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FIGURE 23.6
Marked joint laxity and osteoporosis. The patient in her forties presented with marked joint laxity (A, B) and severe scoliosis
requiring Harrington rodding. X-rays showed untreated bilateral congenital hip dislocation (C) and diffuse osteoporosis. She had some frac-
tures, suggesting that she is affected by an overlap form between EDS and OI. Informed consent for biochemical and molecular studies was
refused (own observation).
(Reprinted by permission from
2
.)
to a lesser degree in procollagen type II) and thus con-
trasts the arthrochalasis type, which results from muta-
tions in the substrate sites of procollagen I chains that
prevent proteolytic processing of type I collagen. As a
consequence of the enzyme deficiency, the uncleaved
pN-propeptides disturb collagen fibril formation lead-
ing to a decrease in the normal tensile strength of tis-
sues. Dermatosparaxis (“torn skin”) in cattle was the
first defect in collagen metabolism to be elucidated,
39
and was only later defined in man.
40
The hallmark
of the dermatosparactic type is the excessive fragil-
ity of the skin with mild to absent involvement of ten-
dons and ligaments. Alterations in bone have not been
described.
Striking abnormalities of the collagen fibril archi-
tecture are observed in skin, with fibrils that have an
irregular, branched, hieroglyphic appearance (
Figure
23.5C
). Longitudinally, the fibrils have a twisted, rib-
bon-like appearance.
37,41
Although distinctive, these
abnormal collagen fibrils may be almost indistinguish-
able from those in certain patients with the arthro-
chalasia type of EDS.
42
Biochemical confirmation is
based on the electrophoretic analysis showing the
accumulation of pNα1(I) and pNα2(I) chains of type I
collagen extracted from dermis in the presence of pro-
tease inhibitors.
37
Direct mutational analysis is usually
performed.
37,43
According to published cases, osteopenia and frac-
tures seem to play a minor role. Clinical variability is to
be expected and depends on the residual activity of the
mutant procollagen N-terminal proteinase, a phenom-
enon that is well known in numerous inborn errors of
metabolism.
and prevent or delay N-propeptide removal. The
pNα1(I) chain is incorporated into the matrix, decreases
fibril size and causes a phenotype with characteristics of
both OI and Ehlers-Danlos syndrome.
44,45
Disruption
of N-propeptide processing by defects in the helical part
of the α2(I) chain also leads to this phenotype.
46-51
In par-
ticular, one patient
51
presented with generalized osteo-
porosis, platyspondyly, Wormian bones, blue sclerae,
but no fractures, similar to the patient shown in
Figure
23.6
, and carried a 19 bp deletion that caused skipping of
exon 11 of
COL1A2
,
48
thus deleting one of the lysyl resi-
dues involved in intermolecular crosslink formation. The
presence of the shortened proα2(I) chain in procollagen
synthesized by the proband's fibroblasts both lowered
the thermal stability of the molecules and prevented or
delayed their processing by procollagen N-proteinase.
46
Thus, the deletion disturbed both the helical domain
and the cleavage site of the molecule, thereby result-
ing in the mixed EDS-OI phenotype. Recently, Malfait
et al.
52
reported seven new patients who presented with
a mixed OI/Ehlers-Danlos syndrome (EDS) phenotype.
They demonstrate that COL1A1 and COL1A2 single
exon skips and glycine substitutions that are located in
the type I collagen helical domain near the N-propeptide
cleavage site affect proper N-propeptide processing and
result in a mixed OI/EDS phenotype. Patients with this
type of mutation do not show a typical OI phenotype
but mainly present as EDS patients displaying severe
joint hyperlaxity, soft and hyperextensible skin, abnor-
mal wound healing, easy bruising and sometimes signs
of arterial fragility. In addition they show subtle signs
of OI including blue sclerae, relatively short stature and
osteopenia or fractures.
ED
S-OI OVERLAP SYNDROM
ES
LOCUS HETEROGENEITY
Glycine substitutions in the first 90 residues of the
α1(I) helical region disrupt a stable N-anchor domain
Locus heterogeneity is exemplified by several
patients (Cases 38-43) who are clinically similar to EDS
