Arterial Tortuosity Syndrome (ATS) is a rare disorder of the connective tissue, characterized by elongation and tortuosity of arteries and associated complications that include aneurysm, dilatation, stenosis, ventricular hypertrophy, and elevated blood pressures, including pulmonary and systemic hypertensions. Apart form these cardiovascular defects, patients also show skin hyperextensibility and cutis laxa, joint laxity, and inguinal hernia. Affected patients have also been noted to have peculiar facial features, including epicanthic folds, flat saggy cheeks, elongated facies, and micrognathia.
Histologically, elastic fibers of the tunica media show disruption, and internal plastic membranes are fragmented. Therapeutic options are limited in most patients, and usually death results at a young age.
ATS is transmitted in an autosomal recessive manner. Recently, mutations in the GLUT10 (Glucose Transporter 10) gene have been found to be responsible for causing the condition. The GLUT10, also known as SLC2A10, gene codes for a facilitative glucose transporter protein that plays a major role in maintaining glucose homeostatsis.
Coucke et al. (2003) described the clinical picture of the disease in Moroccan patients from two consanguineous families that may have had a common ancestor, as they originated from the same town. The clinical picture consisted of tortuosity of the aorta and pulmonary, subclavian, and renal arteries, as shown by echocardiography, angiography, and/or CT scan. Additional clinical features present in some of these patients were hyperlax skin and joints and/or dilation, aneurysms, and stenosis of the pulmonary arteries and ascending aorta.
Abdul Wahab et al. (2003) reported on a large Qatari extended family, belonging to a Bedouin tribe, with multiple affected members, and what they thought as a novel type of EDS. A total of 32 patients (21 males, 11 females; mean age: 7.4 years) belonging to 22 families from this tribe were found to be affected. Parental consanguinity was present in 30 of the patients (93.8%). Clinical and radiological features observed in the patients included moderate to severe hyperextensibility of the skin (100%), moderate to severe laxity of joints (100%), absence of joint dislocations (100%), an elongated aortic arch and tortuosity of the brachiocephalic arteries (93.8%), presence of a prominent aortic knuckle in the chest X-ray (93.8%), characteristic facies with epicanthal folds, full flat and saggy cheeks, and micrognathia (93.8%), and generalized muscular hypotonia (46.9%). Other cardiovascular complications observed in patients included a bifid pulmonary artery (84.4%), dilation of the main pulmonary arteries (70%), and pulmonary stenosis of the pulmonary artery (21.9%). Two patients were found to have ventricular septal defects, one had a mild prolapse of the mitral valve, while another three were found to have aneurysms of the ascending aorta. Other complications observed in some of the patients were diaphragmatic hernia (5 patients), hiatus hernia (3 patients), chronic obstructive sleep apnea secondary to laryngo-tracheoma (2), significant motor delay (15), and mild cognitive delay (4). Elastic staining in two affected siblings showed normal results. Abdul Wahab et al. (2003) conducted linkage analysis to determine if the genetic locus responsible for this condition mapped to any of the known loci for EDS. However, they could find no evidence for linkage to any of the known loci for EDS as well as to other connective tissue disorders, such as Cutis Laxa, familial aneurysm, and osteogenesis imperfecta. Abdul Wahab et al. (2003) suggested that the condition is probably a novel form of EDS caused due to mutations in an as-yet unidentified gene.
Five years later, Faiyaz-Ul-Haque et al. (2008) reported eight families with ATS, all of whom belonged to the large Bedouin tribe described by Abdul Wahab et al. (2003). All affected individual showed arterial tortuosity, stenosis of proximal or distal pulmonary artery, hyperextensible skin, hypermobility of small joints, and typical facial features that included elongated faces, saggy cheeks, and micrognathia. Hernias were observed in four patients. Skin biopsies from four patients showed normal collagen and elastin structures. Faiyaz-Ul-Haque et al. (2008) identified a homozygous mutation (S81R) in affected members of the eight families in addition to two more Qatari families with arterial tortuosity syndrome.
Al Fadley et al. (2000) described 12 patients, from eight non-related families, with similar facial features, skin and joint laxity, of lengthening and tortuosity of systemic, pulmonary and coronary vessels. All patients have elongated facies, prominent ears, micrognathia and laxity of their joints. Angiographic pictures showed a varying degree of lengthening and tortuosity of systemic, pulmonary, and coronary arteries. Pulsatile carotid arteries formed cervical masses in two patients, and three had severe renal arterial stenoses. All showed varying degrees of branch and peripheral pulmonary arterial stenosis, necessitating placement of stents in six. Biopsy of the skin proved normal in all seven patients studied, thus excluding cutis laxa, Ehlers-Danlos and Marfan syndromes.
Faiyaz-Ul-Haque et al. (2009) described two unrelated Saudi consanguineous families affected with Arterial Tortuosity Syndrome. The first family had one affected child, while the second family had six affected children in two sibships. All seven patients had consanguineous parents. The patients showed characteristic arterial, connective tissue, and facial features of ATS. However, there was a lot of inter and intra-familial phenotypic variability, especially with regards to the arterial phenotype. In the second family, only two patients carried extensive stenosis of the main pulmonary artery, while another patient showed severe stenosis of the peripheral pulmonary artery with no such stenosis in the main pulmonary artery. Patients in this family also showed variable degrees of dilatations of aortic arch, brachiocephalic artery, and aortic route. This was in spite of the fact that all patients in this family carried the same mutation in the SLC2A10 gene. On the other hand, the skin and facial phenotype of the patients were less variable, even within the two families, even though they carried different mutations. All patients showed the presence of hyperextensible skin, small joint hypermobility, distinctly elongated faces, long philtrums, prominent ears, loose cheeks, and micrognathia. There was minor variability in the form of bifurcated uvula and macrocephaly in the single patient from the first family, and the presence of some other phenotypes, such as arachodactyly, long feet, bronchial asthma, and myobia in some of the patients.