#609192 LOEYS-DIETZ SYNDROME; LDS

LOEYS-DIETZ AORTIC ANEURYSM SYNDROME

TEXT

A number sign (#) is used with this entry because the Loeys-Dietz syndrome is caused by mutation in the TGFBR1 (190181) or the TGFBR2 (190182) gene.

CLINICAL FEATURES

Loeys et al. (2005) described 10 families with a previously undescribed aortic aneurysm syndrome characterized by hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity with ascending aortic aneurysm and dissection. The syndrome showed autosomal dominant inheritance and variable clinical expression. Other findings in multiple systems included craniosynostosis, structural brain abnormalities, mental retardation, congenital heart disease, and aneurysms with dissection throughout the arterial tree.

Some individuals with Loeys-Dietz syndrome had phenotypes that overlapped to some extent with that of Marfan syndrome (MFS; 154700), but none met the diagnostic criteria for MFS (De Paepe et al., 1996). All individuals with LDS had manifestations in multiple organ systems that are not associated with MFS. In these individuals, aneurysms tended to be particularly aggressive and to rupture at an early age or to be of a size not associated with high risk in MFS. From a management prospective, the distinction from MFS is neither ambiguous nor unimportant. In 93 individuals referred with classic MFS, comprehensive mutation analysis of fibrillin-1 (FBN1; 134797) identified a mutation in 86 individuals (Loeys et al., 2004). Loeys et al. (2005) sequenced TGFBR1 and TGFBR2 in the other 7 individuals and found no mutations.

At the extreme of clinical severity some individuals with LDS had phenotypes that overlapped considerably with the Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), also known as the marfanoid craniosynostosis syndrome. However, SGS is not associated with cleft palate, arterial tortuosity, or risk of aneurysm or dissection other than at the aortic root, and most affected individuals demonstrate no vascular pathology. Loeys et al. (2005) found no mutations in the TGFBR1 and TGFBR2 genes in 5 individuals with classic SGS. Nevertheless, given the extent of phenotypic overlap between SGS, MFS, and selected individuals with mutations in either TGFBR1 or TGFBR2, Loeys et al. (2005) concluded that the pathogenesis of SGS probably relates to alteration in TGF-beta (190180) signaling.

Loeys et al. (2005) reported that histologic analysis in LDS patients with mutations in TGFBR2 showed loss of elastin (130160) content and disarrayed elastic fibers in the aortic media similar to that in patients with classic MFS. Structural analysis showed loss of intimate spatial association between elastin deposits and vascular smooth muscle cells. These characteristics were observed in young children and in the absence of inflammation, suggestive of a severe defect in elastogenesis rather than secondary elastic fiber destruction. In addition, they had previously observed a marked excess of aortic wall collagen in individuals with MFS compared with age-matched controls; this collagen excess was accentuated in individuals with mutations in TGFBR2. As multiple collagens normally expressed in the aorta are derived from early-induced target genes of TGF-beta, including COL1A1 (120150) and COL3A1 (120180), these data were considered consistent with increased TGF-beta signaling.

Loeys et al. (2006) added observations on 30 new probands with a phenotype consistent with Loeys-Dietz syndrome type I. They presented the clinical characteristics of the series of 40 probands, including the 10 previously described patients (Loeys et al., 2005). Of the 30 newly identified probands, 21 had mutations in TGFBR2 (190182) and 9 in TGFBR1 (190181). Besides the triad of hypertelorism, cleft palate or bifid uvula, and arterial tortuosity with aneurysms, patients in this group had additional cardiovascular, skeletal, and cutaneous findings. Neurocognitive signs included delayed development in 6 patients, hydrocephalus in 6 patients, and Arnold-Chiari malformation in 4 patients. When present, delayed development was not always associated with craniosynostosis or hydrocephalus, suggesting that learning disability is a rare primary manifestation. No patient had ectopia lentis, and few patients (18%) had dolichostenomelia.

Loeys et al. (2006) stated that using 3-dimensional reconstruction of images from the head to the pelvis obtained by computed tomography with intravenous contrast material or magnetic resonance angiography, they identified aneurysms distant from the aortic root in 53% of their patients with Loeys-Dietz syndrome type I; these aneurysms were not detected with the use of echocardiography. Most of these lesions were amenable to surgical repair. This imaging technique also detected arterial tortuosity, a finding of diagnostic importance.

