Loeys–Dietz syndrome
| Loeys–Dietz syndrome | |
|---|---|
| Specialty | Cardiology, rheumatology, medical genetics  |
Loeys–Dietz syndrome (LDS) is an autosomal dominant genetic connective tissue disorder. The disorder is marked by aneurysms in the aorta, often in children. The aorta may also undergo sudden dissection in the weakened layers of the wall of aorta. Aneurysms and dissections also can occur in arteries other than the aorta. Because aneurysms in children tend to rupture early, children are at greater risk for dying if the syndrome is not identified. Surgery to repair aortic aneurysms is essential for treatment.
There are four types of the syndrome, labelled types I through IV, which are distinguished by their genetic cause. Type 1, Type 2, Type 3, and Type 4 are caused by mutations in TGFBR1, TGFBR2, SMAD3, and TGFB2 respectively. These four genes encoding transforming growth factors play a role in cell signaling that promotes growth and development of the body's tissues. Mutations of these genes cause production of proteins without function. Although the disorder has an autosomal pattern of inheritance, this disorder results from a new gene mutation in 75% of cases and occurs in people with no history of the disorder in their family.
It has features similar to Marfan syndrome and Ehlers-Danlos syndrome.[1][2][3]
It was identified and characterized by pediatric geneticists Bart Loeys and Harry Dietz at Johns Hopkins University in 2005.
Signs and symptoms
Main symptoms of Loeys–Dietz syndrome arterial tortuosity, widely spaced eyes (hypertelorism), wide or split uvula, and aneurysms at the aortic root. Arterial tortuosity are arteries that twist and wind. Other symptoms include cleft palate the white of the eyes appearing blue or gray. Symptoms at birth include heart defects and club foot. There is considerable variability in the symptoms associated with Loeys-Dietz syndrome. Some people can be severely affected, while others only show mild symptoms.
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, and 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.
Other findings can include:
- Scoliosis or Kyphosis
- Indented or protruding chest wall (pectus excavatum or pectus carinatum)
- Contractures of fingers and toes (camptodactyly)
- Long fingers and lax joints
- Weakened or missing eye muscles (strabismus)
- Club foot
- Premature fusion of the skull bones (craniosynostosis)
- Joint hypermobility
- Congenital heart problems including patent ductus arteriosus (connection between the aorta and the lung circulation) and atrial septal defect (connection between heart chambers)
- Translucency of the skin with velvety texture
- Abnormal junction of the brain and medulla (Arnold-Chiari malformation)
- Bicuspid aortic valves
- Criss-crossed pulmonary arteries
Types
Several genetic causes of Loeys–Dietz syndrome have been identified. A de novo mutation in TGFB3, a ligand of the TGF ß pathway, was identified in an individual with a syndrome presenting partially overlapping symptoms with Marfan Syndrome and Loeys-Dietz Syndrome.[4]
| Type | Gene | Locus | OMIM | Description |
| 1A | TGFBR1 | 9q22 | Template:OMIM2 | Also known as Furlong disease |
| 1B | TGFBR2 | 3p22 | Template:OMIM2 | |
| 2A | TGFBR1 | 9q22 | Template:OMIM2 | |
| 2B | TGFBR2 | 3p22 | Template:OMIM2 | Previously known as Marfan syndrome type 2 |
| 3 | SMAD3 | Template:OMIM2 | Also known as Aneurysms-osteoarthritis syndrome | |
| 4 | TGFB2 | Template:OMIM2 |
Diagnosis
Diagnosis involves consideration of physical features and genetic testing. Presence of split uvula is a differentiating characteristic from Marfan Syndrome, as well as the severity of the heart defects. Loeys-Dietz Syndrome patients have more severe heart involvement and it is advised that they be treated for enlarged aorta earlier due to the increased risk of early rupture in Loeys-Dietz patients. Because different people express different combinations of symptoms and the syndrome was identified in 2005, many doctors may not be aware of its existence. Clinical guidelines were released in 2014-2015 and should be available to the medical community. Dr. Harold Dietz, Dr. Bart Loeyz, and Dr. Kenneth Zahka are considered experts in this condition.
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 interventional radiology or 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 Marfan syndrome patients. Both Marfan syndrome and Loeys–Dietz syndrome are associated with increased TGF-beta signaling in the vessel wall. Therefore, losartan also holds promise for the treatment of Loeys–Dietz syndrome. In those patients in which losartan is not halting the growth of the aorta, irbesartan has been shown to work and is currently also being studied and prescribed for some patients with this condition.
If an increased heart rate is present, atenolol is sometimes prescribed to reduce the heart rate to prevent any extra pressure on the tissue of the aorta. Likewise, strenuous physical activity is discouraged in patients, especially weight lifting and contact sports.
See also
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. PMC 2561071. PMID 17330129.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Loeys BL, Chen J, Neptune ER, et al. (March 2005). "A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2". Nat. Genet. 37 (3): 275–81. doi:10.1038/ng1511. PMID 15731757.
- ^ Rienhoff HY, Yeo C-Y, Morissette R, Khrebtukova I, Melnick J, Luo S, Leng N, Kim Y-J, Schroth G, Westwick J, Vogel H, McDonnell N, Hall JG, Whitman M. 2013. A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis, and clinical features overlapping with Marfan and Loeys–Dietz syndrome. Am J Med Genet Part A. 161A:2040–2046.