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 five types of Loeys-Dietz syndrome, labelled types I through V, which are distinguished by their genetic cause. Regardless of the type, signs and symptoms of Loeys-Dietz syndrome can become apparent anytime from childhood through adulthood, and the severity is variable.

Loeys-Dietz syndrome 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 can also have aneurysms or dissections in arteries throughout the body and have arteries with abnormal twists and turns (arterial tortuosity).

Individuals with Loeys-Dietz syndrome often 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), flat feet (pes planus), or elongated limbs with joint deformities called contractures that restrict the movement of certain joints. A membrane called the dura, which surrounds the brain and spinal cord, can be abnormally enlarged (dural ectasia). In individuals with Loeys-Dietz syndrome, dural ectasia typically does not cause health problems. Malformation or instability of the spinal bones (vertebrae) in the neck is a common feature of Loeys-Dietz syndrome and can lead to injuries to the spinal cord. Some affected individuals have joint inflammation (osteoarthritis) that commonly affects the knees and the joints of the hands, wrists, and spine.

People with Loeys-Dietz syndrome may bruise easily and develop abnormal scars after wound healing. The skin is frequently described as translucent, often with stretch marks (striae) and visible underlying veins. Some individuals with Loeys-Dietz syndrome develop an abnormal accumulation of air in the chest cavity that can result in the collapse of a lung (spontaneous pneumothorax) or a protrusion of organs through gaps in muscles (hernias). Other characteristic features include widely spaced eyes (hypertelorism), eyes that do not point in the same direction (strabismus), 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).

Individuals with Loeys-Dietz syndrome frequently develop immune system-related problems such as food allergies, asthma, or inflammatory disorders such as eczema or inflammatory bowel disease.

The five types of Loeys-Dietz syndrome are distinguished by their genetic cause: TGFBR1 gene mutations cause type I, TGFBR2 gene mutations cause type II, SMAD3 gene mutations cause type III, TGFB2 gene mutations cause type IV, and TGFB3 gene mutations cause type V. These five genes play roles in a cell signaling pathway called the transforming growth factor beta (TGF-β) pathway, which directs the functions of the body's cells during growth and development. This pathway also regulates the formation of the extracellular matrix, an intricate lattice of proteins and other molecules that forms in the spaces between cells and is important for tissue strength and repair.

Mutations in the TGFBR1, TGFBR2, SMAD3, TGFB2, or TGFB3 gene result in the production of a protein with reduced function. Even though the protein is less active, signaling within the TGF-β pathway occurs at an even greater intensity than normal in tissues throughout the body. Researchers speculate that the activity of other proteins in this signaling pathway is increased to compensate for the protein whose function is reduced; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive TGF-β pathway disrupts the development of the extracellular matrix and various body systems, leading to the signs and symptoms of Loeys-Dietz syndrome.

Normal Function

The SMAD3 gene provides instructions for making a protein involved in transmitting chemical signals from the cell surface to the nucleus. This signaling pathway, called the transforming growth factor-beta (TGF-β) pathway, allows the environment outside the cell to affect cell function, including how the cell produces other proteins. The signaling process begins when a TGF-β protein attaches (binds) to a receptor on the cell surface, which activates a group of related SMAD proteins (including the SMAD3 protein). These SMAD proteins combine to form a protein complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA to control the activity of particular genes. Through the TGF-β signaling pathway, the SMAD3 protein also influences many aspects of cellular processes, including cell growth and division (proliferation), cell movement (migration), and controlled cell death (apoptosis).

Health Conditions Related to Genetic Changes

Loeys-Dietz syndrome

At least 35 mutations in the SMAD3 gene have been found to cause Loeys-Dietz syndrome type III. This disorder affects connective tissue, which gives structure and support to blood vessels, the skeleton, and many other parts of the body. Loeys-Dietz syndrome type III is characterized by abnormal blood vessels, skeletal and joint deformities, and skin abnormalities. Some of the mutations that cause this disorder insert or delete small amounts of genetic material in the SMAD3 gene, while other mutations result in a change to single protein building blocks (amino acids) in the SMAD3 protein. These mutations lead to the production of a nonfunctional SMAD3 protein. Despite a reduction in SMAD3 function, the TGF-β pathway is overactive. Researchers speculate that the activity of other proteins in this signaling pathway is increased to compensate for the lack of SMAD3 activity; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway leads to dysregulated cell proliferation and gene activation, specifically affecting blood vessel, cartilage, and skin development. These changes lead to the abnormalities typical of Loeys-Dietz syndrome type III.

