Aneurysm syndromes caused by mutations in the TGF-beta receptor.
BACKGROUND
The Loeys-Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2, respectively).


METHODS
We undertook the clinical and molecular characterization of 52 affected families. Forty probands presented with typical manifestations of the Loeys-Dietz syndrome. In view of the phenotypic overlap between this syndrome and vascular Ehlers-Danlos syndrome, we screened an additional cohort of 40 patients who had vascular Ehlers-Danlos syndrome without the characteristic type III collagen abnormalities or the craniofacial features of the Loeys-Dietz syndrome.


RESULTS
We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys-Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers-Danlos syndrome (Loeys-Dietz syndrome type II). The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women). Patients with Loeys-Dietz syndrome type I, as compared with those with type II, underwent cardiovascular surgery earlier (mean age, 16.9 years vs. 26.9 years) and died earlier (22.6 years vs. 31.8 years). There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys-Dietz syndrome from vascular Ehlers-Danlos syndrome.


CONCLUSIONS
Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease. The severity of the clinical presentation is predictive of the outcome. Genotyping of patients presenting with symptoms like those of vascular Ehlers-Danlos syndrome may be used to guide therapy, including the use and timing of prophylactic vascular surgery.
Loeys
Bart L
BL
McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, and the Kennedy Krieger Institute, Baltimore, USA. bart.loeys@ugent.be
Schwarze
Ulrike
U
Holm
Tammy
T
Callewaert
Bert L
BL
Thomas
George H
GH
Pannu
Hariyadarshi
H
De Backer
Julie F
JF
Oswald
Gretchen L
GL
Symoens
Sofie
S
Manouvrier
Sylvie
S
Roberts
Amy E
AE
Faravelli
Francesca
F
Greco
M Alba
MA
Pyeritz
Reed E
RE
Milewicz
Dianna M
DM
Coucke
Paul J
PJ
Cameron
Duke E
DE
Braverman
Alan C
AC
Byers
Peter H
PH
De Paepe
Anne M
AM
Dietz
Harry C
HC
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D030201:Activin Receptors, Type I / Q000235:genetics*; D000328:Adult; D000784:Aortic Dissection / Q000235:genetics; D001014:Aortic Aneurysm / Q000235:genetics*; D001158:Arteries / Q000002:abnormalities; D024061:Collagen Type III / Q000096:biosynthesis; D019465:Craniofacial Abnormalities / Q000235:genetics*; D004252:DNA Mutational Analysis; D004535:Ehlers-Danlos Syndrome / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D016019:Survival Analysis; D013577:Syndrome
D024061:Collagen Type III; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human