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of different BMD studies in MFS is hampered by differ-
ent methodologies and poor standardization for height,
weight, sex and age.
16,17
Although Loeys-Dietz syndrome shares many skel-
etal findings with MFS, the two syndromes also have
some differences. In general the long bone overgrowth is
less pronounced in LDS. Talipes equinovarus (club foot
deformity) and forefoot varus deformity are common
in LDS and less typically seen in MFS. Also specific for
LDS are cervical spine malformations, most commonly
anterior and posterior arch defects. Increased incidence
of osteoporosis and bone fragility has also been reported
for LDS.
13,18
Finally, based on the study of two LDS
patients, low bone mass and high bone turnover with
increased matrix mineralization of trabecular bone has
been suggested.
19
Prominent bone involvement with early onset osteo-
arthritis and intervertebral disc degeneration has been
reported in the aneurysm-osteoarthritis syndrome,
which phenocopies Loeys-Dietz syndrome.
20
This condi-
tion is caused by loss-of-function mutations in
SMAD3
,
the first downstream intracellular effector of TGFbeta
signaling, and is also characterized by hypertelorism,
bifid uvula, widespread aortic disease and arterial tortu-
osity. Van de Laar et al.
21
described osteochondritis dis-
secans in about half of these patients, mostly affecting
the medial femur condyle. More than 90% of the patients
had intervertebral disc degeneration, most prominent
in the cervical and lumbar spine. Nearly all
SMAD3
mutation-positive patients had osteoarthritis of the knee,
spine, hand or foot. As many LDS patients are in the
pediatric age range, features such as premature osteoar-
thritis have not been fully investigated.
Another subgroup of patients sharing clinical features
with both MFS and LDS were shown to have loss-of-
function mutations in the gene coding for the cytokine
TGFB2 itself. Features shared with MFS and LDS include
aortic aneurysm, pectus deformity, arachnodactyly, sco-
liosis and skin striae. Features shared with LDS but not
with MFS included hypertelorism, bifid uvula, bicuspid
aortic valve, arterial tortuosity, club feet and thin skin
with easy bruising.
22
Two other conditions present with Marfanoid features
and are connected to the TGFbeta signaling pathway:
Camurati-Engelman syndrome and Shprintzen-Goldberg
syndrome. Camurati-Engelman syndrome is radiographi-
cally characterized by hyperostosis in the long bones and
the skull. Other recurrent features are proximal muscle
weakness, limb pain, a wide-based and waddling gait,
and joint contractures. In some families, a Marfanoid body
habitus has been described.
23
The disease is caused by
gain-of-function mutations in the TGFbeta1 gene.
24
Shprintzen-Goldberg syndrome is characterized
by craniosynostosis, distinctive craniofacial features
with dolichocephaly, retrognathia, high arched palate,
Marfanoid skeletal changes including dolichostenome-
lia, arachnodactyly, camptodactyly, pes planus, pectus
excavatum or carinatum, scoliosis, joint hypermobility
or contractures. Cardiovascular anomalies with mitral
valve prolapse, mitral regurgitation and aortic regur-
gitation may occur, but aortic root dilatation is usually
mild. Nearly all SGS patients present with developmen-
tal delay. It was shown that the condition is caused by
de novo
loss-of-function mutations in SKI, a functional
TGFbeta repressor.
25
Finally, CCA, congenital contractual arachnodactyly
or Beals syndrome, belongs to the group of Marfanoid
conditions with links to TGFbeta. Beals syndrome is
characterized by arachnodactyly, crumpled ears, congen-
ital contractures of small and large joints, and progres-
sive scoliosis. This condition is caused by mutations in
the fibrillin-2 gene (
FBN2
), which encodes a protein that
is highly homologous to fibrillin-1.26
26
TGFbeta IN SYNDROMES WITH SHORT
STATURE
Perhaps surprisingly, domain-specific
FBN1
muta-
tions were found in geleophysic and acromicric dyspla-
sia, two skeletal disorders from the group of acromelic
dysplasias.
27
Both forms are characterized by severe
short stature, short extremities and stiff joints.
28
All
FBN1
mutations identified in the geleophysic and acromicric
dysplasias were identified in exons 41 and 42, which
encode TGFbeta-binding protein-like domain 5 (TB5) of
FBN1. In addition a subgroup of patients with acromicric
dysplasia was previously shown to harbor mutations in
the
ADAMTSL2
gene.
29
Importantly, a direct interaction
between ADAMTSL2 and FBN1 was demonstrated, sug-
gesting a disruption of this interaction as the underlying
mechanism of these skeletal dysplasias. The ADAMTS
family encompasses a group of proteins, with a disin-
tegrin-like and metalloproteinase domain with throm-
bospondin type 1 repeats. These proteins have a role in
extracellular matrix degradation and turnover.
30
Of interest, another autosomal recessive connective tis-
sue disorder, the Weill-Marchesani syndrome, character-
ized by short stature, brachydactyly, joint stiffness and
characteristic eye anomalies (microspherophakia, ectopia
of the lenses, severe myopia and glaucoma) was shown to
be caused by mutations in another family member of the
ADAMTS family, namely
ADAMTS10
.
31
Also fascinating
is the fact that rare
FBN1
mutations have been found in
an autosomal dominant form of WMS. No specific pat-
tern emerges from the localization of the
FBN1
mutations
in WMS but specific mutations might alter interaction
with different fibrillin-1 binding partners.
