Search for a rare disease
Other search option(s)
Arterial tortuosity syndrome
A rare autosomal recessive connective tissue disorder characterized by tortuosity and elongation of the large and medium-sized arteries and a propensity towards aneurysm formation, vascular dissection, and stenosis of the pulmonary arteries.
ORPHA:3342Classification level: Disorder
Approximately 100 patients have been described in the literature so far. The male to female ratio is 1:1.
The clinical manifestations are variable, depending on the arteries affected. Onset usually occurs in infancy or early childhood. The cardiovascular anomalies may lead to right ventricular hypertension, acute respiratory symptoms, ventricular hypertrophy and cardiac failure. Patients are prone to aneurysm formation, dissection and ischemic events. Other typical manifestations include facial dysmorphism (features variably include an long face, hypertelorism, downslanting palpebral fissures, beaked nose, sagging cheeks, a high palate, and micrognathia), soft and hyperextensible skin, cutis laxa, hernias (inguinal, diaphragmatic, or hiatal), skeletal abnormalities, joint hypermobility, congenital contractures, keratoconus and generalized hypotonia.
The disease is caused by loss-of-function mutations in the SLC2A10 gene (20q13.12), encoding the glucose/dehydroascorbic acid transporter 10 (GLUT10). So far, 35 SLC2A10 pathogenic variants have been reported in approximately 80 families. The exact role of GLUT10 in the pathogenesis of the disorder remains to be fully clarified. Previous evidences revealed that the deficiency of GLUT10 perturbs the canonical transforming growth factor beta (TGFbeta) pathway, activates a non-canonical alphavbeta3 integrin-TGF beta receptor II signaling and causes the disorganization of different extracellular matrix proteins (i.e. collagens, elastin, fibronectin, decorin), which are essential for the structural integrity of several connective tissues including blood vessels wall. Moreover, as GLUT10 acts as an intracellular transporter of dehydroascorbic acid, the shortage of ascorbate might impair collagen and elastin crosslinking in the endoplasmic reticulum, redox homeostasis in the mitochondria and global and gene-specific methylation/hydroxymethylation affecting the epigenetic regulation in the nucleus.
Diagnosis requires further examination by echocardiography (ECG), angiography, and magnetic resonance angiography (MRA) and/or CT scan. Histology shows disruption of elastic fibers of the medial layer of the arterial wall. Detection of mutations in the SLC2A10 gene allows confirmation of the clinical diagnosis, and allows adapted genetic counseling and prognostic information to be provided to the patients.
The differential diagnosis should include Loeys-Dietz syndrome, Ehlers-Danlos syndromes (particularly the vascular-like classical Ehlers-Danlos syndrome), Marfan syndrome, occipital horn syndrome, and autosomal recessive cutis laxa (particularly the EFEMP2-, FBLN5-, and LTBP4-related Cutis laxa.
Prenatal diagnosis may be suspected by echocardiography and ultrasonography, and can be confirmed by prenatal molecular diagnosis performed on chorionic villi or amniocytes. Pregnancy requires intensive monitoring of both mother and fetus, cesarean delivery, and multidisciplinary postpartum care.
The pattern of inheritance is autosomal recessive. The risk of inheriting the disease is 25% where both parents are unaffected carriers.
Management and treatment
All patients require regular follow-up (periodic EGC, and MRA and/or CT scan) and may benefit from surgical interventions (aortic root replacement for aortic aneurysms and pulmonary artery reconstruction).
The prognosis can be severe and the first few years of life, usually before 5 years of age, might be critical for potentially life-threatening events. The main causes of premature death are respiratory insufficiency due to pulmonary artery stenosis, and heart failure due to either right ventricular hypertension and hypertrophy, myocarditis, and organ failure due to ischemic events.