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

Abstract

Background: Arterial Tortuosity Syndrome (ATS) is a very rare autosomal recessive connective tissue disorder (CTD) characterized by tortuosity and elongation of the large- and medium-sized arteries and a propensity for aneurysm formation and vascular dissection. During infancy, children frequently present the involvement of the pulmonary arteries (elongation, tortuosity, stenosis) with dyspnea and cyanosis. Other CTD signs of ATS are dysmorphisms, abdominal hernias, joint hypermobility, skeletal abnormalities, and keratoconus. ATS is typically described as a severe disease with high rate of mortality due to major cardiovascular malformations. ATS is caused by mutations in the SLC2A10 gene, which encodes the facilitative glucose transporter 10 (GLUT10). Approximately 100 ATS patients have been described, and 21 causal mutations have been identified in the SLC2A10 gene.

Case presentation: We describe the clinical findings and molecular characterization of three new ATS families, which provide insight into the clinical phenotype of the disorder; furthermore, we expand the allelic repertoire of SLC2A10 by identifying two novel mutations. We also review the ATS patients characterized by our group and compare their clinical findings with previous data.

Conclusions: Our data confirm that the cardiovascular prognosis in ATS is less severe than previously reported and that the first years of life are the most critical for possible life-threatening events. Molecular diagnosis is mandatory to distinguish ATS from other CTDs and to define targeted clinical follow-up and timely cardiovascular surgical or interventional treatment, when needed.

Figure 1

Clinical and angiographic features of Patient 1: mild scaphocephaly, elongated face, beaked nose, microretrognathia, elongated philtrum with congenital angioma, large ears (a,b), winged scapulae, scoliosis (c,d), hyperextensible skin over the neck (e), atrophic scar over the right the knee and elbow (f,g), and brachydactyly type D (h). An angiographic study performed between the pulmonary vessel reconstructive surgery and the following stenting revealed the tortuosity of the aorta and the origin of the brachiocephalic vessels (i) and the narrow origin of the pulmonary artery branches and their tortuous course (j).

Figure 2

Clinical and radiological features of Patients 2 and 3. A) Patient 2: mild scaphocephaly, hypotelorism, large ears, elongated face, micro-retrognathia, winged scapulae, scoliosis (a,b), genua valga, easy bruising, small atrophic scar over left knee (c), tortuosity of aortic arch and brachiocephalic vessels (d), marked tortuosity of intraparenchymal arteries (e). B) Patient 3: mild scaphocephaly, epicanthus, hypotelorism, large ears, elongated face, microretrognathia (a,b), winged scapulae, scoliosis (c), pes planus, piezogenic papules (d), right ventricular hypertrophy with left ventricular compression (e), marked tortuosity of intraparenchymal arteries (f).

Figure 3

Molecular characterization. Sequencing of SLC2A10 exons and splice junctions revealed the following: Patient 1 was homozygous for the recurrent mutation c.1309G>A (p.Glu437Lys) in exon 3; Patients 2 and 3 were homozygous for the novel mutation c.254T>C (p.Leu85Pro) in exon 2; the parents of Patient 4 were heterozygous for the novel mutation c.1465G>C (p.Gly489Arg) in exon 4.

Figure 4

Graphical overview of all known SLC2A10 mutations. GLUT10 contains 12 hydrophobic TMDs (rectangles), a hydrophilic endofacial loop between TMDs 6 and 7 as well as a large hydrophilic loop containing a putative N-linked glycosylation site between TMDs 9 and 10. The two novel mutations identified in this study are indicated in bold letters. The numbering is based on the protein reference sequence NP_110404.1.