Alternative titles; symbols
SNOMEDCT: 458432002; ICD10CM: Q87.82; ORPHA: 3342; DO: 0050645;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.12 | Arterial tortuosity syndrome | 208050 | Autosomal recessive | 3 | SLC2A10 | 606145 |
A number sign (#) is used with this entry because of evidence that arterial tortuosity syndrome (ATORS) is caused by homozygous or compound heterozygous mutation in the gene encoding glucose transporter GLUT10 (SLC2A10; 606145) on chromosome 20q13.
Arterial tortuosity syndrome (ATORS) is a rare connective tissue disorder characterized by generalized tortuosity, elongation, stenosis, and aneurysms of the major arteries. Skin and joint abnormalities, including hyperextensibility or hyperlaxity of the skin, joint laxity or contractures, and inguinal hernias, may also be observed. Other abnormalities include micrognathia, elongated face, high palate, beaked nose, sliding hernia, and ventricular hypertrophy (summary by Coucke et al., 2006).
From Ankara, Turkey, Ertugrul (1967) described a 10-year-old girl with generalized tortuosity and elongation of all major arteries including the aorta. Telangiectases of the cheeks, high palate, aortic regurgitation and histologic fragmentation of the internal elastic membrane of arteries were noted. Three brothers were well. The parents were also healthy. No comment on consanguinity was made. The same condition may have been present in the boy reported by Beuren et al. (1969). Multiple pulmonary artery stenoses were present. The child reported by Lees et al. (1969) had tortuous systemic arteries and multiple pulmonary artery stenoses, but the skin was considered excessively stretchable, consistent with the Ehlers-Danlos syndrome (EDS; see 130000). The sibs reported by Welch et al. (1971) had features suggesting cutis laxa (219100) with arterial tortuosity of severe degree. The parents were consanguineous. The father and many of his relatives had joint laxity interpreted as the benign hypermobile form of EDS (130020).
Franceschini et al. (2000) described a male patient with arterial tortuosity syndrome, including generalized tortuosity and elongation of all major arteries, soft skin, joint laxity, severe keratoconus, and diffuse tortuosity of the carotids and intracranial arteries. Cytochemical studies excluded EDS types IV (130050) and VII (225410). The authors suggested that the patient's brother and sister, who died early of unknown causes, probably had the same condition, consistent with an autosomal recessive etiology.
The clinical picture in the Moroccan patients from 2 families studied by Coucke et al. (2003) 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. A third family, originating from southern Sicily, had 4 affected members who showed tortuosity of the major arteries, and 2 members also showed severe pulmonary artery stenosis. Some patients had gastric and inguinal hernias, intestine elongation, and keratoconus. Soft nasal cartilage and micrognathia were noted in some.
Gardella et al. (2004) reported an Italian pedigree with 3 interrelated sibships in which 5 patients showed signs of ATS. In particular, 4 adult patients presented arterial tortuosity and elongation of the main arteries. Two of these patients, with the most severe degree of arterial tortuosity, also showed severe peripheral stenosis of the main pulmonary artery. The fifth young patient showed a severe pulmonary valve stenosis in the absence of arterial tortuosity. All patients showed signs of EDS: soft skin with abundant subcutaneous tissue and joint laxity, hernias, and disorganization of the extracellular matrix of fibronectin and of actin microfilaments in cultured skin fibroblasts. Linkage analysis excluded genes known to be involved in various forms of Ehlers-Danlos syndrome and other connective tissue disorders, thus indicating that ATS is a distinct clinical and molecular entity.
Wessels et al. (2004) described 9 additional ATS patients from 3 consanguineous Moroccan families and reviewed 35 patients with this uncommon disorder. The most specific clinical findings were cardiovascular anomalies, including tortuosity, lengthening, aneurysm, and stenosis of major arteries. Ventricular hypertrophy was frequently present. Other anomalies were skin hyperextensibility and cutis laxa, laxity or contractures of the joints, and inguinal hernias. Histology showed disruption of elastic fibers in the media of large vessels. All these features suggested that ATS is a connective tissue disorder.
Coucke et al. (2006) pictured the typical facial phenotype of ATS with micrognathia, elongated face, downslanting palpebral fissures, blepharophimosis, and a beaked nose.
