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CHAPTER
20
Osteog enesis Imperfecta Type V
Tae-Joon Cho 1 and Pierre Moffatt 2
1 Seoul National University Children's Hospital and Seoul National University College of Medicine,
Seoul, Republic of Korea, 2 McGill University, Shriners Hospital for Children, Montreal, QC, Canada
Most cases of autosomal dominant osteogenesis
imperfecta (OI) are caused by mutations in the genes
encoding α1 or α2 chains of type I collagen ( COL1A1
[MIM120150] and COL1A2 [MIM120160]). In 2000,
Glorieux et  al. proposed a subtype of OI patients who
used to be categorized as Sillence type IV, but has spe-
cific clinical, radiological, and histological characteris-
tics without any pathogenic mutation in either COL1A1
or COL1A2 as type V. 1 Its characteristic features include
radioulnar interosseous membrane ossification (RUIMO),
radial head dislocation (RHD), hyperplastic callus forma-
tion (HC), metaphyseal radiodense band (MRB), autoso-
mal dominant inheritance and mesh-like lamellar pattern
on histopathologic examination.
Before it was proposed as a specific disease entity, there
had been several individual cases or family reports in the
literature that seem to describe patients with OI type V.
HC was their main issue, but figures or descriptions of
the cases indicated an association with RUIMO, MRB or
RHD. 2-4 Kozlowski and Bittner described an 8-year-old
girl under the title of a new demineralizing disease, who
had a fracture with minor trauma, multiple vertebral col-
lapse, MRB, RUIMO and RHD. 5 In 1993, Stöss et  al., 6
based upon their histopathologic investigation of unin-
jured bone tissue from those developing HC, suggested
that OI with HC was probably a separate subform of OI
besides the four types of Sillence classification.7 7 In 1997,
Nakamura et  al. reported an OI family of a mother and
son with recurrent HC as well as other features of OI type
V such as absence of blue sclera, dentinogenesis imper-
fecta, or joint laxity, RUIMO and RHD. They proposed HC
as an additional criterion in the classification of OI. 8
Some authors have argued whether to include this
entity as OI, 9 it is widely accepted as a unique subset of
OI due to bone fragility as well as spine and limb defor-
mity which are common features of OI. A diagnosis of
OI type V can be made without difficulty by clinical and
radiographic findings as long as the treating physician/
surgeon is well aware of this disease entity.
MO LECULAR GENETIC ASPE CT
Genotype
Using whole exome sequencing and/or linkage
analysis, a recurrent heterozygous point mutation of
c.-14C>T at the 5′ untranslated region (UTR) of the gene
encoding IFITM5 (interferon-induced transmembrane
protein 5) [MIM614757], also named as BRIL (bone-
restricted IFITM-like protein) 10 ( Figure 20.1 ) was found
to be a common mutation in 19 Korean patients 11 and
two German patients, 12 and in 42 patients of diverse
geographic origins including European, Mediterranean,
Arabic, Asian, and North, Central and South
Americans. 13 It is unique that, so far, all the OI type V
patients share the same mutation in IFITM5 without any
exception. This mutation introduces a new start codon
upstream of the coding region in-frame with it, and
the mutant protein is predicted to have five additional
amino acids (Met-Ala-Leu-Glu-Pro) at this N-terminus,
which was confirmed by in vitro transfection experiments
( Figures 20.2 and 20.3 ). 11,12
What is BRIL/IFITM5?
Bril was discovered as part of a high throughput
screen for cDNAs encoding secreted and membrane pro-
teins in osteoblastic cells. 14 BRIL is part of an evolutionary
conserved family of so-called interferon inducible trans-
membrane (IFITM) proteins for which there are at least
four closely related members in the human (IFITM1, 2, 3
 
 
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