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mutation, is known as LDS1B. LDS type II has cutaneous manifestations including velvety and
translucent skin, easy bruising, widened and atrophic scars, and uterine rupture. LDS type II caused by a
TGFBR1 mutation is known as LDS2A, whereas LDS type II caused by a TGFBR2 mutation is known as
LDS2B. Identical mutations can lead to LDS type I or type II, supporting the belief that both types are
part of a clinical continuum. Mutations in the TGFBR2 gene have also been identified in conditions with
phenotypic overlap with LDS. Marfan syndrome (MFS) is a systemic connective tissue disorder involving
the ocular, skeletal, and cardiovascular systems. MFS is most often associated with mutations in the
FBN1 gene; however some individuals who meet, or nearly meet, the clinical diagnostic criteria for MFS
have been shown to have mutations in TGFBR2. Familial thoracic aortic aneurysm and dissection
(TAAD), which involves cardiovascular manifestations only, has also been associated with mutations in
TGFBR2. Shprintzen-Goldberg syndrome, a rare disorder characterized by marfanoid habitus,
cardiovascular anomalies, mental retardation, and craniosynostosis, has been associated with a TGFBR2
mutation. TGFBR2 mutations have also been identified in individuals who phenotypically presented with
vascular type Ehlers-Danlos syndrome (EDS), but tested negative for COL3A1 mutations (the gene
typically associated with vascular EDS). Transforming growth factor-beta receptor II (TGFBR-II) is a 70
to 80 kDa protein that belongs to the serine-threonine kinase family of cell surface receptors. This group
of receptors regulates a variety of cellular processes including proliferation, differentiation, cell cycle
arrest, apoptosis, and formation of the extracellular matrix. Receptor activation occurs upon binding of
transforming growth factor-beta (TGFB) to TGFBR-II, which then recruits and phosphorylates TGFBR-I,
propagating the signal to downstream transcription factors. TGFBR-II is encoded by the TGFBR2 gene,
which contains 7 exons plus 2 variant exons and is located on chromosome 3p22. Excluding TGFBR2
mutations reported in malignancies, more than 50 pathogenic TGFBR2 mutations have been associated
with the syndromic features described above. The majority of these are missense mutations, although
splice site and nonsense mutations have also been reported. The great majority of pathogenic mutations
are located in the intracellular serine/threonine kinase domains. Few genotype-phenotype correlations
exist for TGFBR2 mutations; indeed, identical mutations have been reported to cause MFS in some
individuals and LDS in others. Approximately 25% of individuals with LDS have an affected parent,
while 75% have a de novo mutation. TGFBR2 mutations can manifest with a range of phenotypes and
variable ages of onset both between families and among affected members of the same family. Thus,
TGFBR2-related disorders can be diagnostically challenging. Genetic testing for TGFBR2 mutations
allows for the confirmation of a suspected genetic disease. Confirmation of LDS or other
TGFBR2-associated genetic diseases allows for proper treatment and management of the disease, and
preconception/prenatal and family counseling. For example, in LDS, aortic dissection has been observed
at aortic dimensions that do not confer risk in MFS caused by FBN1 mutations. Therefore, a more
aggressive treatment strategy or earlier surgical intervention might be considered if an individual were
found to have a TGFBR2 mutation rather than an FBN1 mutation.
Useful For: Aiding in the diagnosis of TGFBR2-associated Loeys-Dietz syndrome, Marfan or
Marfan-like syndrome, familial thoracic aortic aneurysm and dissection syndrome, and
Shprintzen-Goldberg syndrome
Interpretation: An interpretive report will be provided.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Loeys B, Chen J, Neptune E, et al: A syndrome of altered cardiovascular,
craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat
Genet 2005;37(3):275-281 2. Loeys B, Schwarze U, Holm T, et al: Aneurysm syndromes caused by
mutations in the TGF-B receptor. NEJM 2006:355(8):788-798 3. Akutsu K, Morisaki H, Takeshita S, et
al: Phenotypic heterogeneity of Marfan-like connective tissue disorders associated with mutations in the
transforming growth factor-beta receptor genes. Circ J 2007;71(8):1305-1309 4. Singh K, Rommel K,
Mishra A, et al: TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and
Loeys-Dietz syndrome. Hum Mut 2006;27(8):770-777 5. Stheneur C, Collod-Beroud G, Faivre L, et al:
Mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II,
Loeys-Dietz syndrome and related disorders. Hum Mutat 2008 Mutation in Brief #1031,29:E284-E295
(online Epub ahead of print)
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