what-when-how
In Depth Tutorials and Information
differential diagnosis of AOI. In fact, the current diag-
nosis of MS based on the Ghent nosology requires only
aortic root aneurysm and ectopia lentis.
48
The genetic
abnormality is fibrillin-1, which is an important part
of the extracellular matrix. Fibrillin is a glycoprotein
important for the structure of microfibrils, interacts
with elastin and locally regulates TGF-beta and BMP
levels. In fact, based upon our clinical experience and
mouse model abnormalities, TGF-beta signaling seems
to be responsible for most of the clinical manifestations
of Marfan's disease and aortic aneurysm development
in several disease processes.
49
The Marfan skeletal phenotype includes bone over-
growth yielding tall height, arachnodactyly (long in-
gers), long extremities and pectus deformities. Patients
may also have scoliosis or kyphosis. The BMD studies
generally show reduced femoral neck BMD in both men
and women and bone losses appear to be greater in the
cortical bone.
In 2005, a group of patients with similarities to MFS,
but without the ectopia lentis and negative fibrillin-1
genetic studies, were found to have genetic abnor-
malities in TGFBR1 or 2 and the syndrome was named
Loeys-Dietz syndrome (LDS) after the founders.
50
There appears to be little difference in the clini-
cal presentation between TGFBR1 and 2. LDS type 1
is diagnosed on the basis of craniofacial abnormali-
ties and aneurysms, while LDS type 2 is without cra-
niofacial manifestations. Osteoporosis was mentioned
in the phenotype, but the severity and incidence were
not reported; however, two recent reports suggest that
the bone phenotype is likely more severe in LDS than
MFS. Kirmani described two patients with LDS and
multiple childhood fractures.
51
The first was a 17-year-
old male with craniofacial abnormalities as well as
talipes equinovarus, aortic root dilatation necessitat-
ing surgical repair and a history of numerous fragility
fractures leading to significant skeletal deformity. The
second was a 26-year-old with a cleft palate, talipes
equinovarus, pectus excavatum requiring surgery and
multiple aneurysms in the ascending aorta, abdominal
aorta, carotid and subclavian, vertebral and brachial
arteries requiring surgical repairs. He had multiple
fractures in childhood and a low bone mineral density.
Both patients had mutations in the TGFBR2. Ben Amor
recently reported on two adolescents with LDS caused
by TGFBR2 mutations emphasizing bone histopathol-
ogy.
52
Both adolescents had z-scores more than 2 SD
below age-matched controls and the male had several
fractures and responded to intravenous pamidronate
therapy. The female had no fractures, very low BMD
and had a small response to bisphosphonate therapy.
Interestingly, the bone formation rate was elevated
and mineralization was rapid and there was increased
osteoid.
The differences between LDS and MFS include mul-
tiple aneurysms at younger ages, craniofacial abnormal-
ities including bifid uvula, cleft palate, hypertelorism
and arterial tortuousity, normal stature and probably
more childhood fractures and lower BMD. Interestingly,
both MFS and LDS patients may have blue sclera and
joint laxity. Both groups may have arachnadactyly, but
the LDS group does not have long extremities. The
LDS type 2 may be confused with ED4 and it is not
unusual to find TGFBR abnormalities in patients previ-
ously diagnosed with ED4. There are many similarities
between LDS and AOI, but the craniofacial abnormali-
ties and location of aneurysms are major differences.
The craniofacial abnormalities are not always present
and aneurysms may go undiagnosed until a cata-
strophic presentation.
JOIN
T HYPERMOBILITY SYNDR
OME
Joint hypermobility is defined as a condition in
which most of an individual's synovial joints move
beyond the normal limits taking into consideration
age, gender and ethnic background of the individual.
53
Hypermobility may be inherited,
54
and when it causes
symptoms it is referred to as the joint hypermobility
syndrome (JHS). Grahame envisioned this disease as a
more subtle presentation of OI, ED and MFS. JHS is the
most common of the hereditary connective tissue dis-
eases. There appears to be some overlap in the literature
between ED type 3 and the hypermobility syndrome.
Occasional cases of type 3 hypermobility are related
to tenacin mutations, but in many cases the genes are
not identified and it is more of a phenotypic diagnosis.
It is possible that this is a disease with multiple subtle
genetic abnormalities causing not only joint hypermo-
bility but low BMD.
References
