Loeys-Dietz syndrome
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| Loeys-Dietz syndrome | |
| OMIM | 609192 |
|---|---|
| DiseasesDB | 34032 |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]
Synonyms and keywords: Furlong's syndrome
Overview
Loeys-Dietz syndrome is a recently-discovered autosomal dominant genetic syndrome which has many features similar to Marfan syndrome, but which is caused by mutations in the genes encoding transforming growth factor beta receptor 1 (TGFBR1) or 2 (TGFBR2). It is characterized by numerous site of aneurysms in the aorta (outpouchings in the weakened areas) in children [1][2][3]. These aneurysms are more prone to rupture at a smaller diameter, putting the children at risk for major internal bleeding or dying if they are not detected and treated in a timely manner.
Historical Perspective
It was identified and characterized by American physician Harry C. Dietz and Belgian physician Bart L. Loeys, for whom it is named.
Classification
- LDS type I - Presence of craniofacial involvement
- LDS type II - Absence of craniofacial involvement
Pathophysiology
Many of the physical findings typical in Loeys-Dietz syndrome are also found in Marfan syndrome cases, including increased risk of ascending aortic aneurysm and aortic dissection:
- Abnormally long limbs and fingers
- Dural ectasia (a gradual stretching and weakening of the dura mater that can cause abdominal and leg pain).
However, it also has some additional traits not typical of Marfan patients, including widely spaced eyes, a split uvula in the back of the throat, and skin findings such as easy bruising or abnormal scars.
Diagnosis
Symptoms
The main clinical characteristics include:
- Widely spaced eyes (orbital hypertelorism)
- Cleft palate or bifid uvula (a split in the tissue that hangs down in the back of the throat)
- Aortic and arterial aneurysms/dissections with tortuosity (corkscrew structure) of the arteries.
Physical Examination
Skin
- Translucency of the skin with velvety texture
Bones and Joints
- Scoliosis
- Indented or protruding chest wall (pectus excavatum or pectus carinatum)
- Contractures of fingers and toes (camptodactyly)
- Long fingers and lax joints
- Club foot
- Premature fusion of the skull bones (craniosynostosis)
- Joint hypermobility
Heart
- Murmurs:
- Systolic ejection murmur: Bicuspid Aortic valves
- Machinery murmur: Congenital heart problems including patent ductus arteriosus (connection between the aorta and the lung circulation)
- Early or mid-diastolic murmur: atrial septal defect (connection between heart's atrial chambers)
Neurological examination
- Abnormal junction of the brain and medulla (Arnold-Chiari malformation)
Treatment
As there is no known cure, Loeys-Dietz syndrome is a lifelong condition. Due to the high risk of death from aortic aneurysm rupture, patients should be followed closely to monitor aneurysm formation, which can then be corrected with vascular surgery.
Previous research in laboratory mice has suggested that the angiotensin II receptor antagonist losartan, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome. A large clinical trial sponsored by the National Institutes of Health is currently underway to explore the use of losartan to prevent aneurysms in Loeys-Dietz patients.
2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guideline Recommendations: Evaluation and Management of Acute Thoracic Aortic Disease (DO NOT EDIT)[4]
Aortic Imaging in Genetic Syndromes (DO NOT EDIT)[4]
| Class I |
| "1. Patients with Loeys-Dietz syndrome or a confirmed genetic mutation known to predispose to aortic aneurysms and aortic dissections (TGFBR1, TGFBR2, FBN1, ACTA2, or MYH11) should undergo complete aortic imaging at initial diagnosis and 6 months thereafter to establish if enlargement is occurring[5][6][7][8]. (Level of Evidence: C)" |
| "2. Patients with Loeys-Dietz syndrome should have yearly magnetic resonance imaging from the cerebrovascular circulation to the pelvis[9][10][11]. (Level of Evidence: B)" |
Genetic Syndromes of Familial Thoracic Aortic Aneurysms and Dissections (DO NOT EDIT) [4]
| Class I |
| "1. If the mutant gene (FBN1, TGFBR1, TGFBR2, COL3A1, ACTA2, MYH11) associated with aortic aneurysm and/or dissection is identified in a patient, first-degree relatives should undergo counseling and testing. Then, only the relatives with the genetic mutation should undergo aortic imaging. (Level of Evidence: C)" |
| Class IIa |
| "1. Sequencing of the ACTA2 gene is reasonable in patients with a family history of thoracic aortic aneurysms and/or dissections to determine if ACTA2 mutations are responsible for the inherited predisposition[12][13][8][10][14][15]. (Level of Evidence: B)" |
| Class IIb |
| "1. Sequencing of other genes known to cause familial thoracic aortic aneurysms and/or dissection (TGFBR1, TGFBR2, MYH11) may be considered in patients with a family history and clinical features associated with mutations in these genes. (Level of Evidence: B)" |
Treatment Guideline:
| Class IIa |
| "1. It is reasonable to consider surgical repair of the aorta in all adult patients with Loeys-Dietz syndrome or a confirmed TGFBR1 or TGFBR2 mutation and an aortic diameter of 4.2 cm or greater by transesophageal echocardiogram (internal diameter) or 4.4 to 4.6 cm or greater by computed tomographic imaging and/or magnetic resonance imaging (external diameter)[10]. (Level of Evidence:C)" |
References
- ↑ Loeys BL, Schwarze U, Holm T; et al. (2006). "Aneurysm syndromes caused by mutations in the TGF-beta receptor". N. Engl. J. Med. 355 (8): 788–98. doi:10.1056/NEJMoa055695. PMID 16928994.
