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including FKBP10, SERPINF1 and SERPINH1 are
also associated with moderate to severe OI. OI can be
caused by noncollagen genes, and abnormalities of
collagen genes can cause diseases other than OI (see
below).
Finally, there is the recent description of severe OI
caused by a mutation of the osterix gene. 1 An Egyptian
child had about seven fractures per year, could not
walk until 6 years old and the parents were consan-
guineous. The osterix null mouse was reported to
have similar bone problems, slowed osteoblast dif-
ferentiation and decreased type 1a1 expression among
other genes. The osterix genes are found primarily in
the bone explaining the bone phenotype, but without
blue sclera or hyperflexibility. Thus, similar to type
I OI there is likely a quantitative defect in type I col-
lagen, but also deficiencies in other osteoblast protein
products. Interestingly, there is a suggestion from sev-
eral genome-wide association studies that variations
in the osterix region are associated with low bone min-
eral density (BMD). A simple but important concept is
that the bone phenotype may be related to quantitative
deficiencies of type I collagen caused by various genes
including osterix and more subtle changes may be
related to osteoporosis.
In addition to the complexity of collagen forma-
tion, there is the complexity of the bone, skin and
tendon and ligament matrixes. There are multiple
collagen and noncollagen proteins that bind to type I
collagen, including types III and V collagen, fibrillin,
integrins, proteoglycans and growth factors. These fac-
tors may regulate collagen formation and destruction
and may interact structurally with the type I collagen.
Ligamentous laxity may be related to collagen fiber
diameter and when it is the primary manifestation, ED
disease is a prime consideration. Unfortunately, there
are many types of ED caused by different genes. The
Beighton Index is the most commonly used metric to
quantitate flexibility.2 2
Skin contains both collagens type I and III and may
reflect similar changes in the bone collagen and thus thin
skin may be associated with low bone mass. 3 Pinching
the skin over the dorsum of the hand can give a quick
appreciation of the skin thickness and elasticity and
glancing at the hands and arms quickly reveals bruises.
Classic ED may be associated with increased elas-
ticity, old scars and new ecchymoses. Several diseases
adversely affect both the skin and the bone: exogenous
or endogenous glucocorticoids, anorexia nervosa,
hyperthyroidism, estrogen deficiency and aging. The
converse is also seen with insulin resistance and acro-
megaly associated with thick skin and large bones or
higher BMD.
The ratio of the length of bone to the width has
important biomechanical implications. If a tree and
a pencil were made of the same materials, intuitively
we know that the bending forces to break the tree are
greater than those needed to break the pencil. The areal
BMD assumes that the depth of bone is the same in all
individuals and therefore petite individuals will have
lower areal BMD than large individuals. Thus, the
dual energy X-ray absorptiometry bone mineral den-
sity (DXA BMD) scan measures both density and size.
Apposition of the thumb to third inger around the
wrist is a quick way to assess the bone length to width
ratio. Marfan's disease immediately comes to mind
as a disease process that has the greatest digital over-
lap. At the mention of Marfan's disease, aneurysms
are frequently the first concern, but Marfan's patients
also have osteopenia. In fact, it is our experience that
there is significant digital overlap for all of the follow-
ing diseases: OI type I, ED, Marfan's disease and some
patients with osteoporosis.
More subtle clinical manifestations may appear to be
a combination of OI, ED and Marfan's and are some-
times referred to as the hypermobility syndrome. The
genetics of this disease are not well studied nor is the
natural history clear.
The differential diagnosis of AOI in this chapter
will be limited to Ehlers-Danlos disease, osteoporo-
sis, Marfan's and hypermobility syndrome. The phe-
notypes will be explored and the similarities and
differences to AOI will be stressed. The genetics of
the disease will be reviewed and emphasis placed on
the protein product interactions with type I collagen.
Finally, transforming growth factor beta (TGF-beta)
which is commonly stored in the matrix in a latent form
and is crucial to aneurysm formation in Marfan's dis-
ease will be discussed in relation to the various other
diseases as appropriate.
EDS AND TYPE I OI
Ehler-Danlos syndrome (EDS) is a group of heritable
connective tissue disorders that share the common fea-
tures of skin hyperextensibility, articular hypermobility
and tissue fragility. 4 There are many types of EDS and it
is important to be familiar with their characteristics in
order to differentiate them from adult OI.
Beighton et  al. 15 reported a revised nosology of the
EDS, designated the Villefranche classification. It includes
six main descriptive types that substituted earlier types
numbered with Roman numerals (see Table 28.1 ). 15
Marini et  al. reported a discrete subgroup of OI
patients with combined OI/EDS which is an overlap
of the skeletal fragility of OI and the joint laxity of the
EDS. 5-7 It is a rare disorder caused by mutations to the
collagen type I gene, but demonstrates the potential
overlap between these two diseases.
 
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