OVERVIEW: What every practitioner needs to know
Are you sure your patient has Loeys-Dietz syndrome? What are the typical findings for this disease?
The most common manifestations of Loeys-Dietz syndrome (LDS) are vascular (including arterial aneurysms in the cerebral circulation, thoracic and abdominal aorta, and dissections) and skeletal (including joint laxity, pectus deformity, scoliosis, arachnodactyly, and talipes equinovarus)
Type 1 LDS may exhibit craniofacial features, which are seen in approximately 75% of persons with this condition and may include craniosynostosis, hypertelorism, cleft palate, or bifid uvula.
Approximately 25% of patients have type 2 LDS, with cutanious manifestations including easy bruising, wide atrophic scars and soft translucent skin. There is no clear distinction between types 1 and 2 LDS, and one may see both craniofacial and cutaneous expression of the disorder in a family or indeed in a single individual.
What other disease/condition shares some of these symptoms?
Aneurysms of the thoracic and abdominal aorta are a hallmark of Marfan syndrome, with which LDS also shares skeletal features including arachnodactyly, talipes equinovarus, scoliosis, and pectus deformity. The natural history of aneurysms in LDS is generally more aggressive than is seen in Marfan syndrome and is more widespread throughout the vascular tree.
Joint laxity with soft, velvety skin and easy bruising with atrophic scarring are also seen in the classic type of Ehlers-Danlos syndrome (EDS), whereas the fragility of hollow organs such as the uterus is typical of the vascular type of EDS.
Cleft palate or bifid uvula in the setting of joint laxity are features shared with Stickler syndrome.
What caused this disease to develop at this time?
Loeys-Dietz syndrome is a hereditary disorder of connective tissue caused by mutations in genes encoding TGFBR1 or TGFBR2. The condition is inherited as an autosomal dominant trait.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Molecular genetic testing for TGFBR1 or TrGFBR2 mutations should be performed. Sensitivity for alterations in one of these two genes in individuals in whom there is a high suspicion based on clinical examination is greater than 90%.
Would imaging studies be helpful? If so, which ones?
Total body magnetic resonance angiography is recommended to look for arterial aneurysms and arterial tortuosity.
Echocardiography is of limited utility becausethere are often aneurysms of the ascending aorta distal to the aortic root, which would not be detected by echocardiography.
Radiography will document severity of scoliosis, pectus deformity, or cervical spine instability.
Craniofacial examination should be carried out to look for cleft palate or bifid uvula.
Eye examination by an opthalmologist familiar with the ocular manifestations of hereditary disorders of connective tissue is necessary to look for distinguishing characteristics of Marfan syndrome and Stickler syndrome, including lens dislocation, assessment of vitreal and/or retinal anomalies, and blue sclerae.
Confirming the diagnosis
It is most cost-efficient to begin molecular genetic testing by looking at TGFBR2, which harbors mutations in approximately 75% of cases. If a TGFBR2 mutation is not found, sequencing of TGFBR1 is then undertaken.
If you are able to confirm that the patient has Loeys-Dietz syndrome, what treatment should be initiated?
Cardiovascular: Management in a center familiar with the syndrome is recommended. Aortic dissection may occur at lower diameters than is usual in Marfan syndrome and is not limited to the proximal aortic root. Beta-blockers are used to limit hemodynamic stress on the vulnerable arterial tree. Early surgical intervention is advisable when aneurysms are detected because of the tendency to dissect at relatively small diameters.
Skeletal: Surgical correction of talipes equinovarus may be necessary. Laxity of the cervical spine may also require surgical intervention. If pectus deformity compromises lung function, surgical intervention may be medically necessary.
Craniofacial: A craniofacial team is necessary for management of cleft palate, which is treated as it is in any other case whether syndromic or nonsyndromic. Similarly, craniosynostosis is managed as it is in any other clinical setting.
What are the possible outcomes of this disease?
Loeys-Dietz syndrome is characterized by aggressive arterial aneurysms and a high risk of uterine rupture with pregnancy. The mean age at death in initial reports of the disorder was 26.1 years.
Early and aggressive surgical management of aortic aneurysms may be lifesaving. Pregnancy-related complications, including death and uterine rupture, occurred in 6/11 women in early reports of the condition.
What causes this disease and how frequent is it?
Prevalence is unknown.
Mutations in TGFBR2 are found in 75% of clinically suspected cases, including LDS 1B and LDS 2B.
Mutations in TGFBR1 are found in 25% of cases. These include LDS 1A and LDS 2A.
SMAD3 mutations cause Loeys-Dietz syndrome 1C, with a phenotype of arterial tortuosity and early osteoarthritis.
How do these pathogens/genes/exposures cause the disease?
Mutations in TGFBR1 and TGFBR2 cause Loeys-Dietz syndrome through dysregulation of the transforming growth factor-beta (TGFBR) signaling pathway.
What complications might you expect from the disease or treatment of the disease?
See What are the possible outcomes of this disease? above.
How can this disease be prevented?
If the disease-causing mutation has been identified in a family, prenatally, or at preimplantion, the diagnosis may be offered to at-risk couples.
What is the evidence?
Loeys, BL, Chen, J, Neptune, ER. “A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2”. Nat Genet. vol. 37. 2005. pp. 275-81. (The first paper to describe Loeys-Dietz syndrome.)
Loeys, BL, Schwarze, U, Holm, T. “Aneurysm syndromes caused by mutations in the TGF-beta receptor”. N Engl J Med. vol. 355. 2006. pp. 788-798. (Defined the phenotypes of LDS types 1 and 2.)
Akutu, K, Morisaki, H, Takeshita, S. “Phenotypic heterogeneity of Marfan-like connective tissue disorders associated with mutations in the transforming growth factor-beta receptor genes”. Circ J. vol. 71. 2007. pp. 1305-9. (A review of the variety of phenotypes associated with mutations in the TGFBR genes.)
Williams, JA, Loeys, BL, Nwakanma, LU. “Early surgical experience with Loeys-Dietz: a new syndrome of aggressive thoracic aortic aneurysm disease”. Ann Thorac Surg. vol. 83. 2007. pp. S757-63. (Results of surgical intervention in aortic aneurysms associated with Loeys-Dietz syndrome.)
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has Loeys-Dietz syndrome? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- Confirming the diagnosis
- If you are able to confirm that the patient has Loeys-Dietz syndrome, what treatment should be initiated?
- What are the possible outcomes of this disease?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- What complications might you expect from the disease or treatment of the disease?
- How can this disease be prevented?
- What is the evidence?