Arterial Tortuosity Syndrome
Arterial Tortuosity Syndrome
National Organization for Rare Disorders, Inc.
It is possible that the main title of the report Arterial Tortuosity Syndrome is not the name you expected.
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.
Symptoms of the following disorders can be similar to those of arterial tortuosity syndrome. Comparisons may be useful for a differential diagnosis.
Loeys-Dietz syndrome (LDS) is a rare disorder characterized by a variety of symptoms that overlap with arterial tortuosity syndrome. Individuals with LDS have skeletal and cardiovascular abnormalities. Affected individuals may experience bulging of the wall of the thoracic aorta (aneurysm), tearing (dissection) of the aorta or rupture of the aorta. The aorta in individuals with LDS is prone to tearing or rupturing early in childhood and at a relatively small size. Affected blood vessels tend to follow a very winding course (tortuosity) and aneurysms and tears of blood vessels can occur throughout the entire arterial tree. Additional findings that may occur include long, slender fingers (arachnodactyly), abnormal curvature of the spine (scoliosis), a sunken or protruding chest (pectus excavatum or pectus carinatum), widening of the spinal sac (dural ectasia), and loose joints. Additional symptoms include accumulation of excessive cerebrospinal fluid (CSF) in the skull causing pressure on the tissues of the brain (hydrocephalus), incomplete closure of the roof of the mouth (cleft palate), premature closure of the fibrous joints (sutures) between certain bones of the skull (craniosynostosis), bluish discoloration of the whites of the eyes (blue sclerae), deviation of one of the eyes outward away from the other eye (exotropia) and abnormally formed or unstable joints in the spine of the neck (cervical spine malformation or instability). The fleshy mass (uvula) hanging in the back of the throat may be unusually broad or split (bifid uvula). Characteristic facial features often include widely spaced eyes (hypertelorism), a highly-arched roof of the mouth (palate), an abnormally small jaw (micrognathia) that is recessed farther back than normal (retrognathia), and underdeveloped cheek bones (malar hypoplasia). The skin in LDS can be soft with easily visible underlying veins (translucency). The skin also tends to bruise easily and to develop abnormal (wide) scars. People with LDS can be prone to severe allergies and to inflammation of the gastrointestinal tract (eosinophilic esophagitis or colitis). Loeys-Dietz syndrome is inherited as an autosomal dominant trait and is caused by mutations in any of the four genes that are all known to influence the activity of TGFbeta (TGFBR1, TGFBR2, SMAD3 or TGFB2).
Marfan syndrome is a genetic disorder that affects connective tissues. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), indentation or protrusion of the chest wall (pectus), dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and tear (dissection) of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse) and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of Marfan syndrome vary greatly from case to case. Marfan syndrome is inherited as an autosomal dominant trait, meaning that only one abnormal copy of the Marfan gene inherited from one parent is sufficient to have the condition. Defects or disruptions (mutations) of the fibrillin-1 (FBN1) gene have been linked to Marfan syndrome and related disorders. (For more information on this disorder, choose "Marfan" as your search term in the Rare Disease Database.)
Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders characterized by defects of the major structural proteins in the body (collagens). Collagens, tough, fibrous proteins, play an essential role in holding together and strengthening the tissues of the body. Due to defects of collagen, primary EDS symptoms and findings include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated; unusually loose, thin, stretchy (elastic) skin; and excessive fragility of the skin, small blood vessels, and other bodily tissues and membranes. The different types of EDS were originally categorized in a classification system that used Roman numerals (e.g., EDS I to EDS XI), based upon each form's associated symptoms and findings (clinical evidence) and underlying cause. A revised, simplified classification system has since been described in the medical literature that categorizes EDS into six major subtypes, based upon clinical evidence, underlying biochemical defects, and mode of inheritance. Each subtype of EDS is a distinct hereditary disorder that may affect individuals within certain families (kindreds). Depending upon the specific subtype present, EDS is usually transmitted as an autosomal dominant or autosomal recessive trait. Only certain rare types of EDS include a predisposition for severe cardiovascular issues (such as vascular EDS); other types predominantly alter the skin and joints (e.g. hypermobile EDS). (For more information on this disorder, choose "Ehlers Danlos" as your search term in the Rare Disease Database.)
