October 03, 2022
Years published: 2022
NORD gratefully acknowledges Gregory Cichon, MD candidate, Creighton School of Medicine and Lois J. Starr, MD, PhD, FAAP, FACMG University of Nebraska Medical Center, for the preparation of this report.
Loeys-Dietz syndrome (LDS) is a genetic condition affecting the connective tissue and involving multiple organ systems including the blood vessels, skeleton, eyes and skin. It was first described in 2005 and has many shared characteristics with Marfan syndrome. While not all individuals have characteristic craniofacial features, individuals with this disorder often have widely spaced eyes, tortuous blood vessels, a uvula that splits in two (bifid uvula) and/or cleft palate.
LDS is an autosomal dominant genetic condition that can be inherited from a parent or occur for the first time in an individual as a result of a new pathogenic variant in one of several genes: GFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3.
People with LDS are at risk for blood vessel aneurysms, particularly at the root of the aorta, but also in other locations of the arterial tree, that can be life-threatening. Therefore, it is extremely important to screen, diagnose, and prevent complications early.
LDS is a disorder of connective tissue, so it affects the bones, ligaments, arterial walls, and skin most significantly. A patient may not have all of the findings listed here, or maybe just one or two of the findings and still have the disease.
Widely spaced eyes (hypertelorism)
Bifid uvula/cleft palate
Aortic root aneurysm
Long, thin fingers (arachnodactyly)
Protruded or caved in chest (pectus carinatum or pectus excavatum)
Flat feet (Pes planus)
Thin, translucent skin
Early fused skull (craniosynostosis)
During development in the womb and during childhood the eyes may be more noticeable widely set apart than normal, the hard palate may not close completely and/or the skull sutures to close too quickly causing a misshapen head and possibly elevated pressure inside of the skull. In other parts of the body, the chest may be either caved-in (pectus excavatum) or protruded out (pectus carinatum), the joints may be flexible, the fingers/toes may be abnormally long and the spine may be curved. Sometimes the joints can also become too tight. The eyes and skin are affected as well in some patients, resulting in thin skin. It can be easy to see the veins through the skin as well as excessive bruising.
The artery walls also are prone to expanding/dilating more than they should and once this reaches a certain threshold it is called an aneurysm. These blood vessels may grow abnormally long and twisted or tortuous, making them more likely to split or dissect. Arteries in the head/neck, where the aorta exits the heart and, in the abdomen, as low as the popliteal area behind the knee have been reported to have aneurysms. These malformed and weakened arteries tend to balloon outwards with high risk of bursting. A ruptured aneurysm is an emergency and can be life-threatening if left untreated. Approximately 2/3 of people with LDS will have an aortic aneurysm at diagnosis and nearly all will have some aortic ballooning.
About 1/3 of individuals with LDS have an affected parent, while 2/3 of cases are caused by new or de novo pathogenic gene variants (mutations). These variants may then be passed down to children in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The non-working abnormal gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Since it was first described relatively recently (2005) and is a rare disease, more research is needed to fully understand the pathogenesis of LDS. Currently, researchers have identified several genes in the transforming growth factor beta (TGFβ) pathway which may be mutated in the disease including: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, and TGFB3. The genes in this pathway are important for gene expression, cell growth, differentiation and controlled cell death (apoptosis). Notably, the gene SMAD3 has been associated with a condition known as aneurysm-osteoarthritis syndrome (AOS), which shares some of the characteristics of LDS. Disease causing variants in all of these genes cause them to lose their normal function, resulting in many of the symptoms of LDS.
LDS is a rare disorder that affects males and females in equal numbers. The prevalence of LDS is unknown though with more availability of genetic testing the number of patients diagnosed has increased significantly in recent years. The condition occurs in all ethnic groups.
The diagnosis of LDS is based on clinical suspicion and molecular confirmation through genetic testing to look for pathogenic variants in the causal genes: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB, and TGFB3. Genetic testing should be considered in patients with typical signs/symptoms described previously and in families with known histories of thoracic aortic aneurysms. Cleft palate/bifid uvula, widely spaced eyes, translucent skin, arthritis and/or arterial tortuosity or aneurysm should prompt a physician to consider testing for LDS.
Prenatal diagnosis by genetic testing is possible for pregnancies at increased risk for LDS if the disease-causing variant in the family is already known.
There is no known cure for LDS, but there are treatments directed at specific symptoms. These treatments typically require a team of specialists including a geneticist, cardiologist, heart (cardiothoracic) and bone (orthopedic) surgeons, rheumatologist, among others.
Most importantly, the goal of treatment is to screen and correct blood vessel weaknesses before they tear. The physician may prescribe a beta- or angiotensin receptor blocker such as losartan to slow down the ballooning/stretching of the aortic root. Every 6 months to 1 year, the individual should be screened for aneurysms of the entire arterial tree (from head to hips). This screening includes blood vessel imaging by CT angiography or MR angiography and heart imaging by echocardiography. If repeated imaging does not show any changes or concern for aneurysms, it may be acceptable to image less frequently. The doctors will be looking to see whether the aortic root balloons to larger than 4 cm (1.5 inches), at which point they may recommend a surgery to replace the ballooning section of the aorta and sometimes the aortic valve of the heart. This surgery is typically safe and effective in fixing the problem.
To treat some of the musculoskeletal abnormalities associated with LDS, the care team may recommend nonsurgical management of the symptoms such as bracing or surgical correction of the abnormalities. These abnormalities include an abnormally curved spine (scoliosis), an indented or protruding chest, and issues with the bones of the neck. Doctors will recommend X-rays and CT scans to determine whether surgery should be performed. These surgeries can be complicated and require close attention for complications afterwards.
Staying active and conditioned is recommended for individuals with LDS. Athletic goals and limits should be discussed with the cardiologist and the care team to determine an individualized health plan.
The relationship between different variants in genes that cause LDS and specific physical characteristics is being studied to improve clinical and surgical recommendations.
Clinical trials around the world are investigating which drugs are best to slow the growth of the aortic root and which surgeries are the most effective for individuals with LDS.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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