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40 years!
Last updated:
4/12/2024
Years published: 2014, 2017, 2020, 2024
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.
Summary
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 multiple systems of the body are soft or doughy hyperextensible skin, joint hypermobility, inguinal hernia and diaphragmatic hernia. Skeletal findings include pectus deformities, scoliosis and knee/elbow contractures. 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 variants in the SLC2A10 gene and is inherited in an autosomal recessive manner.
Introduction
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 (e.g., collagens), proteins bound to sugar 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.
Researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, but much about ATS is not fully understood. It has been difficult to determine a complete picture of associated symptoms and prognosis because of the small number of identified patients, the lack of large clinical studies and the possibility of other genes influencing the disorder.
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. 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, heart 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), down-slanted 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. Cutis laxa can be present. 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 variants 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 protein, this can affect many organ systems of the body, including the brain.
To date, a total of 36 variants in approximately 82 families (110 individuals) 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. Variants in SLC2A10 lead to low levels of functional GLUT10 protein in ATS patients. Although the pathogenic mechanism underlying all the SLC2A10 variants is the loss of GLUT10 function, the specific role of the GLUT10 transporter in the pathogenesis of ATS is still debated.
ATS is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having 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 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).
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).
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 are 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.
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. The diagnosis can be confirmed with molecular genetic testing for variants in the SLC2A10 gene.
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 used for magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of 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.
Treatment
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 plan an affect child’s treatment systematically and comprehensively.
Aortic aneurysm medical treatment could include beta-adrenergic blockers or other medications such as angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor 1 (ATIIR1) antagonists such as losartan, though their efficacy has not been established in ATS and should be used with caution in presence of arterial stenosis (anatomic or functional due to severe tortuosity), especially renal artery stenosis, as such treatment may increase risk for renal failure. Aortic aneurysm surgical treatment could include valve-sparing procedure that precludes need for chronic anticoagulation.
Focal stenosis of aorta and aortic branches requires catheterization and/or surgery; surgery, catheterization or a hybrid transcatheter-surgical procedure are adopted for pulmonary artery stenosis and pulmonary hypertension.
Based on a literature review, complications have rarely been observed during cardiovascular surgery in ATS patients, and the risk of fatal events is similar to the general population.
Other treatment is symptomatic and supportive and can include surgery to repair hernias, skeletal malformations or intestinal diverticula.
ATS in pregnancy has not been well studied, but 4 women with ATS have been reported to have successful pregnancies and uncomplicated deliveries. These data suggest that pregnancy in women with ATS can be safely handled with multidisciplinary management including close maternal and fetal surveillance.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
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
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
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
25123 Brescia
Italy
Phone +39 0303717240
e-mail marina.colombi@unibs.it
JOURNAL ARTICLES
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Adamo CS, Beyens A, Schiavinato A, et al. EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis. Am J Hum Genet. 2022;109(12):2230-2252. doi:10.1016/j.ajhg.2022.10.010
Boel A, Veszelyi K, Németh CE, Beyens A, Willaert A, Coucke P, Callewaert B, Margittai É. Arterial tortuosity syndrome: an ascorbate compartmentalization disorder? Antioxid Redox Signal. 2019 Nov 14. doi: 10.1089/ars.2019.7843. https://www.ncbi.nlm.nih.gov/pubmed/31621376.
Németh CE, Nemoda Z, Lőw P, Szabó P, Horváth EZ, Willaert A, Boel A, Callewaert BL, Coucke PJ, Colombi M, Bánhegyi G, Margittai É. Decreased nuclear ascorbate accumulation accompanied with altered genomic methylation pattern in fibroblasts from arterial tortuosity syndrome patients. Oxid Med Cell Longev. 2019:8156592. https://www.ncbi.nlm.nih.gov/pubmed/30800210
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Kocova M, Kacarska R, Kuzevska-Maneva K, Prijic S, Lazareska M, Dordoni C, Ritelli M, Colombi M. Clinical variability in two Macedonian families with arterial tortuosity syndrome. Balkan J Med Genet. 2018 Oct 29;21(1):47-52. https://www.ncbi.nlm.nih.gov/pubmed/30425910
Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26. doi:10.1002/ajmg.c.31552
Gamberucci A, Marcolongo P, Németh CE, Zoppi N, Szarka A, Chiarelli N, Hegedűs T, Ritelli M, Carini G, Willaert A, Callewaert BL, Coucke PJ, Benedetti A, Margittai É, Fulceri R, Bánhegyi G, Colombi M. GLUT10-Lacking in arterial tortuosity syndrome-Is localized to the endoplasmic reticulum ofhHuman fibroblasts. Int J Mol Sci. 2017 Aug 22;18(8). pii: E1820. https://www.ncbi.nlm.nih.gov/pubmed/28829359.
Ritelli M, Palit A, Giacopuzzi E, Inamadar AC, Dordoni C, Mujja A, Murgude MS, Colombi M. Clinical and molecular characterization of a 13-year-old Indian boy with cutis laxa type 2B: Identification of two novel PYCR1 mutations by amplicon-based semiconductor exome sequencing. J Dermatol Sci. 2017 Oct;88(1):141- 143 https://www.ncbi.nlm.nih.gov/pubmed/28499588
Németh CE, Marcolongo P, Gamberucci A, et al. Glucose transporter type 10 – lacking in arterial tortuosity syndrome – facilitates dehydroascorbic acid transport. FEBS letters. 2016; 590:1630- 40. https://www.ncbi.nlm.nih.gov/pubmed/27153185
Albuisson J, Moceri P, Flori E, Belli E, Gronier C, Jeunemaitre X. Clinical utility gene card for: Arterial tortuosity syndrome. Eur J Hum Genet. 2015;23(10). https://www.ncbi.nlm.nih.gov/pubmed/25604859
Zoppi N, Chiarelli N, Cinquina V, Ritelli M, Colombi M. GLUT10 deficiency leads to oxidative stress and non-canonical αvβ3 integrin-mediated TGFβ signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts. Hum Mol Genet. 2015; 24:6769- 6787. https://www.ncbi.nlm.nih.gov/pubmed/26376865.
Ritelli M, Chiarelli N, Dordoni C, et al. Arterial Tortuosity Syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review. BMC Medical Genetics. 2014; 15:122. https://www.ncbi.nlm.nih.gov/pubmed/25373504
MacCarrick G, Black JH , Bowdin, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014; [Epub ahead of print]. http://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. http://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. http://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. http://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. http://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. http://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. http://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. http://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. http://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. http://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. http://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. http://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;131:134-43. http://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. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735278/
INTERNET
Arterial Tortuosity Syndrome (ATX). MedlinePlus. Last Update Nov 2015. Available at: http://ghr.nlm.nih.gov/condition/arterial-tortuosity-syndrome Accessed March 27, 2024.
Arterial Tortuosity Syndrome. Online Mendelian Inheritance in Man (OMIM). Entry No:208050; Last Update: 06/01/2020. Available at: http://omim.org/entry/208050 Accessed March 27, 2024.
Colombi M. Arterial Tortuosity Syndrome. Orphanet Encyclopedia, November 2019. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=3342. Accessed March 27, 2024.
Callewaert B, De Paepe A, Coucke P. Arterial Tortuosity Syndrome. 2014 Nov 13 [Updated 2023 Feb 23]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK253404/ Accessed March 27, 2024.
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