Cartwright et al. (2006) reported a 14-year-old African American girl who presented with right arm posturing and decreased verbal output consistent with ischemic stroke. She had a history of congenital rectal prolapse and colonic diverticulitis, and physical examination showed arachnodactyly and joint laxity. Brain imaging showed an acute infarct due to ischemic stroke in the left caudate head, internal capsule, and putamen, as well as extreme tortuosity of the carotid, vertebral, and internal arteries consistent with ATS. Cartwright et al. (2006) postulated that fragmentation of the internal elastic membrane may have altered the endothelial surface of a vessel, leading to thrombosis and ischemic stroke.
Callewaert et al. (2008) reported 16 individuals with arterial tortuosity syndrome from 12 families, 3 of which were consanguineous. Six probands presented with cardiac murmur before age 15 months. Two patients presented with ischemic stroke at ages 8 months and 23 years, respectively. All patients had tortuosity of the aorta or large arteries. Five patients had aberrant origins of aortic side branches, 2 adult patients had aortic root dilation, 7 patients had localized arterial stenoses, and 5 had long stenotic stretches of the aorta. Other common clinical features included long slender face with sagging cheeks, beaked nose, thin skin, large ears, high-arched palate, hernias, and joint laxity. About half of the patients had an aged appearance. Miscellaneous features included macrocephaly in 2 patients, tracheal abnormalities in 2 patients, duplication of the right renal collecting system in 1 patient, and ectopic left kidney and bladder diverticula in 1 patient. All patients and carriers had normal oral glucose tolerance testing and no evidence of hyperglycemia, except 1 carrier who had mild hyperinsulinemia following a recent weight gain. Callewaert et al. (2008) emphasized that their patients were significantly older than previously reported, including 10 patients who were over the age of 5 years.
Faiyaz-Ul-Haque et al. (2008) reported 8 families with ATS, all of whom belonged to a large Bedouin tribe in Qatar. 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 4 patients. Skin biopsies from 4 patients showed normal collagen and elastin structures. The large Bedouin kindred had previously been reported by Abdul Wahab et al. (2003) as having a unique form of Ehlers-Danlos syndrome (see, e.g., 130000).
Zaidi et al. (2009) emphasized that congenital diaphragmatic abnormalities, including diaphragmatic hernia, gastric hernia, sliding hernia, and hiatal hernia, have often been reported in patients with ATS (see, e.g., Franceschini et al., 2000, Abdul Wahab et al., 2003, Wessels et al., 2004, Callewaert et al., 2008). These diaphragmatic abnormalities are consistent with other connective tissue defects seen in ATS.
Beyens et al. (2018) retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. Among the 50 novel patients, 20 had a cardiovascular presentation, 7 had a respiratory presentation (dyspnea or infantile respiratory distress syndrome), and 7 had a cutaneous presentation (4 with cutis laxa and 3 with stretchable skin). Two patients had a gastrointestinal presentation, 1 with pyloric stenosis and 1 with failure to thrive. One presented with gross motor delay. Five were diagnosed because of familial analysis, and for 8 patients their presentation was unknown. Among their 50 patients, 50% had parental consanguinity. Two-thirds of patients had a long face, downslanting palpebral fissures, and/or a high-arched palate. About half had micrognathia, sagging cheeks, or a beaked nose. Half had cutis laxa. In a review of all patients (50 novel and 52 previously reported), the only features reaching greater than 50% were long face (73%), micrognathia (58%), sagging cheeks (54%), hyperextensible skin (61%), joint laxity (76%), aortic tortuosity (92%), tortuosity of other arteries (80%), and stenosis of pulmonary arteries (57%). The authors reported that severe but rare vascular complications included early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. At the time of the report, no reports had unequivocally documented vascular dissections or ruptures. The authors noted that diaphragmatic hernia and infant respiratory distress syndrome were frequently observed. Skin and vascular biopsies showed fragmented elastic fibers and increased collagen deposition. Electron microscopy of skin elastic fibers showed a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue did not indicate increased TGF-beta signaling.
Coucke et al. (2003) reported localization of the arterial tortuosity syndrome locus to chromosome 20q13 by homozygosity mapping in 2 families, and possibly a third. The parents of patients in all cases were consanguineous. Two of the families were Moroccan and may have had a common ancestor, as they originated from the same town.
