Bone Histomorphometry - Osteogenesis Imperfecta - page 214

Genotype-Phenotype Correlations in Patients
with Collagen Type I Mutations
There are two general classes of mutations in type I
collagen that result in OI. 21 The first are mutations that
cause a failure to synthesize the products of one COL1A1
allele and thus lead to haploinsufficiency.22 22 The second
class of mutations results in the synthesis of collagen
molecules with structural abnormalities. This is most fre-
quently caused by the substitution of glycine by another
amino acid in the triple-helical domain of either the
alpha 1 or the alpha 2 chain. 21 The relationship between
genotype and histomorphometric phenotype in OI types
I, III and IV was examined in a study on 96 patients. 23
Core width (outer bone size) and trabecular bone
volume were similar between patients with haploinsuf-
ficiency mutations and those with helical glycine muta-
tions, but cortical width was about 50% higher in the
haploinsufficiency group. Parameters reflecting the activ-
ity of bone turnover varied significantly with genotype
and were lowest in the haploinsufficiency group. This
suggests that bone mass differences between these geno-
typic groups are mainly caused by differences of bone
modeling on periosteal and endocortical bone surfaces
and less by differences in trabecular bone metabolism.
For helical mutations, there was no obvious relation-
ship between the type of substituting amino acid or the
position of the mutation and histomorphometric param-
eters. The data also suggest that the classification of OI
according to phenotypic types provides a better reflec-
tion of histological disease severity than the grouping of
patients according to mutation type.

in bone formation and resorption rates. However, those
parameters that reflect bone formation activity in indi-
vidual remodeling sites were clearly decreased. The rate
of bone matrix deposition was less than half of the con-
trol value, and correspondingly osteoid seams were very
thin. Thus, bone remodeling in OI type V is characterized
by a normal rate of activation of remodeling units but
impaired bone formation within individual remodeling
units. Recent studies have found that OI type V is caused
by a recurrent mutation in a gene named IFITM5 . 25,26 At
present it is unclear by which pathways this mutation
leads to the bone tissue abnormalities that are character-
istic for this disorder.

OI Type VI
Bone histology and bone histomorphometry also
led to the initial identification of another subgroup of
OI patients. 27 These individuals initially had been diag-
nosed with OI type IV on clinical grounds. However,
evaluation of iliac crest biopsy samples yielded surpris-
ing results. There was loss of the normal orientation of
the lamellae and a “fish-scale” pattern under polarized
light. A large amount of osteoid was present, and inspec-
tion under fluorescent light revealed poor or diffuse
uptake of the tetracycline labels. These findings sug-
gested that there was a defect in matrix mineralization in
these patients.
Quantitative histomorphometry revealed that cortical
width and trabecular thickness were diminished in OI
type VI. 27 However, the amount of unmineralized oste-
oid was significantly increased in OI type VI patients and
mineralization lag time was increased, showing a delay
of mineralization. Thus, OI type VI is characterized by a
mineralization defect on the tissue level. Recent studies
have shown that this phenotype is caused by mutations
in a gene called SERPINF1 . 28-30 However, it is unclear at
present how this genetic defect leads to the mineraliza-
tion defect of OI type VI.

THE BONE TISSUE LEVEL IN NEWER OI
TYPES

OI Type V
Many OI patients present unusual clinical features.
One of these is hyperplastic callus formation, which can
appear spontaneously, following fracture or with intra-
medullary rodding. While studying bone sections from
OI patients, it was realized that those with a history of
hyperplastic callus formation also showed an abnormal
pattern of lamellation under polarized light. 24 Lamellae
were arranged in an irregular fashion and had a coars-
ened or even mesh-like appearance under polarized
light. It was then noted that patients with this particular
histological pattern also had distinctive features, includ-
ing calcifications of the interosseous membrane at the
forearm, hyperdense metaphyseal bands and a lack of
mutations in collagen type I. These observations led to
the classification of this disease entity as OI type V. 24
Comparison of quantitative histomorphometric
results in OI type V and controls revealed no difference

OI Type VII
OI type VII is an autosomal recessive form of OI that
is caused by mutations in the CRTAP gene. 31 This group
is a moderate to severe OI phenotype that is character-
ized by fractures at birth, bluish sclerae, early deformity
of the lower extremities, coxa vara, osteopenia and rhi-
zomelia. 32 Similar to OI type I, bone size is small, corti-
cal width is reduced and cancellous bone volume is low
in this form of OI. Histomorphometric analyses show
that bone turnover is increased but that the activity of
osteoblast in individual remodeling sites is low. 32 Thus,
the bone tissue-level findings in OI type VII are very
similar to those of OI types caused by mutations in col-
lagen type I.