MOLECULAR GENETICS

Because TGF-beta signaling has a prominent role in vascular and craniofacial development in mouse models (Sanford et al., 1997; Azhar et al., 2003) and because conditional knockout of TGFBR2 in neural crest cells causes cleft palate and defects of the calvaria (Ito et al., 2003), Loeys et al. (2005) considered TGFBR2 (190182) as a candidate gene in LDS. They sequenced all exons of the TGFBR2 gene and identified heterozygous mutations in 6 of the 10 families with LDS. No mutations in TGFBR2 were found in the 4 other families with a clinically indistinguishable phenotype. Therefore Loeys et al. (2005) sequenced all exons of the TGFBR1 gene (190181) and found a unique missense mutation in each family.

In a Japanese boy with clinical findings reported as Shprintzen-Goldberg syndrome, Kosaki et al. (2006) identified heterozygosity for a splice site mutation in the TGFBR2 gene (190182.0016). Because the patient had a bifid uvula and sigmoid configuration of the brachycephalic, left common carotid, and left subclavian arteries, Robinson et al. (2006) suggested that the diagnosis of Loeys-Dietz syndrome would also be appropriate for this patient.

REFERENCES

1. Azhar, M.; Schultz, J. E. J.; Grupp, I.; Dorn, G. W., II; Meneton, P.; Molin, D. G. M.; Gittenberger-de Groot, A. C.; Doetschman, T. :

Transforming growth factor beta in cardiovascular development and function. Cytokine Growth Factor Rev. 14: 391-407, 2003.
PubMed ID : 12948523

2. De Paepe, A.; Devereux, R. B.; Dietz, H. C.; Hennekam, R. C. M.; Pyeritz, R. E. :

Revised diagnostic criteria for the Marfan syndrome. Am. J. Med. Genet. 62: 417-426, 1996.
PubMed ID : 8723076

3. Ito, Y.; Yeo, J. Y.; Chytil, A.; Han, J.; Bringas, P., Jr.; Nakajima, A.; Shuler, C. F.; Moses, H. L.; Chai, Y. :

Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects. Development 130: 5269-5280, 2003.
PubMed ID : 12975342

4. Kosaki, K.; Takahashi, D.; Udaka, T.; Kosaki, R.; Matsumoto, M.; Ibe, S.; Isobe, T.; Tanaka, Y.; Takahashi, T. :

Molecular pathology of Shprintzen-Goldberg syndrome. (Letter) Am. J. Med. Genet. 140A: 104-108, 2006.

5. Loeys, B.; De Backer, J.; Van Acker, P.; Wettinck, K.; Pals, G.; Nuytinck, L.; Coucke, P.; De Paepe, A. :

Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum. Mutat. 24: 140-146, 2004.
PubMed ID : 15241795

6. Loeys, B. L.; Chen, J.; Neptune, E. R.; Judge, D. P.; Podowski, M.; Holm, T.; Meyers, J.; Leitch, C. C.; Katsanis, N.; Sharifi, N.; Xu, F. L.; Myers, L. A.; and 12 others :

A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature Genet. 37: 275-281, 2005.
PubMed ID : 15731757

7. Loeys, B. L.; Schwarze, U.; Holm, T.; Callewaert, B. L.; Thomas, G. H.; Pannu, H.; De Backer, J. F.; Oswald, G. L.; Symoens, S.; Manouvrier, S.; Roberts, A. E.; Faravelli, F.; and 9 others :

Aneurysm syndromes caused by mutations in the TGF-beta receptor. New Eng. J. Med. 355: 788-798, 2006.
PubMed ID : 16928994

8. Robinson, P. N.; Neumann, L. M.; Tinschert, S. :

Response to Kosaki et al. (Letter) Am. J. Med. Genet. 140A: 109-110, 2006.

9. Sanford, L. P.; Ormsby, I.; Gittenberger-de Groot, A. C.; Sariola, H.; Friedman, R.; Boivin, G. P.; Cardell, E. L.; Doetschman, T. :

TGF-beta-2 knockout mice have multiple developmental defects that are non-overlapping with other TGF-beta knockout phenotypes. Development 124: 2659-2670, 1997.
PubMed ID : 9217007

CONTRIBUTORS

Victor A. McKusick - updated : 9/20/2006
Marla J. F. O'Neill - updated : 3/7/2006
Victor A. McKusick - updated : 8/19/2005

CREATION DATE

Victor A. McKusick : 2/4/2005

EDIT HISTORY

alopez : 10/11/2006
terry : 9/20/2006
wwang : 3/7/2006
terry : 1/25/2006
terry : 8/19/2005
carol : 5/10/2005
alopez : 4/27/2005
alopez : 3/2/2005
alopez : 2/9/2005
alopez : 2/7/2005

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