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 SLC2A10 identified on molecular genetic testing.

Management.

Treatment of manifestations: 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.

Surveillance: 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.

Agents/circumstances to avoid: Contact sports, competitive sports, and isometric exercise; scuba diving; agents that stimulate the cardiovascular system (including routine use of decongestants); tobacco use; sun tanning.

Evaluation of relatives at risk: 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.

Pregnancy management: 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 antagonists [ATIIR1] 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 SLC2A10 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 SLC2A10 pathogenic variants have been identified in an affected family member.

Suggestive Findings

Arterial tortuosity syndrome should be suspected in individuals with severe and widespread elongation and tortuosity of the aorta and mid-sized arteries along with the following additional possible findings:

• Cardiovascular findings including:
  • Stenosis of the main and peripheral pulmonary arteries
  • Focal stenosis of the aorta and large stenotic stretches
  • Aortic and arterial aneurysms, dissections, and ischemic events
  • Large-vein dilation and tortuosity
• Characteristic facial features (more prominent with aging) (see Figure 1):
  • Blepharophimosis or periorbital fullness
  • Downslanted palpebral fissures
  • Convex nasal ridge
  • Midface retrusion
  • Micrognathia
  • Large ears
  • Long face
  • High palate and dental crowding
• Evidence of a generalized connective tissue disorder including:
  • Soft or doughy hyperextensible skin with normal recoil on stretching, with or without loose skin folds and redundancy (as seen in cutis laxa syndromes) and atrophic scars, especially after surgery
  • Joint hypermobility
  • Inguinal hernia
  • Diaphragmatic hernia or sliding hernia
• Skeletal findings including:
  • Pectus excavatum/carinatum
  • Arachnodactyly
  • Scoliosis
  • Knee/elbow contractures
  • Camptodactyly
• Family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Figure 1.

Craniofacial findings in ATS A:VI-2, male age 12 years

Establishing the Diagnosis

The diagnosis of arterial tortuosity syndrome is established in a proband with generalized arterial tortuosity and biallelic (homozygous or compound heterozygous) pathogenic variants in SLC2A10 identified by molecular genetic testing (see Table 1).

Note: Identification of biallelic SLC2A10 variants of uncertain significance (or identification of one known SLC2A10 pathogenic variant and one SLC2A10 variant of uncertain significance) does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of ATS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

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.

ATS is a highly variable disorder ranging from early mortality during infancy to limited manifestations in adulthood [Pletcher et al 1996, Callewaert et al 2008, Castori et al 2012, Beyens et al 2018].

Most affected individuals are identified in early childhood, often because of a cardiac murmur or cyanosis. Subsequently manifestations of a generalized connective tissue disorder are often observed, prompting an echocardiogram that reveals aortic abnormalities with or without pulmonary artery stenosis.

• About 12% of all affected individuals are admitted to the neonatal intensive care unit because of a primary presentation with infant respiratory distress syndrome. Underlying causes may be diverse and include insufficient lung maturation, pulmonary hypertension, and/or diaphragmatic hernia.
• Few reports mention cardiorespiratory failure as the initial presentation during infancy or young childhood.
• Cutaneous (cutis laxa, stretchable skin) and gastrointestinal (pyloric stenosis, failure to thrive) manifestations have been infrequently reported as the initial presenting symptoms.
• Rare patients have been identified initially in adulthood, with joint aches and premature aging as the main presenting features [Castori et al 2012].

To date, 106 individuals with ATS and biallelic pathogenic variants in SLCA10 have been identified [Beyens et al 2018, de Marcellus et al 2018, Kocova et al 2018, Zoma et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.

Cardiovascular involvement. The cardiovascular system is the major source of morbidity and mortality. Cardiovascular manifestations include congenital widespread tortuosity of the large and mid-sized arteries. There is increased risk at any age for aneurysm formation and dissection both at the aortic root and throughout the arterial tree [Pletcher et al 1996, Wessels et al 2004, Drera et al 2007a, Callewaert et al 2008, Castori et al 2012]. Although aortic dissections have been mainly reported in early clinically diagnosed cases [Pletcher et al 1996, Wessels et al 2004], some of which had molecular genetic confirmation later [Coucke et al 2006], no dissections have been reported since the initial publication of the causative gene [Coucke et al 2006]. Nevertheless, aggressive aortic root dilatation has been reported in infancy and young childhood [Beyens et al 2018]. Arterial aneurysms are amenable to surgery [Bottio et al 2007] (see Management).

The risk is also increased at any age for ischemic vascular events involving cerebrovascular circulation (resulting in non-hemorrhagic stroke) and the abdominal arteries (resulting in infarctions of abdominal organs). Although arterial dissections have been reported, it is unclear if thrombosis due to endothelial damage caused by increased shear stress on the wall of the tortuous arteries may have precipitated some of these ischemic events.

