe
OI phenotypes and recently have been given the des-
ignation OI types IX, X, XI and XII. FKB10 mutations
have also been associated with the Bruck phenotype
that is also associated with PLOD2 mutations.
14
Barnes
et al. identified two arms of a Palestinian pedigree
that included both moderate and lethal forms of reces-
sive OI caused by mutations in
FKBP10
or
PPIB
which
encode chaperone/isomerases FKBP65 and CyPB. In
one pedigree branch, both parents carry a deletion in
PPIB
(c.563_566delACAG), encoding cytophyllin, caus-
ing lethal type IX OI in their two children. In another
branch, a child with mild/moderate type XI OI has a
homozygous
FKBP10
mutation (c.1271_1272delCCinsA).
However, because of overlap in characteristic signs,
characterization of these phenotypes both clinically or
radiologically does not permit definition of these pheno-
types as distinct clinical entities.
Another level of complexity is added in that Pyott et al.
have now reported that mutations involving PPIB may
be associated with a phenotype that varies from perina-
tal lethal to moderately severe OI.
15
Recognition of mark-
edly variable expression questions the value of assigning