There are many additional disorders in which similar skin symptoms occur. Such disorders include Cantu syndrome, SCARF syndrome, Lenz-Majewski hyperostotic dwarfism, Barber-Say syndrome, Hutchinson-Gilford progeria syndrome, Cockayne syndrome, Wiedemann-Rautenstrauch syndrome, Kabuki syndrome, Williams syndrome, Patterson pseudoleprechaunism syndrome, Costello syndrome, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome, and ablepharon-macrostomia syndrome. These disorders have other features that can clearly distinguish them from arterial tortuosity syndrome. NORD has individual reports on many of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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:
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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
MacCarrick G, Black JH , Bowdin, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014; [Epub ahead of print]. //www.ncbi.nlm.nih.gov/pubmed/24577266
Van Laer L, Proost D, Loeys BL. Educational paper. Connective tissue disorders with vascular involvement: from gene to therapy. Eur J Pediatr. 2013;72:997-1005. //www.ncbi.nlm.nih.gov/pubmed
Castori M, Ritelli M, Zoppi N, et al. Adult presentation of arterial tortuosity syndrome in a 51-year-old woman with a novel homozygous c.1411+1G>A mutation in the SLC2A10 gene. Am J Med Genet A. 2012;158A:1164-1169. //www.ncbi.nlm.nih.gov/pubmed/22488877
Nauheim MR, Walcott BP, Nahed BV, et al. Arterial tortuosity syndrome with multiple intracranial aneurysms: a case report. Arch Neurol. 2011;68:369-371. //www.ncbi.nlm.nih.gov/pubmed/21403023
Al-Khaldi A, Mohammed Y, Tamimi O, Alharbi A. Early outcomes of total pulmonary arterial reconstruction in patients with arterial tortuosity syndrome. Ann Thorac Surg. 2011;92:698-704. //www.ncbi.nlm.nih.gov/pubmed/21704298
Segade F. Glucose transporter 10 and arterial tortuosity syndrome: the vitamin C connection. FEBS Lett. 2010;584:2990-2994. //www.ncbi.nlm.nih.gov/pubmed/20547159
Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476-85. //www.ncbi.nlm.nih.gov/pubmed/20591885
Ritelli M, Drera B, Vicchio M, et al. Arterial tortuosity syndrome in two Italian paediatric patients. Orphanet J Rare Dis. 2009;4:20. //www.ojrd.com/content/4/1/20
Allen VM, Horne SG, Penney LS, et al. Successful outcome in pregnancy with arterial tortuosity syndrome. Obstet Gynecol. 2009;114:494-498. //www.ncbi.nlm.nih.gov/pubmed/19622975
Callewaert BL, Willaert A, Kerstjens-Frederikse WS, et al. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat. 2008;29:150-158. //www.ncbi.nlm.nih.gov/pubmed/17935213
Coucke PJ, Willaert A, Wessels MW, et al. Mutations in the facilitative glucose transporter (GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet. 2006;38:452-457. //www.ncbi.nlm.nih.gov/pubmed/16550171
Gardella R, Zoppi N, Assanelli D, Muiesan ML, Barlati S, Colombi M. Exclusion of candidate genes in a family with arterial tortuosity syndrome. Am J Med Genet. 2004;126A:221-228. //www.ncbi.nlm.nih.gov/pubmed/15054833
Wessels MW, Catsman-Berrevoets CE, Mancini GM, et al. Three new families with arterial tortuosity syndrome. Am J Med Genet A. 2004;131:134-143. //www.ncbi.nlm.nih.gov/pubmed/15529317
Coucke P, Wessels M, van Acker P, et al. Homozygosity mapping of a gene for arterial tortuosity syndrome to chromosome 20q13. J Med Genet. 2003;40:747-751. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1735278/
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:208050; Last Update:11/29/2012. Available at: //omim.org/entry/208050 Accessed on: March 2, 2014.
Colombi M. Arterial Tortuosity Syndrome. Orphanet Encyclopedia, November 2009. Available at: //www.orpha.net/ Accessed on: March 2, 2014.
Genetics Home Reference. Arterial Tortuosity Syndrome (ATX). January 2013. Available at: //ghr.nlm.nih.gov/condition/arterial-tortuosity-syndrome Accessed On: March 2, 2014.
John Hopkins Medicine. McKusick-Nathans Institute of Genetic Medicine. Arterial Tortuosity Syndrome (ATX). Available at: https://igm.jhmi.edu/ats-syndrome Accessed On: March 2, 2014.
A Twist of Fate-ATS
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Last Updated: 7/4/2014
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