what-when-how
In Depth Tutorials and Information
VIIB) during pre-mRNA maturation, thus affecting the
processing of the amino terminal end of the pro-α1(I) or
pro-α2(I) chains of collagen I, respectively. It is charac-
terized as follows:
1,2
Clinical Findings
All cases known to date are summarized, with case
numbers, in
Table 23.1
(see also Addendum).
The hallmark of EDS VIIA and VIIB is the involvement
of ligaments and joint capsules. The disorder is character-
ized by severe multiple joint hypermobility and recurrent
subluxations and luxations of both small and large joints,
and ligamentous tears. All patients are ascertainable in
the newborn period, although the correct diagnosis is
still frequently only made years later. Congenital bilateral
hip dislocation is the rule (
Figures 23.1-23.3
), and mus-
cular hypotonia is prominent; both factors predispose
to the high incidence of breech presentation (Cases 2, 7,
16, 29, 38; see
Table 23.1
) and delayed gross motor devel-
opment. Short stature, if present, is due to severe thora-
columbar scoliosis and hip dislocation (Cases 34, 38).
Spondylolisthesis of L5-S1 was noted in Case 20.
In striking contrast to dermatosparaxis, the skin is
only moderately affected; it is usually thin, velvety, and
moderately extensible, doughy and redundant over the
limbs. An unusual criss-cross patterning of the skin on
the hands and feet has been observed in Case 37, occa-
sionally affected by poor healing of wounds with atro-
phic and hemosiderotic scars, especially in the adult. The
facies appear to be normal; however, facial dysmorphic
features with frontal bossing, hypertelorism, depressed
nasal bridge, macrostomia, micrognathia and bluish
sclerae have been described (Case 37).
35
Judging by six
affected members from a three-generation family, intrafa-
milial variability is slight (Case 1).
The occurrence of recurrent fractures, Wormian bones,
and abnormally wide fontanelles (
Table 23.1
) indicates
that the EDS VII phenotype includes bone changes and
fragility similar to those reported in mild OI.
11
Wormian
bones were noted initially in one family (Case 13) and
have since also been observed in Cases 4, 7, 17 and 32
(
Table 23.1
). Fractures seem to heal normally but docu-
mentation in the literature is sparse.
Major diagnostic criteria
Severe generalized joint hypermobility, with
recurrent subluxations
Congenital bilateral hip dislocation
Minor diagnostic criteria
Skin hyperextensibility
Tissue fragility, including atrophic scars
Easy bruising
Muscular hypotonia
Kyphoscoliosis
Radiologically mild osteopenia, occasionally
fractures
Historical Overview
Hass and Hass in 1958
3
suggested that there is a
distinct entity of loose-jointedness, which they called
arthrochalasis multiplex congenita (congenital lac-
cidity of the joints), which “represents, to some extent,
the antithesis of arthrogryposis multiplex congenita,”
and which may occur with or without skin changes.
In 1973, three patients with EDS VII were reported
who accumulated procollagen in their skin and ten-
don, and it was thought, therefore, that their disorder
resembled dermatosparaxis in cattle.
4
Since it was felt
that the accumulation of procollagen was most likely
to be due to a defect in the conversion of procollagen
to collagen, the activity of the converting proteinase
was determined in the culture medium of fibroblasts
from these patients and found apparently to be reduced
to between 10 and 40% of normal.
4,5
However, when
Steinmann and colleagues
6
reinvestigated the young-
est of the three reported patients
5
(Case 5 in
Table 23.1
)
they found the presence of mutant pNα2(I)-like chains
in collagen extracted from skin or produced by fibro-
blasts, and the activity of the procollagen N-proteinase
to be normal in cell extracts. The authors concluded that
there was a structural abnormality in the portion of the
pro-α2(I) chain that is normally cleaved by N-proteinase
(and other proteinases). The authors speculated further
that for sterical reasons molecules containing pNα2(I)
chains would interfere with fibrillogenesis and cross-
linking, thus leading to abnormal collagen fibrils and
increased solubility of collagen. After the description of
a similar patient, in whom the condition was due to a
mutant pNα1(I) rather than pNα2(I) chain,
32
the classi-
fication of EDS VII was subdivided into types VIIA and
VIIB, respectively, depending on whether the α1(I) or
α2(I) chain was affected.
1
Defect and Pathogenesis
The molecular defect in all cases elucidated to date
is remarkably homogeneous (
Table 23.1
). The entire
or partial loss of exon 6 during pre-mRNA process-
ing determines the lack of the N-telopeptide linking
the N-propeptide to the major triple helical domain of
the α1(I) and the α2(I) chains, respectively. Deletion of the
N-telopeptides in the pro-α1(I) (24 amino acid residues)
and the pro-α2(I) chain (18 amino acid residues) results in
loss of the small globular region of the N-propeptide (pres-
ent only in the pro-α1(I) chain), the N-proteinase cleavage
sites (Pro-Gln and Ala-Gln, respectively), the crosslink-
ing lysine residue of the N-telopeptide, the cleavage site
