Arterial Tortuosity Syndrome - A Connective Tissue Disorder

Introduction:

Arterial tortuosity syndrome (ATS) is an extremely rare congenital autosomal recessive disorder that is characterized by abnormalities in the connective tissues throughout the body, especially in the blood vessels in which bulgings or aneurysms develop. The condition develops due to aberrancy in the extracellular matrix. ATS causes widespread elongation and tortuosity of the aorta and mid-sized arteries, as well as focal stenosis of the pulmonary arteries and aorta, along with generalized connective tissue disruption.

Who Is Susceptible to Arterial Tortuosity Syndrome?

Arterial tortuosity syndrome is a rare inheritable disorder with about 100 reported cases with equal gender predilection. The onset of ATS is usually during infancy or early childhood. The exact prevalence of the condition is unclear.

What Causes Arterial Tortuosity Syndrome?

Arterial tortuosity syndrome is a congenital condition with an autosomal recessive inheritance. ATS is caused due to mutations in the SLC2A10 gene present in the long arm of chromosome 20 (20q13.12). The gene encodes GLUT10 protein, which is intimately involved in the transforming growth factor-beta (TGF-beta) signaling pathway.

What Is the Pathophysiology of Arterial Tortuosity Syndrome?

Arterial tortuosity syndrome is caused due to mutations resulting in increased signaling of the TGF-beta pathway. The pathway is involved in cell growth, proliferation, and differentiation. The signaling pathway is also involved in the development of bone, and blood vessels, the formation of the extracellular matrix, lipid metabolism, and the maintenance of intracellular redox homeostasis. The extracellular matrix contains the intricate lattice of proteins and other molecules in the spaces between the cells, and it defines the structure and function of the connective tissues.

SLC2A10 gene mutations cause a reduction or elimination of GLUT10 protein function. Due to certain mechanisms requiring further studies, a lack of functional GLUT10 protein leads to the upregulation of TGF-beta signaling. GLUT10 protein transports DHA into the endoplasmic reticulum. It has also been demonstrated that a lack of vitamin C in cells lacking GLUT10 leads to altered production of collagen and elastins. A decreased nuclear ascorbate accumulation in dermal fibroblasts suggests an epigenetic role of ascorbic acid transport in the disease pathophysiology.

Excessive growth signaling shows elongation of the arteries, leading to the characteristic arterial tortuosity. Oversignaling also interferes with the regular formation of the connective tissue in other parts of the body, which manifests the other clinical features characteristic of ATS.

What Are the Signs and Symptoms of Arterial Tortuosity Syndrome?

The clinical features of arterial tortuosity syndrome are

Cardiovascular Manifestations

• Stenosis of the pulmonary artery (narrowing of the pulmonary artery).

• Stenosis of the peripheral pulmonary arteries (narrowing of the peripheral pulmonary artery).

• Aortic aneurysms(bulging of the aorta).

• Aortic root aneurysm (weakness in the aortic root).

• Arterial aneurysms (bulging in the artery).

• Aortic dissections (tear in the aorta).

• Arterial dissection (tear in an artery).

• Hypertension (high blood pressure).

• Hypertrophic cardiomyopathy (thickening of the heart walls).

• Ischaemic events (decreased oxygen to an organ).

• Large vein dilation (enlarged vein).

• Large vein tortuosity (twisting of the vein).

• Dilated cardiomyopathy (thinning of the heart chambers and stretching).

• Abnormal carotid artery morphology.

• Abnormal myocardium (heart muscles) morphology.

Craniofacial Manifestations

• Blepharophimosis or periorbital fullness (abnormal eyelid development).

• Downslanted palpebral fissures (slanted eyes).

• Convex nasal ridge (curved nasal bone).

• Midface retrusion (flat face).

• Micrognathia (small lower jaw).

• Large ears.

• Long face.

• Craniosynostosis (premature joining of skull join).

• Keratoconus (thinning of cornea).

• Malar flattening (underdeveloped cheekbone).

• High palate.

• Dental crowding.

• Myopia.

• Hypertelorism.

• Macrocephaly (large head).

• Median cleft lip (vertical cleft at the center of the lip).

• Cleft palate.

Skeletal Manifestations

• Pectus excavatum (sunken chest).

• Pectus carinatum (pigeon breast).

• Arachnodactyly (long, slender fingers).

• Scoliosis (curved spine).

• Clinodactyly of the 5th finger (curved pinky finger).

• Abnormality of the zygomatic bone.

• Knee contractures (inability to straighten the knee).

• Elbow contractures (inability to straighten the elbow).

• Camptodactyly (bent fingers that cannot be straightened).

• Slender fingers.

• Coxa valga (type of hip deformity).

• Long palm.

