Arterial Tortuosity Syndrome

CLINICAL CHARACTERISTICS

Arterial tortuosity syndrome (ATS) is characterized by widespread elongation and tortuosity of the aorta and mid-sized arteries as well as focal stenosis of segments of the pulmonary arteries and/or aorta combined with findings of a generalized connective tissue disorder, which may include soft or doughy hyperextensible skin, joint hypermobility, inguinal hernia, and diaphragmatic hernia. Skeletal findings include pectus excavatum or carinatum, arachnodactyly, scoliosis, knee/elbow contractures, and camptodactyly. The cardiovascular system is the major source of morbidity and mortality with increased risk at any age for aneurysm formation and dissection both at the aortic root and throughout the arterial tree, and for ischemic vascular events involving cerebrovascular circulation (resulting in non-hemorrhagic stroke) and the abdominal arteries (resulting in infarctions of abdominal organs).

DIAGNOSIS/TESTING: The diagnosis of ATS is established in a proband with generalized arterial tortuosity and biallelic (homozygous or compound heterozygous) pathogenic variants in identified on molecular genetic testing.

MANAGEMENT

Individuals with ATS benefit from a coordinated approach of multidisciplinary specialists in a medical center familiar with ATS. Although hemodynamic stress on arterial walls can be reduced with use of beta-adrenergic blockers or other medications including angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor 1 (ATIIR1) antagonists such as losartan, the efficacy of these treatments has not been established in ATS and caution is warranted when using blood pressure-lowering medications in the presence of arterial stenosis (anatomic or functional due to severe tortuosity), especially renal artery stenosis. Aneurysms and focal stenoses are amenable to surgical intervention. Wound healing may be delayed following surgery; thus, stitches should be placed without traction and remain in place approximately ten days. A supporting mesh can be used in the surgical repair of hernias to reduce recurrence risk. Skeletal manifestations such as scoliosis require management by an orthopedist; ocular manifestations require management when possible by an ophthalmologist with expertise in connective tissue disorders. Regular cardiovascular follow up with: echocardiography every three months until age five years; and MRA or CT scan with 3D reconstruction from head to pelvis annually starting at birth or at the time of diagnosis. Monitoring of blood pressure at every visit. Orthodontic evaluation for possible dental crowding during eruption of permanent teeth; radiographs to evaluate for the progression of scoliosis, especially during periods of rapid growth; follow up for refractive errors and keratoconus with ophthalmologist with expertise in connective tissue disorders. Contact sports, competitive sports, and isometric exercise; scuba diving; agents that stimulate the cardiovascular system (including routine use of decongestants); tobacco use; sun tanning. It is appropriate to evaluate the older and younger sibs of a proband with ATS in order to identify as early as possible those who would benefit from treatment and surveillance for complications. Data on the management of women with arterial tortuosity syndrome during pregnancy and delivery are limited. Preconception counseling should include possible pregnancy-associated risks to the mother (mainly aortic root dilatation and dissection) and recommendation to discontinue medications with possible teratogenic effects (e.g., angiotensin-converting enzyme inhibitors [ACE-I], angiotensin II receptor 1 [ATIIR1] antagonists such as losartan, and anticoagulant therapy) and to begin therapy with β-blockers.

GENETIC COUNSELING

ATS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible once the pathogenic variants have been identified in an affected family member