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In Depth Tutorials and Information
genetic techniques and discoveries about collagen gene
structure were being made.
65
However, in terms of
sheer scholarship relating to the clinical delineation of
OI, this topic has not been surpassed. It gives the most
complete account of the rare type of OI now known as
OI with calcification of interosseous membranes and
tendency to hyperplastic callus (OI type V).
In terms of applied basic research in OI, Peter Byers
and his many colleagues and collaborators over the
years stand out for thoughtful and consistent progress
in discovery in OI. Their contribution up to 2002 is pre-
sented in Royce and Steinmann's second edition.
47
However, it should not be forgotten that progress in
understanding OI, its pathogenesis, genetic basis and
clinical implications has been enormously enhanced
by the many doctoral contributions which have been
undertaken. Knud Seedorf's doctorate
3
reported
detailed clinical and genetic analysis of 55 Danish fami-
lies comprising 180 affected members.
3
It stands alone
as the most comprehensive clinical reporting of indi-
viduals and families, with many photographs showing
OI as we remember it before the era of bisphosphonate
modified OI. Gunnar Smars
66
reported on 274 Swedish
patients of whom 190 were included in detailed studies
comparing clinical findings in 160 patients with OI with
blue sclerae with 30 with normal sclerae.
66
There were
many striking differences including a high frequency of
arcus corneae and bruising tendency in those with OI
type I. The thesis also included a detailed sociomedical
study and assessment of the consequent impairments
in OI. Antony (A.J.T.M.) Garretson
67
concentrated on
the clinical, genetic and otolaryngologic features in 103
patients from 144 pedigrees in the Netherlands with
classic OI type I.
67
The average frequency of hearing
loss was 43% with subjects showing progressive hear-
ing loss with age such that 95% of subjects over 30 had
hearing loss on audiometric testing. Kaija Kuurila
68
returned to the natural history, genetics and hearing
loss ascertaining to 299 living Finnish patients.
68
She
again showed that hearing loss was progressive with
age. Patients with OI type I and type III appeared to
have more hearing loss than those with OI type IV, but
this was not significant. A high frequency of vertigo, in
over 50% of adults, was encountered.
Two doctoral theses have dealt with the dental
anomalies in OI. Janna Waltimo
69
undertook a den-
tal clinical, radiographic and ultra-structural study in
the various types of dentin dysplasia including OI.
69
Not all patients with OI have abnormal dentin at the
clinical and radiographic level. Nevertheless, meticu-
lously performed ultrastructural studies identified
abnormalities in dentinal tubules or collagen fiber size
in some patients with clinically normal teeth. Barbro
Malmgren's doctoral studies in 2004 of genetic, den-
tal, clinical, radiographic and histopathologic studies
of opalescent dentin in 68 patients with different types
of OI found an overall prevalence of 42%.
70
The pres-
ence of opalescent dentin was to some extent associ-
ated with severity of the OI. Furthermore, impaction of
second molars was more common that in controls and
OI was highly heritable. Raoul Engelbert
71
presented
a thesis on the musculoskeletal impairments and dis-
ability found in a large cohort of 54 children with OI.
71
The studies included a 1-year prospective study and
the impact of an orthopedic intervention with intra-
medullary rodding. The study confirmed a correlation
between the finding of opalescent dentin and a higher
prevalence of basilar impression and scoliosis. David
Sillence
72
set out to resolve the genetic relationship
between OI with distinctly blue sclerae and tendency to
adult onset hearing loss (Van der Hoeve syndrome) and
perinatally lethal and progressively deforming OI phe-
notypes.
72
It appeared that not only did these pheno-
types remain discrete entities but it was hypothesized
they might have a separate genetic basis. Dr. McKusick
recommended that the four OI syndromes which were
most clearly delineated be numbered OI types I-IV in
order of their delineation. Shireen Lamande
73
devel-
oped new rapid methods to screen for and identify
glycine mutations in type I collagen genes and showed
that collagen chains with mutant C-propeptides were
degraded by an ER-associated mechanism,
73
thus pav-
ing the way for future studies on the role of ER stress in
OI phenotypes. Fleur Van Dijk
74
returned to the central
question in OI, revisiting current concepts of the clini-
cal and genetic heterogeneity.
74
The thesis addressed
the clinical heterogeneity arising from mutations in the
three genes for the proteins of the propyl 3-hydroxylase
complex CRTAP, LEPRE1 and PPIB. A further report of
a novel FKBP10 mutation in a patient with Bruck type
I rounded out the delineation of four of the eight reces-
sive loci (known up to 2011) which result in autosomal
recessive forms of OI. The International Nomenclature
Committee noted these recommendations as a signifi-
cant advance on the original Sillence classification and
incorporated these suggestions as shown in
Table 1.2
,
which summarizes the present nomenclature of dis-
orders which may result in a progressively deforming
OI phenotype. The thesis is encapsulated in two of the
eight papers arising from this work, one revisiting the
nomenclature of OI syndromes,
6
the other deriving best
practice guidelines for laboratory study of OI patients.
75
PAMIDRONATE MODIFIED OI (LESS
SEVERE)
Since the discovery that the systematic use of inter-
mittent infusions of pamidronate resulted in reduced
fracture frequency, reduced deformity, improved