• Coxa vara (type of hip deformity).

• Femoral hernia (abdominal component bulges near the groin or thigh).

• Hip dislocation.

• Hip dysplasia (underdeveloped hip joint).

• Avascular necrosis of the capital femoral epiphysis (necrosis of a part of the hip joint).

Other Manifestations

• Hyperextensible skin (elastic skin).

• Joint hypermobility (unusual movement of the joint).

• Inguinal hernia (abdominal contents .

• Dyspnea (shortness of breath).

• Pyloric stenosis (abnormal thickening of the pylorus muscle in the stomach).

• Diaphragmatic hernia (congentital perforation of the diaphragm).

• Sliding hernia (hernia that moves up and down the esophagus).

• Elongation of the intestines.

• Diverticula (small bulging in the digestive tract).

• Esophagitis (inflammation of the esophagus).

• Fatigue.

• Hypotonia (decreased muscle tone).

• Hiatus hernia (part of the stomach squeezes up into the chest through an opening in the diaphragm).

• Prematurely aged appearance.

• Gastroesophageal reflux (stomach contents come back up into the esophagus).

• Developmental delays.

• Intellectual disability.

• Keratoglobus (noninflammatory corneal thinning).

• Redundant skin (too much skin).

How to Diagnose Arterial Tortuosity Syndrome?

The diagnosis of arterial tortuosity syndrome is based on clinical features followed by various diagnostic procedures like echocardiography (ECG), angiography, ultrasound, magnetic resonance angiography (MRA), and CT (computed tomography) scan.

The diverse manifestations are detected by various diagnostic procedures like:

• ECG, angiography, and MRA detect cardiovascular symptoms.

• Other abdominal deformities may be detected by ultrasound.

• The histopathological image shows the disruption of elastic fibers of the medial layer of the arterial wall.

Imaging studies show:

• The plain radiograph and coronal CT show a meandering vessel sign and an aortic elongation sign.

• Sagittal CT and MRI images show a cluster of vessel signs.

• Coronal CT and MRI show a V sign of pulmonary bifurcation.

• A CT axial echo shows an inverted V sign of bifurcation.

How to Treat Arterial Tortuosity Syndrome?

The treatment regime of arterial tortuosity syndrome is directed towards specific symptoms tailored to each individual. Certain cardiovascular symptoms, like hypertension, can be managed by medications. Occular symptoms require ophthalmic consultation and may require corrective lenses or sometimes surgery. Blood vessel or aortic aneurysms and dissections require surgical intervention. Treatment requires a coordinated effort of a team consisting of pediatricians, surgeons, dermatologists, neurologists, cardiologists, pulmonologists, ophthalmologists, and genetic specialists. Hernia repair, skeletal deformities, and intestinal diverticula require surgical repair. Pregnant ATS patients require special care and uncomplicated deliveries to achieve a successful pregnancy.

Aortic aneurysms can be managed conservatively with beta-adrenergic blockers or angiotensin-converting enzyme inhibitors and surgically repaired by a valve-sparing procedure. Focal stenosis of the aorta and its branches requires surgical catheterization. Pulmonary artery stenosis requires surgery, catheterization, or a transcatheter-surgical procedure. Abnormal skin healing requires careful postoperative wound care. Hernias require surgical repair with mesh to avoid recurrences. The patient's general well-being should be managed with psychological guidance and therapy.

What Is the Prognosis of Arterial Tortuosity Syndrome?

Arterial tortuosity syndrome may be severe during the first few years of onset, usually before the age of five, and might be critical with potential life-threatening events. ATS shows about 12 % mortality, mainly from respiratory insufficiency from pulmonary artery stenosis. ATS may also cause heart failure due to right ventricular hypertension, hypertrophy, myocarditis, and organ failure due to tissue ischemia.

What Is the Differential Diagnosis of Arterial Tortuosity Syndrome?

The differential diagnosis of arterial tortuosity syndrome include:

• Loeys-Dietz syndrome.

• Ehlers-Danlos syndromes.

• Marfan syndrome.

• Occipital horn syndrome.

• Autosomal recessive cutis laxa.

What Are the Complications of Arterial Tortuosity Syndrome?

The complications of arterial tortuosity syndrome include:

• Cardiac arrest.

• Cardiorespiratory arrest.

• Congestive heart failure.

• Myocardial infarction.

• Myocarditis.

Conclusions:

Arterial tortuosity syndrome is a rare condition affecting large to medium-sized arteries. Increased advancement in cross-sectional imaging has improved the chances of diagnosing this extremely rare entity. Prenatal and preimplantation genetic testing should be performed to avoid any unwanted complications. Further studies are required to understand the disease's natural progression and the long-term prognostic value of surgical treatment.