Arterial tortuosity syndrome in two Italian paediatric patients

Abstract

Background: Arterial tortuosity syndrome (ATS) (OMIM #208050) is a rare autosomal recessive connective tissue disorder characterized by tortuosity and elongation of the large and medium-sized arteries, propensity to aneurysms formation, vascular dissection, and pulmonary arteries stenosis. ATS is caused by mutations in SLC2A10 gene, encoding for the facilitative glucose transporter 10 (GLUT10). So far, 17 SLC2A10 mutations have been reported in 32 families, two of which were Italian with a total of five patients. Here we present the clinical and molecular characterization of two novel Italian paediatric ATS patients.

Methods: The exons and intronic flanking regions of SLC2A10 gene were amplified and direct sequencing was performed.

Results: In both patients, the involvement of major- and medium-sized arteries was characteristic; the nonvascular connective tissue manifestations were mild and not pathognomic of the disorder. Both patients, born from non-consanguineous parents, were heterozygous for two different SLC2A10 mutations, three of which were recurrent and one was novel (p.Arg231Trp). This mutation is localized at the endofacial loop between the transmembrane domains 6 and 7 of GLUT10.

Conclusion: Two novel ATS patients were characterized at clinical and molecular level. Overall, four ATS unrelated families are known in Italy so far. Though ATS clinical delineation improved in the last years, further works in the comprehension of disease presentation and complications onset, particularly in paediatric age, and on ATS molecular basis are needed to add new insights for diagnosis and prevention strategies for related complications.

Figure 1

Radiographic and facial features of the two Patients. i) MRA of Patient 1 showed tortuosity and kinking of aortic arch, mild hypoplasia of descending and abdominal aorta, tortuosity of all the sovraortic trunks with kinking of left common carotid and left subclavian arteries, ectasia of the innominate artery origin, and bilateral reduction of peripheral pulmonary branches. ii) Patient 1 showed elongated face, micrognathia, mild blepharophimosis, downslanting palpebral fissures, beaked nose, high-arched palate. iii) Patient 2 showed elongated face, low-set and anteverted ears, down-slanting palpebral fissures, high nasal bridge.

Figure 2

Molecular characterization of the patients by SLC2A10 sequencing on genomic DNA, obtained from whole peripheral blood of the patients, after written informed consent given by the parents. A) Patient 1 genotyping: the c.685C>T transition and the c.756C>A transversion, both in exon 2 and leading to p.Arg229X and the p.Cys252X nonsense mutations, respectively B) Chromatograms of mutations identified in Patient 2: the recurrent c.1334delG microdeletion in exon 3 and the novel c.691C>T transition in exon 2.