Familial thoracic aortic aneurysm and dissection

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Other Names for This Gene

• hMAD-3
• hSMAD3
• JV15-2
• MAD homolog 3
• MAD, mothers against decapentaplegic homolog 3
• mad3
• MADH3
• mothers against decapentaplegic homolog 3
• SMAD, mothers against DPP homolog 3
• SMAD3_HUMAN

Genomic Location

Normal Function

The TGFB2 gene provides instructions for producing a protein called transforming growth factor beta-2 (TGFβ-2). This protein is found throughout the body and is required for development before birth and throughout life. To carry out its functions, TGFβ-2 attaches (binds) to receptor proteins on the surface of cells. This binding triggers the transmission of signals within cells, controlling various cellular activities. As part of a signaling pathway called the TGF-β pathway, the TGFβ-2 protein helps control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (motility), and controlled cell death (apoptosis). Because the TGFβ-2 protein keeps cells from growing and dividing too rapidly or in an uncontrolled way, it can suppress the formation of tumors.

The TGFβ-2 protein plays a role in the formation of blood vessels, the regulation of muscle tissue and body fat development, wound healing, and immune system function. TGFβ-2 is especially abundant in tissues that make up the skeleton, where it helps regulate bone growth, and in the intricate lattice that forms in the spaces between cells (the extracellular matrix).

Health Conditions Related to Genetic Changes

Loeys-Dietz syndrome

At least 20 mutations in the TGFB2 gene have been found to cause Loeys-Dietz syndrome type IV. This disorder affects connective tissue, which gives structure and support to blood vessels, the skeleton, and many other parts of the body. Loeys-Dietz syndrome type IV is characterized by blood vessel abnormalities, heart defects, and skeletal deformities. The TGFB2 gene mutations that cause this condition lead to the production of a TGFβ-2 protein with little or no function. As a result, the protein cannot bind to its receptors. Although the TGFβ-2 protein and its receptors are not bound, TGF-β pathway signaling occurs at an even greater intensity than normal. Researchers speculate that the activity of other proteins in this signaling pathway is increased to compensate for the reduction in TGFβ-2 activity; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway disrupts development of connective tissue and various body systems and leads to the signs and symptoms of Loeys-Dietz syndrome type IV.

A few mutations have been found that delete the entire TGFB2 gene and some nearby genetic material. People with these deletions often have the features of Loeys-Dietz syndrome as well as features not usually associated with the condition, such as intellectual disability and movement problems. Researchers are working to determine which genes are missing as a result of these deletions and how their loss contributes to these additional signs and symptoms.

Other Names for This Gene

• BSC-1 cell growth inhibitor
• cetermin
• G-TSF
• glioblastoma-derived T-cell suppressor factor
• polyergin
• TGF-beta2
• transforming growth factor beta-2
• transforming growth factor, beta 2

Genomic Location

Normal Function

The TGFB3 gene provides instructions for producing a protein called transforming growth factor beta-3 (TGFβ-3). This protein is found throughout the body and is required for development before birth and throughout life. To carry out its functions, TGFβ-3 attaches (binds) to receptor proteins on the surface of cells. This binding triggers the transmission of signals within the cell, controlling various cellular activities. As part of a signaling pathway, called the TGF-β pathway, the TGFβ-3 protein helps control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (motility), and controlled cell death (apoptosis). Because the TGFβ-3 protein keeps cells from growing and dividing too rapidly or in an uncontrolled way, it can suppress the formation of tumors.

The TGFβ-3 protein is especially abundant in tissues that develop into the muscles used for movement (skeletal muscles), and plays a key role in their development. The protein is also involved in the formation of blood vessels, regulation of bone growth, wound healing, and immune system function.