Zaidi et al. (2005) reported a consanguineous Kurdish family in which an affected child manifested elongation and severe tortuosity of the aorta, carotid, and other arteries, as well as loose skin, hypermobile joints, hernias, and facial features resembling those in EDS. Homozygosity analysis revealed that the affected child was homozygous, whereas the unaffected parents and 3 sibs were heterozygous, for microsatellite markers on 20q13. Additional typing refined the tortuosity locus to a 37-cM region between markers D20S885 and D20S893. No mutations were found in the coding regions of 3 candidate genes, but in the promoter region of the prostaglandin I2 synthase gene (PTGIS; 601699) the affected child was homozygous for 8 variable number tandem repeats whereas her parents and sibs carried 6 repeats.
The transmission pattern of aterial tortuosity syndrome in the families reported by Coucke et al. (2006) was consistent with autosomal recessive inheritance.
Coucke et al. (2006) narrowed the arterial tortuosity syndrome candidate region on chromosome 20q13.1 to a 1.2-Mb region containing 7 genes. Homozygous mutations in 1 of these genes, SLC2A10, were identified in 6 ATS families. The parents in all 6 families were carriers of the mutation. Deficiency of the facilitative glucose transporter GLUT10, which is encoded by SLC2A10, is associated with upregulation of the TGF-beta (see 190180) pathway in the arterial wall, a finding also observed in Loeys-Dietz syndrome (609192), in which aortic aneurysms associate with arterial tortuosity. The identification of a glucose transporter gene responsible for altered arterial morphogenesis is notable in light of the previously suggested link between GLUT10 and type 2 diabetes (125853) (Dawson et al., 2001; McVie-Wylie et al., 2001). The findings of Coucke et al. (2006) could provide new insight on the mechanisms causing microangiopathic changes associated with diabetes and suggested that therapeutic compounds intervening with TGF-beta signaling represent a new treatment strategy.
In 16 patients from 12 families with ATS, Callewaert et al. (2008) identified 11 different mutations in the SLC2A10 gene (see, e.g., 606145.0005-606145.0006). Several mutations represented founder effects.
Faiyaz-Ul-Haque et al. (2008) identified a homozygous mutation (S81R; 606145.0004) in affected members of 10 Qatari families with arterial tortuosity syndrome. Eight of the families belonged to a large consanguineous kindred that was part of an extended Bedouin tribe originally reported as having an unique form of Ehlers-Danlos syndrome (Abdul Wahab et al., 2003).
By immunohistochemical analysis, Zoppi et al. (2015) observed disarray of several structural components of the extracellular matrix in skin fibroblasts from 3 ATS patients with different GLUT10 mutations. Expression profiling and quantitative RT-PCR of control and patient fibroblasts revealed differential expression of genes involved in TGF-beta signaling and of genes that influence lipid metabolism, intracellular redox homeostasis, and maintenance of extracellular matrix. Immunofluorescence microscopy, Western blot analysis, and flow cytometry confirmed increased synthesis of ALDH1A1 (100640) and PPAR-gamma (PPARG; 601487) and increased production of reactive oxidative species in ATS patient fibroblasts. Patient fibroblasts also showed activation of a noncanonical alpha-V (ITGAV; 193210)/beta-3 (ITGB3; 173470) integrin-mediated TGF-beta signaling pathway. Stable expression of GLUT10 partially normalized ATS fibroblasts.
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Zaidi, S. H. E., Peltekova, V., Meyer, S., Lindinger, A., Paterson, A. D., Tsui, L.-C., Faiyaz-Ul-Haque, M., Teebi, A. S. A family exhibiting arterial tortuosity syndrome displays homozygosity for markers in the arterial tortuosity locus at chromosome 20q13. Clin. Genet. 67: 183-188, 2005. [PubMed: 15679832] [Full Text: https://doi.org/10.1111/j.1399-0004.2004.00391.x]
Zoppi, N., Chiarelli, N., Cinquina, V., Ritelli, M., Colombi, M. GLUT10 deficiency leads to oxidative stress and non-canonical alpha-V/beta-3 integrin-mediated TGF-beta signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts. Hum. Molec. Genet. 24: 6769-6787, 2015. [PubMed: 26376865] [Full Text: https://doi.org/10.1093/hmg/ddv382]