- ↑ LeMaire SA, Pannu H, Tran-Fadulu V, Carter SA, Coselli JS, Milewicz DM (2007). "Severe aortic and arterial aneurysms associated with a TGFBR2 mutation". Nature clinical practice. Cardiovascular medicine. 4 (3): 167–71. doi:10.1038/ncpcardio0797. PMID 17330129.
- ↑ Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M,Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak Pj, Cameron DE, Backer JD, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. 2005. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet 37:275-281.
- ↑ 4.0 4.1 4.2 Hiratzka LF, Bakris GL, Beckman JA; et al. (2010). "2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine". Circulation. 121 (13): e266–369. doi:10.1161/CIR.0b013e3181d4739e. PMID 20233780. Unknown parameter
|month=ignored (help) - ↑ Pearson GD, Devereux R, Loeys B; et al. (2008). "Report of the National Heart, Lung, and Blood Institute and National Marfan Foundation Working Group on research in Marfan syndrome and related disorders". Circulation. 118 (7): 785–91. doi:10.1161/CIRCULATIONAHA.108.783753. PMC 2909440. PMID 18695204. Unknown parameter
|month=ignored (help) - ↑ Svensson LG, Crawford ES, Coselli JS, Safi HJ, Hess KR (1989). "Impact of cardiovascular operation on survival in the Marfan patient". Circulation. 80 (3 Pt 1): I233–42. PMID 2766531. Unknown parameter
|month=ignored (help) - ↑ Svensson LG, Blackstone EH, Feng J; et al. (2007). "Are Marfan syndrome and marfanoid patients distinguishable on long-term follow-up?". Ann. Thorac. Surg. 83 (3): 1067–74. doi:10.1016/j.athoracsur.2006.10.062. PMID 17307461. Unknown parameter
|month=ignored (help) - ↑ 8.0 8.1 Zhu L, Vranckx R, Khau Van Kien P; et al. (2006). "Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus". Nat. Genet. 38 (3): 343–9. doi:10.1038/ng1721. PMID 16444274. Unknown parameter
|month=ignored (help) - ↑ LeMaire SA, Pannu H, Tran-Fadulu V, Carter SA, Coselli JS, Milewicz DM (2007). "Severe aortic and arterial aneurysms associated with a TGFBR2 mutation". Nat Clin Pract Cardiovasc Med. 4 (3): 167–71. doi:10.1038/ncpcardio0797. PMC 2561071. PMID 17330129. Unknown parameter
|month=ignored (help) - ↑ 10.0 10.1 10.2 Loeys BL, Schwarze U, Holm T; et al. (2006). "Aneurysm syndromes caused by mutations in the TGF-beta receptor". N. Engl. J. Med. 355 (8): 788–98. doi:10.1056/NEJMoa055695. PMID 16928994. Unknown parameter
|month=ignored (help) - ↑ Williams JA, Loeys BL, Nwakanma LU; et al. (2007). "Early surgical experience with Loeys-Dietz: a new syndrome of aggressive thoracic aortic aneurysm disease". Ann. Thorac. Surg. 83 (2): S757–63, discussion S785–90. doi:10.1016/j.athoracsur.2006.10.091. PMID 17257922. Unknown parameter
|month=ignored (help) - ↑ Pannu H, Fadulu VT, Chang J; et al. (2005). "Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections". Circulation. 112 (4): 513–20. doi:10.1161/CIRCULATIONAHA.105.537340. PMID 16027248. Unknown parameter
|month=ignored (help) - ↑ Guo DC, Pannu H, Tran-Fadulu V; et al. (2007). "Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections". Nat. Genet. 39 (12): 1488–93. doi:10.1038/ng.2007.6. PMID 17994018. Unknown parameter
|month=ignored (help) - ↑ Stheneur C, Collod-Béroud G, Faivre L; et al. (2008). "Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders". Hum. Mutat. 29 (11): E284–95. doi:10.1002/humu.20871. PMID 18781618. Unknown parameter
|month=ignored (help) - ↑ Guo DC, Papke CL, Tran-Fadulu V; et al. (2009). "Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease". Am. J. Hum. Genet. 84 (5): 617–27. doi:10.1016/j.ajhg.2009.04.007. PMC 2680995. PMID 19409525. Unknown parameter
|month=ignored (help)