Health Conditions Related to Genetic Changes

Loeys-Dietz syndrome

At least 11 mutations in the TGFB3 gene have been found to cause Loeys-Dietz syndrome type V. This disorder affects connective tissue, which gives structure and support to blood vessels, the skeleton, and many other parts of the body. Loeys-Dietz syndrome type V is characterized by blood vessel abnormalities, heart defects, and skeletal deformities. The TGFB3 gene mutations that cause this condition lead to the production of a TGFβ-3 protein with little or no function. As a result, the protein cannot bind to its receptors. Although the TGFβ-3 protein and its receptors are not bound, TGF-β pathway signaling occurs at an even greater intensity than normal. Researchers speculate that the activity of other proteins in this signaling pathway is increased to compensate for the reduction in TGFβ-3 activity; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway disrupts development of connective tissue and various body systems and leads to the signs and symptoms of Loeys-Dietz syndrome type V.

Arrhythmogenic right ventricular cardiomyopathy

MedlinePlus Genetics provides information about Arrhythmogenic right ventricular cardiomyopathy

Other Names for This Gene

• RNHF
• TGF beta 3
• TGF-beta3

Genomic Location

Normal Function

The TGFBR1 gene provides instructions for making a protein called transforming growth factor-beta (TGF-β) receptor type 1. This receptor transmits signals from the cell surface into the cell through a process called signal transduction. Through this type of signaling, the environment outside the cell affects activities inside the cell such as stimulation of cell growth and division.

To carry out its signaling function, TGF-β receptor type 1 spans the cell membrane, so that one end of the protein projects from the outer surface of the cell (the extracellular domain) and the other end remains inside the cell (the intracellular domain). A protein called TGF-β attaches (binds) to the extracellular domain of TGF-β receptor type 1, which turns on (activates) the receptor and allows it to bind to another receptor on the cell surface. These three proteins form a complex, which triggers signal transduction by activating other proteins in a signaling pathway called the TGF-β pathway.

Signals transmitted by the TGF-β receptor complex trigger various responses by the cell, including the growth and division (proliferation) of cells, the maturation of cells to carry out specific functions (differentiation), cell movement (motility), and controlled cell death (apoptosis). Because TGF-β receptor type 1 helps prevent cells from growing and dividing too rapidly or in an uncontrolled way, it can suppress the formation of tumors.

Health Conditions Related to Genetic Changes

Loeys-Dietz syndrome

More than 35 mutations in the TGFBR1 gene have been found to cause Loeys-Dietz syndrome type I. Loeys-Dietz syndrome affects connective tissue, which gives structure and support to blood vessels, the skeleton, and other parts of the body. This type of Loeys-Dietz syndrome is characterized by blood vessel abnormalities and skeletal deformities. The TGFBR1 gene mutations that cause Loeys-Dietz syndrome are present in one copy of the gene in each cell. Most of these mutations change single protein building blocks (amino acids) in TGF-β receptor type 1, resulting in a receptor with little or no function. Although the receptor has severely reduced function, TGF-β pathway signaling occurs at an even greater intensity than normal. Researchers speculate that the activity of other proteins in this signaling pathway is increased to compensate for the reduction in TGF-β receptor type 1 activity; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway disrupts development of connective tissue and various body systems and leads to the varied signs and symptoms of Loeys-Dietz syndrome type I.

Familial thoracic aortic aneurysm and dissection

MedlinePlus Genetics provides information about Familial thoracic aortic aneurysm and dissection

Prostate cancer

MedlinePlus Genetics provides information about Prostate cancer

Other cancers

More than 10 mutations in the TGFBR1 gene have been found to increase the risk of developing a form of skin cancer called multiple self-healing squamous epithelioma (MSSE). This condition, also known as Ferguson-Smith disease, is characterized by the formation of multiple invasive skin tumors that grow uncontrollably for a few weeks, but then suddenly shrink and die off, leaving a noncancerous scar.

People with MSSE have a mutation in one copy of the TGFBR1 gene in each cell. An additional mutation in the second copy of the TGFBR1 gene is needed for tumors to form in MSSE. The second mutation, which is called a somatic mutation, is found only in the tumor cells and is not inherited. Unlike TGFBR1 gene mutations that cause Loeys-Dietz syndrome type I (described above), the mutations that cause MSSE prevent the production of any protein at all. A complete lack of functional receptor in certain cells results in a total loss of TGF-β pathway signaling and severely reduced tumor suppression, allowing the skin cancers to form. The mechanism responsible for the spontaneous healing of the multiple skin tumors in MSSE is unknown.