Focal stenoses of the aorta and aortic branches are congenital and amenable to treatment (see Management). In addition, long stenotic stretches of the aorta may occur.

Hypertension and ventricular hypertrophy have been reported in individuals and may require aggressive management [Beyens et al 2018, de Marcellus et al 2018]. Increased media thickness and arterial stiffness (as indicated by increased pulse wave velocity) may be associated [de Marcellus et al 2018].

Stenosis of the main and peripheral pulmonary arteries may lead to pulmonary hypertension [Wessels et al 2004, Callewaert et al 2008, Beyens et al 2018].

Large-vein dilation [Callewaert et al 2008, Beyens et al 2018] or in some cases tortuosity [Moceri et al 2013] may be present.

Valvular regurgitation and mitral valve prolapse [Drera et al 2007b, Callewaert et al 2008, Castori et al 2012, Beyens et al 2018] have been reported.

A higher rate of Raynaud phenomenon and orthostatic hypotension is reported; the causal relation remains to be established [Callewaert et al 2008, Beyens et al 2018].

Craniofacial involvement. Typical facial characteristics (see Figure 1) can be present from early childhood, but usually become more prominent in older children and adults.

Generalized connective tissue disorder. The skin is usually soft and loose in ATS. Some affected individuals have a hyperextensible skin and rarely may present with frank cutis laxa [Callewaert et al 2008, Beyens et al 2018].

Individuals often present with hypotonia and joint hypermobility and are at risk for sprains and luxations. Adults are at increased risk for joint pain and fatigue [Castori et al 2012].

Diaphragmatic hernia and sliding hiatal hernias are reported in up to 50% of affected individuals [Callewaert et al 2008, Zaidi et al 2009].

Affected women are more prone to prolapse of the bladder, uterus, and rectum, especially following childbirth [Castori et al 2012].

Skeletal findings. Growth of the long bones may be excessive. Although clear dolichostenomelia (disproportionately long arms and legs compared to the trunk) is rarely present, overgrowth of the ribs may result in pectus deformity, and the hands often show arachnodactyly. Scoliosis is rare and ranges from mild to severe; it can be progressive, mostly during periods of fast growth. Pes planus with hindfoot valgus may be present. Knee and/or elbow contractures and camptodactyly have been reported.

Osteopenia has been observed in rare individuals [Authors, unpublished data].

Eye. Thin corneas and/or pellucid marginal degeneration of the corneas were present in five children assessed in detail [Hardin et al 2018]. Keratoconus has been reported in eight affected individuals, two of whom also had keratoglobus and deep corneal opacification [Callewaert et al 2008, Hasler et al 2011, Hardin et al 2018]. Note that the corneal findings become more pronounced with age, and that many children have not been assessed properly to identify corneal thinning (which often precedes keratoconus). Ectopia lentis has not been described. It is unclear whether myopia and astigmatism occur more frequently than in the general population.

Other

• Respiratory tract. Infants may present with infant respiratory stress syndrome, requiring admission to a neonatal intensive care unit. Pulmonary hypertension may cause shortness of breath, fatigue, and cyanotic episodes. Single cases of early-onset emphysema [Takahashi et al 2013] and pneumonia [Wessels et al 2004] have been described, but it is unclear if individuals with ATS are truly at risk for these features.
• Urogenital anomalies. Pyeloectasia and bladder diverticula have been reported in multiple individuals. Hypospadias, urine retention, and hematuria (underlying cause unknown) were each reported in single individuals.

Life span. Although early reports mentioned 40% mortality before age four years [Wessels et al 2004], larger series of individuals with a molecularly confirmed diagnosis indicate a milder disease spectrum [Callewaert et al 2008, Beyens et al 2018]. It is likely some individuals in whom the diagnosis was not molecularly confirmed had a similar disorder with a poorer prognosis – including EFEMP2-related cutis laxa (see Differential Diagnosis). The earlier literature may also have been biased toward reporting the more severe end of the phenotypic spectrum.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

Lees et al [1969] were likely the first to report the syndrome, which they called "Ehlers-Danlos syndrome with multiple pulmonary artery stenoses and tortuous systemic arteries." Following this initial description, the disorder has always been considered distinct from Ehlers-Danlos syndrome, and the designation "arterial tortuosity syndrome" has been used consistently. Molecular genetic testing has not yet been performed in the individual published by Lees et al [1969].

Of note, in some reports "arterial tortuosity syndrome" refers to EFEMP2-related cutis laxa, which is a related but distinct disorder [Satish et al 2008].

Prevalence

No reliable estimates of prevalence exist. ATS is considered rare (<1:1,000,000 live births). However, some authors suggest that it may be more frequent than estimated [Callewaert et al 2008].

ATS occurs in all populations, but most reported cases to date are from Europe and the Middle East.