Loeys-Dietz syndrome

Loeys-Dietz syndrome is a disorder that affects the connective tissue in many parts of the body. Connective tissue provides strength and flexibility to structures such as bones, ligaments, muscles, and blood vessels.

There are three types of Loeys-Dietz syndrome, which are distinguished by their signs and symptoms.

Loeys-Dietz syndrome type I is characterized by enlargement of the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). People with Loeys-Dietz syndrome type I may have other kinds of heart defects. These individuals can also have aneurysms or dissections in arteries throughout the body and have arteries with abnormal twists and turns (arterial tortuosity). Other characteristic features of Loeys-Dietz syndrome type I include widely spaced eyes (hypertelorism), a split in the soft flap of tissue that hangs from the back of the mouth (bifid uvula), and an opening in the roof of the mouth (cleft palate). People with this condition may bruise easily and develop abnormal scars after wound healing. Affected individuals may also have skeletal problems including premature fusion of the skull bones (craniosynostosis), an abnormal side-to-side curvature of the spine (scoliosis), either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum), an inward- and upward-turning foot (clubfoot), or elongated limbs with joint deformities called contractures that restrict the movement of certain joints.

Loeys-Dietz syndrome type II has features that overlap with those of type I, such as enlargement of the aorta and other arteries and arterial tortuosity. But other features of type I, such as skeletal signs, are typically less severe or absent in type II. People with Loeys-Dietz syndrome type II have skin abnormalities, such as velvety skin that is sometimes described as translucent, often with the underlying veins visible. As in type I, people with type II bruise easily and have abnormal scarring.

The cardinal features of Loeys-Dietz syndrome type III are aortic and arterial aneurysms and dissections along with joint pain (osteoarthritis) that typically becomes apparent in early to mid-adulthood. The joints most commonly affected are the knees and joints of the hands, wrists, and spine. Because of these characteristic features, Loeys-Dietz syndrome type III is sometimes referred to as aneurysms-osteoarthritis syndrome. Other signs and symptoms of Loeys-Dietz syndrome type III include the breakdown (degeneration) of the discs that separate the bones of the spine (vertebrae) from one another, scoliosis, and flat feet (pes planus). People with type III can also have skeletal, facial, and skin features that overlap with those of Loeys-Dietz syndrome types I and II.

The signs and symptoms of all types of Loeys-Dietz syndrome can become apparent anytime from childhood into adulthood. The aorta problems associated with Loeys-Dietz syndrome are often fatal by mid- to late adulthood.

The prevalence of Loeys-Dietz syndrome is unknown. Loeys-Dietz syndrome type I is the most common form, accounting for 75 percent of all cases. Loeys-Dietz syndrome type III is the rarest form, with approximately 45 cases reported in the scientific literature.

Mutations in either the TGFBR1 or TGFBR2 gene can cause Loeys-Dietz syndrome types I and II. SMAD3 gene mutations cause Loeys-Dietz syndrome type III. These three genes play a role in cell signaling that promotes growth and development of the body's tissues.

The TGFBR1 and TGFBR2 genes provide instructions for making proteins called transforming growth factor-beta (TGF-β) receptors. These proteins are found in the membranes of cells and transmit signals from the cell surface into the cell. In particular, TGF-β receptor proteins transmit signals that help control cell growth and division (proliferation) and the process by which cells mature to carry out special functions (differentiation). The TGF-β receptor proteins also help with bone and blood vessel development and play a part in the formation of the extracellular matrix, an intricate lattice of proteins and other molecules that forms in the spaces between cells.

As part of the signaling pathway, a protein called transforming growth factor-beta (TGF-β) attaches (binds) to TGF-β receptor proteins, causing the receptors and bound proteins to form a complex with each other. The receptor protein complex turns on (activates) a group of related proteins called SMAD proteins. Once activated, the SMAD proteins combine to form a protein complex (which includes the SMAD3 protein produced from the SMAD3 gene). The SMAD protein complex moves to the cell nucleus where it binds to specific areas of DNA to control the activity of particular genes and regulate cell proliferation.

Mutations in the TGFBR1 and TGFBR2 genes result in the production of nonfunctional TGF-β receptor proteins. Although these receptors are nonfunctional, cell signaling still occurs at an even greater frequency than normal, indicating that other, unknown mechanisms compensate for the lack of receptor activity. The overactive signaling disrupts the development of connective tissue, the extracellular matrix, and various body systems, leading to the varied signs and symptoms of Loeys-Dietz syndrome types I and II.

Mutations in the SMAD3 gene also lead to the production of a nonfunctional protein. As with nonfunctional TGF-β receptor proteins, the lack of SMAD3 protein leads to overactive SMAD protein complexes, indicating compensatory mechanisms. This overactivity leads to dysregulated cell proliferation and gene activation, specifically affecting blood vessel and cartilage development as seen in individuals with Loeys-Dietz syndrome type III.

Read more about the SMAD3, TGFBR1, and TGFBR2 genes.

Loeys-Dietz syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In about 75 percent of cases, this disorder results from a new gene mutation and occurs in people with no history of the disorder in their family. In other cases, an affected person inherits the mutation from one affected parent.