Other Names for This Gene

• serine/threonine-protein kinase receptor R4
• TBR-i
• TBRI
• TGF-beta receptor type I
• TGF-beta receptor type-1
• TGF-beta type I receptor
• TGFR-1
• TGFR1_HUMAN
• transforming growth factor beta receptor I
• transforming growth factor-beta receptor type I

Genomic Location

Normal Function

The TGFBR2 gene provides instructions for making a protein called transforming growth factor-beta (TGF-β) receptor type 2. This receptor transmits signals from the cell surface into the cell through a process called signal transduction. Through this type of signaling, the environment outside the cell affects activities inside the cell such as stimulation of cell growth and division.

To carry out its signaling function, the TGF-β receptor type 2 spans the cell membrane, so that one end of the protein projects from the outer surface of the cell (the extracellular domain) and the other end remains inside the cell (the intracellular domain). A protein called TGF-β attaches (binds) to the extracellular domain of the TGF-β receptor type 2, which turns on (activates) the receptor and allows it to bind to another receptor on the cell surface. These three proteins form a complex, which triggers signal transduction by activating other proteins in a signaling pathway called the TGF-β pathway.

Signals transmitted by the TGF-β receptor complex trigger various responses by the cell, including the growth and division (proliferation) of cells, the maturation of cells to carry out specific functions (differentiation), cell movement (motility), and controlled cell death (apoptosis). Because TGF-β receptor type 2 helps prevent cells from growing and dividing too rapidly or in an uncontrolled way, it can suppress the formation of tumors.

Health Conditions Related to Genetic Changes

Familial thoracic aortic aneurysm and dissection

At least nine TGFBR2 gene mutations have been identified in people with familial thoracic aortic aneurysm and dissection (familial TAAD). This disorder involves problems with 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). Aortic aneurysm and dissection can cause life-threatening internal bleeding.

The TGFBR2 gene mutations that cause familial TAAD disturb signal transduction. The disturbed signaling can impair cell growth and development. It is not known how these changes result in the specific aortic abnormalities associated with familial TAAD.

Loeys-Dietz syndrome

More than 100 mutations in the TGFBR2 gene have been found to cause Loeys-Dietz syndrome type II. Loeys-Dietz syndrome affects connective tissue, which gives structure and support to blood vessels, the skeleton, and other parts of the body. This type of Loeys-Dietz syndrome is characterized by blood vessel abnormalities and skeletal deformities. Most TGFBR2 gene mutations that cause Loeys-Dietz syndrome change single protein building blocks (amino acids) in TGF-β receptor type 2, resulting in a receptor with little or no function. Although the receptor has severely reduced function, TGF-β pathway signaling occurs at an even greater intensity than normal. Researchers speculate that the activity of other proteins in this signaling pathway is increased to compensate for the reduction in TGF-β receptor type 2 activity; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway disrupts development of connective tissue and various body systems and leads to the varied signs and symptoms of Loeys-Dietz syndrome type II.

Some TGFBR2 gene mutations that cause Loeys-Dietz syndrome type II have also been found to cause familial TAAD (described above). Affected families can include some individuals with Loeys-Dietz syndrome and others with familial TAAD.

Cancers

Some TGFBR2 gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. People with somatic mutations in the TGFBR2 gene appear to have an increased risk of developing various cancers. Somatic TGFBR2 gene mutations probably disrupt the signaling process that helps regulate cell division. Unchecked cell division can lead to the formation of tumors, particularly when TGFBR2 gene mutations occur in the colon, rectum, and esophagus. It is estimated that 30 percent of cancerous (malignant) colon tumors have TGFBR2 gene mutations in their cells.

Other Names for This Gene

• HNPCC6
• MFS2
• RIIC
• TBR-ii
• TBRII
• TGF-beta receptor type IIB
• TGF-beta type II receptor
• TGFbeta-RII
• TGFR-2
• TGFR2_HUMAN
• transforming growth factor beta receptor II
• transforming growth factor, beta receptor II (70/80kDa)

Genomic Location

Loeys-Dietz syndrome has an autosomal dominant pattern of inheritance, 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.

The prevalence of Loeys-Dietz syndrome is unknown. Loeys-Dietz syndrome types I and II appear to be the most common forms.