April 16, 2020
Years published: 2014, 2017, 2020
NORD gratefully acknowledges Prof. Marina Colombi, Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, for assistance in the preparation of this report.
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 ATS is not fully understood. Several factors including the small number of identified affected individuals, 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.
Nevertheless, life expectancy seems to be longer than initially observed and in adolescence/adulthood life-threatening cardiovascular events seem to be rare; in adulthood complications commonly observed are chronic systemic and pulmonary hypertension, heart conduction defects, aortic root dilatation, stroke, and intracranial aneurysms. The first few months/years of life appear to be the most critical for possible life-threatening events, particularly complications related to stenosis of the pulmonary arteries (PAS) such as acute respiratory symptoms.
It is important to note that affected individuals may not have all of the symptoms discussed below. For example, affected individuals may have uncomplicated arterial tortuosity 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 ATS 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. The patients with tortuous arteries are prone to aneurysm formation, dissection and ischemic events and other 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 ATS 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), downslanted palpebral fissures, eyelids that are abnormally narrowed horizontally (blepharophimosis or periorbital fullness), an abnormally enlarged head (macrocephaly) and a highly arched roof of the mouth (palate) and dental crowding. Less often, individuals may develop progressive changes in the shape of the cornea (keratoconus), resulting in blurred vision and other vision problems.
The skin of individuals with ATS may be 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 especially of knees and elbows), loose (lax) joints, a sunken chest or a chest that protrudes outward, abnormal sideways curvature of the spine (scoliosis), and indentation or protrusion of the chest wall (pectus excavatum/carinatum)
Additional symptoms have been reported in individuals with ATS 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 mutations 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.
To date, a total of 35 mutations in approximately 80 families have been identified in the SLC2A10 gene.
The SLC2A10 gene creates (encodes) a protein known as facilitative glucose transporter 10 (GLUT10) that regulates the transport of sugars (i.e., glucose) and dehydroascorbic acid (DAA), the oxidized form of vitamin C, across cellular membranes. Mutation(s) in SLC2A10 lead to low levels of functional GLUT10 protein in ATS patients. Although the pathogenic mechanism underlying all the SLC2A10 mutations is the loss of GLUT10 function, the specific role of the GLUT10 transporter in the pathogenesis of ATS is still debated.
Mutations in the SLC2A10 gene are inherited in an autosomal recessive pattern. 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.
In 2015, a study, performed on skin fibroblasts (a type of cell found in connective tissue that synthesizes the extracellular matrix, collagens, and other proteins) derived from ATS patients, showed that the lack of GLUT10 protein perturbs the canonical transforming growth factor beta (TGFβ) pathway and causes the disorganization of different structural proteins (i.e., collagens, elastin, fibronectin, decorin), essential for the structural integrity of several connective tissues including blood vessels wall. In addition, molecular findings, obtained by analyzing all mRNAs in skin fibroblasts of different ATS patients, revealed that the lack of GLUT10 alters TGFβ signaling, extracellular matrix integrity, expression of genes that influence the lipid metabolism, and related to the cellular response against the oxidative stress (maintenance of intracellular redox homeostasis).
Moreover, in 2016 it was demonstrated that the GLUT10 is able to transport DAA across cellular endomembranes system (i.e., endoplasmic reticulum, and nuclear envelope). DAA is the oxidized form of vitamin C (ascorbic acid). Vitamin C is an essential nutrient for humans that acts both as a potent antioxidant, which protects cells from oxidative damage by acting as a scavenger of different free radicals, and as a cofactor essential for the function of enzymes (proteins) that are involved in the synthesis (production) of collagens and elastin proteins. The exact manner in which deficient levels of GLUT10 results in the signs and symptoms of ATS 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, thus affecting the structural integrity of the wall of the main arteries (i.e., aorta, pulmonary arteries).
Finally, in 2019 it was demonstrated that the decreased nuclear ascorbate accumulation in dermal fibroblasts from ATS patients is accompanied with altered genomic methylation pattern, strongly suggesting an epigenetic role of ascorbic acid transport in the disease pathomechanism. In view of all these observations, ATS is considered as an ascorbate compartmentalization disorder.
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. The male to female ratio is 1:1. Because affected individuals 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 ATS 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 ATS 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 ATS. 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, pneumologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Based on a literature review, complications have rarely been observed during cardiovascular surgery in ATS patients, and the risk of fatal events should be similar to the general population.
Other treatment is symptomatic and supportive and can include surgery to repair hernias, skeletal malformations, or intestinal diverticula.
Obstetric aspects of ATS have not been elucidated, to date in literature are reported 4 ATS women with successful pregnancy and uncomplicated deliveries. These data suggest that in ATS, pregnancy can be safely handled with multidisciplinary management including close maternal and fetal surveillance.
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
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Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
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
Phone +39 0303717240
e-mail [email protected]
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