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OSTEOGENESIS IMPERFECTA (OI)
PATIENTS WITH DISTINGUISHING
CHARACTERISTICS
linkage analysis mapped the critical region to chromo-
some 3p22-24.1.
31
This is a region where no type I col-
lagen genes are located and therefore represented the
formal proof of genetic heterogeneity underlying the
pathogenesis of OI.
Elsewhere, concomitant studies were aimed at iden-
tifying the role of the Crtap protein during mouse skel-
etal formation. The generation of
Crtap
-null mice and
the study of their phenotype (
Figure 14.2
- discussed in
detail in the section “Mouse Phenotypes with Mutations
in
Crtap
,
Lepre1
and
Ppib
Genes,” below) revealed a strik-
ing osteopenia with kyphosis and rhizomelia which was
reminiscent of the clinical feature observed in OI VII.
11
Moreover, the human
CRTAP
gene was mapped earlier
on 3p22
32
making it an excellent candidate gene for caus-
ing OI VII when mutated. Genomic DNA prepared from
primary fibroblasts of two patients diagnosed with OI
type VII showed no sequence abnormalities in the cod-
ing region of
CRTAP
but further investigations identified
a single base-pair substitution in intron 1 that created a
novel splice site. This caused about 90% abnormal splic-
ing with the inclusion of a cryptic exon, a frameshift
and a degradation of the transcript.
11
About 10% of the
mRNA was properly spliced and translated into a small
amount of normal protein which likely explained the
less severe phenotype. Therefore, the single base change
was deleterious and created a “hypomorphic allele” that
was present in homozygosity in all affected individu-
als of the pedigree.
11
True null-mutations of the
CRTAP
gene were identified shortly after in either severely
affected newborns or in fetal fibroblasts derived from
terminated pregnancies in which the fetus was diag-
nosed
in utero
with severe type II
/
III OI.
11,33
Thus,
CRTAP
was the first identified gene whose mutations cause
recessive OI. As of today, several mutations have been
described (for an updated list and description see
www.
1 and exon
/
intron 4 (out of a total of seven exons) and
the majority of them result in null alleles either due to a
nonsense mutation or a frameshift that generates a pre-
mature termination codon.
11,17,33-37
Compound hetero-
zygosity for a null allele and a missense allele has been
described
36
as well as homozygosity for a missense or a
small 6 base-pair in-frame deletion.
18
Irrespective of the
sequence alteration,
CRTAP
mutations usually result
in loss-of-function and a severe to lethal form of reces-
sive OI. Ultrasound prenatal diagnosis consistently
reveals shortening of the limbs and multiple fractures.
Newborns most often present with normocephaly,
Wormian bones, white to grayish sclerae, very severe
generalized hypomineralization, short undertubulated
femurs often in abducted position, rhizomelia, bowing
and multiple fractures of the long bones (
Figure 14.3
).
38
A differential molecular diagnosis between type II
/
III
The clinical presentation of OI shows great vari-
ability and Dr. David Sillence, at the end of the 1970s,
developed a classification of the disease based on clini-
cal severity and radiological findings.23,24
23,24
This classifi-
cation has been and continues to be effectively used for
clinical diagnosis and management. It identifies four
types of OI: type I OI being the mildest form and then
types IV, III and II in increasing order of severity, with
type II OI being almost invariably lethal. All of the non-
lethal, severe, deforming forms of OI were classified as
type III OI, while all other cases from mild to moder-
ate that did not it well into type I, II or III ended up
being classified as type IV (often with short stature).
Therefore, although variability of presentation was also
found in the other groups, especially in type II, patients
with type IV OI probably represented the most het-
erogeneous group.
24
Moreover, the recurrence of sib-
lings affected with OI in families with healthy parents,
especially in geographic regions where consanguine-
ous marriages are fairly common, strongly suggested
the existence of genetic heterogeneity and recessively
inherited OI not caused by mutations in type I collagen
genes.
24-27
Beginning in the year 2000, careful clinical
definition in some patients originally diagnosed with
type IV OI led to an extension of the original classifi-
cation with the description of new types of OI. Type V
OI, for instance, was recognized among a few patients
who consistently presented with hyperplastic bone cal-
lus formation, a unique calcification of the interosseous
membrane between the radius and ulna and a radio-
dense metaphyseal band close to the growth plate. This
type of OI is inherited in a dominant fashion.
28
Type
VI OI, in contrast, could only be distinguished by bone
histomorphometry analysis due to its pathognomonic
bone mineralization defect with prolonged mineraliza-
tion lag time and osteomalacia phenotype. In addition,
a mild elevation of serum alkaline phosphatase was
noted.
29
Another distinct type of OI, termed OI type
VII, was instead identified in a large pedigree of First
Nation Indians in northern Quebec. It was described
as clinically moderate to severe with neonatal frac-
tures, low bone mass, early bone deformities and blu-
ish sclerae but also coxa vara and rhizomelia which was
a distinctive characteristic.
30
The clinical rhizomelia
raised the possibility of a concurrent chondrodysplastic
process. Bone histomorphometry of iliac crest biopsies
showed a decrease in both trabecular and cortical bone
thickness similar to type I OI, with preserved birefrin-
gent pattern of bone lamellae and increased bone turn-
over.
30
Importantly, it was recessively inherited and
