Arterial tortuosity syndrome (ATS) is an extremely rare genetic disorder characterized by lengthening (elongation) and twisting or distortion (tortuosity) of arteries throughout the body. Arteries are the blood vessels that carry oxygen-rich blood away from the heart. Affected arteries are prone to developing balloon-like bulges (aneurysms) on the wall of the artery, tearing (dissection), or narrowing (stenosis). The main artery that carries blood from the heart and to the rest of the body (aorta) can be affected. The pulmonary arteries are especially prone to narrowing. Additional symptoms affecting connective tissues entering in multiple systems of the body can also be present. Affected individuals may have distinctive facial features that are noticeable at birth or during early childhood. Arterial tortuosity syndrome can potentially cause severe life-threatening complications during infancy or early childhood, although individuals with milder symptoms have also been described. Arterial tortuosity syndrome is caused by mutations in the SLC2A10 gene and is inherited in an autosomal recessive manner.
Arterial tortuosity syndrome is a connective tissue disorder. Connective tissues are the major components of the body forming skeleton, joints, skin, vessels, and other organs. Connective tissues are characterized by the presence of cells included in an extracellular matrix network of a large variety of proteins (i.e. collagens), proteins bound to sugars chains of big dimension (proteoglycans), and sugars (hyaluronic acid, etc.). This complex mesh of molecules gives the tissue form and strength and ensures the passage of nutrients and factors controlling cell growth and proliferation.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about arterial tortuosity syndrome is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. For example, affected individuals may have arterial abnormalities without extravascular symptoms or only mild ones. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
The specific symptoms and severity of arterial tortuosity syndrome can vary greatly from one person to another depending, in part, upon the specific arteries that are affected. Usually, large or medium sized arteries are affected such as the aorta, the pulmonary arteries, the carotid artery, and kidney (renal) arteries. In extremely rare cases, blood vessels within the skull can be affected (intracranial arteries). Affected arteries can be abnormally lengthened causing them to become twisted or distorted, possibly forming kinks and loops. These arteries are prone to narrowing and tearing and affected individuals are at risk for developing aneurysms. These arterial abnormalities can lead to various cardiovascular and respiratory complications. Cardiovascular complications can include high blood pressure of various blood vessels throughout the body (systemic hypertension), enlargement of one of the right chambers (ventricles) of the heart (ventricular hypertrophy), stroke, and tissue death caused by lack of oxygen (infarction). Respiratory complications can include acute respiratory symptoms such as repeated pulmonary infections and difficulty breathing or respiratory distress. Eventually, in severe cases, cardiac or respiratory failure can occur.
Individuals with arterial tortuosity syndrome often have distinctive facial features such as an elongated face, beaked nose, highly arched palate, small chin (micrognathia), an abnormally long groove between the nose and upper lip (long philtrum), widely spaced eyes (hypertelorism), eyelids that are abnormally narrowed horizontally (blepharophimosis), and an abnormally enlarged head (macrocephaly). Less often, individuals may develop progressive changes in the shape of the cornea (keratoclonus), resulting in blurred vision and other vision problems.
The skin of individuals with arterial tortuosity syndrome may be very soft, velvety/silky, and easily stretched (hyperextensible or hyperelastic) to a variable extent. Abnormal scarring due to diminished wound healing can occur with atrophic scars. Skeletal malformations may occur including abnormally long, thin and curved fingers and toes (arachnodactyly), joints that are permanently fixed in a flexed or straightened position (joint contractures), loose (lax) joints, a sunken chest or a chest that protrudes outward, and abnormal sideways curvature of the spine (scoliosis).
Additional symptoms have been reported in individuals with arterial tortuosity syndrome in some cases. Such symptoms include the development of small, sac-like protrusions or bulges (diverticuli) in the genitourinary tract, protrusion of abdominal tissue or part of the small intestines through a bulge or tear in the abdominal muscles near the groin (inguinal hernias), protrusion of part of the stomach into the chest through an opening in the diaphragm (hiatal hernia), softening or weakening of the cartilage of the trachea (tracheomalacia), and decreased muscle tone (generalized hypotonia).
Arterial tortuosity syndrome is caused by a mutation in the SLC2A10 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
Mutations in the SLC2A10 gene are inherited as an autosomal recessive trait. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that the SLC2A10 gene is located on the long arm (q) of chromosome 20 (20q13.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 20q13.1″ refers to band 13.1 on the long arm of chromosome 20. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The SLC2A10 gene creates (encodes) a protein known as facilitative glucose transporter 10 (GLUT10). The GLUT10 protein regulates the transport of sugars (i.e. glucose), as well as of dehydroascorbic acid, the precursor of vitamin C, across cells membranes. Because of the mutation there are low levels of functional GLUT10 protein. The exact manner in which deficient levels of this protein results in the signs and symptoms of arterial tortuosity syndrome is not fully understood, but it is speculated that the decrease of vitamin C inside the cells lacking GLUT10 leads to the altered production of collagens and elastin, the main structural components of the extracellular matrix of connective tissues and of blood vessels. GLUT10 is involved in the transforming growth factor (TGF) beta pathway and may be necessary to signal other proteins in this pathway. The TGF beta pathway is implicated in Loeys-Dietz syndrome, a related disorder that is also characterized by arterial tortuosity, and in Marfan syndrome and other genetic disorders involving the thoracic aorta with aneurysm and dissection (TAAD).
Arterial tortuosity syndrome affects males and females in equal numbers. Approximately 100 cases have been reported in the medical literature. The exact incidence and prevalence is unknown. Because cases may go undiagnosed or misdiagnosed, determining the true frequency of arterial tortuosity syndrome in the general population is difficult. Onset is usually in infancy or early childhood.
A diagnosis of arterial tortuosity syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests and SLC2A10 gene molecular analysis.
Clinical Testing and Workup
Microscopic (histologic) examination of affected arteries can reveal disruption of elastic fibers of affected arterial walls.
A diagnosis of arterial tortuosity syndrome requires a variety of specialized tests to assess the extent of the disease. Such tests include echocardiography, angiography, magnetic resonance angiography (MRA), and computed tomography (CT) scan. During echocardiography, sound waves are bounced off the heart (echoes), enabling physicians to study cardiac function and motion. Angiographies are traditional x-rays designed to evaluate the health and function of blood vessels. An MRA is done with the same equipment use for magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular structures or tissues within the body. An MRA provides detailed information about blood vessels. In some cases, before the scan, an intravenous line is inserted into a vein to release a special dye (contrast). This contrast highlights the blood vessels, thereby enhancing the results of the scan. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.
Molecular genetic testing confirms or excludes a diagnosis of arterial tortuosity syndrome. Molecular genetic testing can detect mutations in the SLC2A10 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
The treatment of arterial tortuosity syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dermatologists, neurologists, cardiologists, pulmonologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with arterial tortuosity syndrome.
Surgical intervention for arterial and pulmonary abnormalities has been successful in specific cases reported in the medical literature (e.g. aortic root replacement for aortic aneurysms, pulmonary arterial reconstruction)
Other treatment is symptomatic and supportive and can include surgery to repair hernias, skeletal malformations or intestinal diverticula. The successful outcome of pregnancy in arterial tortuosity syndrome is reported in the medical literature.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Contact for additional information about arterial tortuosity syndrome:
Prof. Marina Colombi
Division of Biology and Genetics
Department of Molecular and Translational Medicine
University of Brescia
Viale Europa 11
Tel/Fax +39 0303717265
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