Arterial tortuosity syndrome

Actionability Pediatric Summary Report

Gene: SLC2A10 (HGNC:13444)
Mode(s) of Inheritance:
Literature Search: 10/18/2017
Curation Status: In Preparation
Release History
Related Reports
Adult Summary Report: (1.4.0)

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

Actionability Assertions

Gene Condition (MONDO ID) OMIM ID Final Assertion
SLC2A10 arterial tortuosity syndrome (0008818) 208050 Assertion Pending

Actionability Assertion Rationale

  • This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair Severity Likelihood Effectiveness Nature of Intervention Total Score
No scores were found.

Prevalence of the Genetic Condition

The prevalence of arterial tortuosity syndrome (ATS) is unknown but the disorder is exceedingly rare, with approximately 100 cases described in literature. Incidence estimates vary between <1/1,000,000 to 1/100,000 live births.
View Citations

Arterial tortuosity syndrome. Orphanet encyclopedia, ORPHA: 3342., Albuisson J, et al. (2015) PMID: 25604859, Ritelli M, et al. (2014) PMID: 25373504

Clinical Features (Signs / symptoms)

ATS is a connective tissue disorder characterized by tortuosity (twisting) and elongation of the aorta and large- and medium-sized arteries. Clinical manifestations are variable, depending on the arteries affected. Cardiovascular manifestations are the major source of morbidity and mortality, with an increased risk at any age for aneurysm formation and dissection both at the aortic root and throughout the arterial tree and increased risk at any age for ischemic events. Cardiovascular anomalies may lead to right ventricular hypertension, acute respiratory symptoms, ventricular hypertrophy, pulmonary hypertension, and cardiac failure. In addition, large veins may be dilated and valvular regurgitation and mitral valve prolapse can occur. Other manifestations include dysmorphic features (e.g., an elongated face, high palate, dental crowding, and beaked nose) usually becoming more prominent in older children and adults, soft and hyperextensible skin, loose skin folds, hernias, skeletal abnormalities (e.g., scoliosis), joint hypermobility, congenital contracture, ocular involvement (myopia, keratoconus), and generalized hypotonia. Joint hypermobility leads to increased risk for sprains and dislocation, and adults are at increased risk for joint pain and fatigue. Although the causal relation remains to be established, a higher rate of Raynaud phenomenon and orthostatic hypotension is reported.
View Citations

Arterial tortuosity syndrome. Orphanet encyclopedia, ORPHA: 3342., Albuisson J, et al. (2015) PMID: 25604859, Ritelli M, et al. (2014) PMID: 25373504, Online Medelian Inheritance in Man. (2016) OMIM: 208050, B Callewaert, et al. (2014) NCBI: NBK253404, Pyeritz RE, et al. (2012) PMID: 22237449

Natural History (Important subgroups & survival / recovery)

ATS is a highly variable disorder ranging from early mortality during infancy to limited manifestations in adulthood. Onset and identification usually occurs in infancy or early childhood, often because of a cardiac murmur or cyanosis; however, there are cases where ATS is revealed in late childhood or adulthood by cardiovascular complications or with joint aches and premature aging as the main presenting features. The prognosis can be severe, with a mortality rate of up to 12%, usually before the age of five years. The main causes of premature death are respiratory insufficiency, ventricular hypertrophy resulting in global heart failure, myocarditis, and ischemic events leading to organ infarction. Women are more prone to prolapse of the bladder, uterus, and rectum, especially following childbirth.The frequency of ATS does not seem to vary between different ethnical backgrounds. Most reported cases are from Europe and the Middle East. The male to female ratio is 1:1.
View Citations

Arterial tortuosity syndrome. Orphanet encyclopedia, ORPHA: 3342., Albuisson J, et al. (2015) PMID: 25604859, Ritelli M, et al. (2014) PMID: 25373504, Online Medelian Inheritance in Man. (2016) OMIM: 208050, B Callewaert, et al. (2014) NCBI: NBK253404

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Mode of Inheritance

Prevalence of Genetic Variants

Unknown
No evidence regarding prevalence of pathogenic variants was identified. However, because nearly all cases of ATS are explained by a pathogenic variant in SLC2A10, the prevalence is likely approximate to that of the disorder itself, which is rare and estimated at <1/1,000,000 to 1/100,000 live births.
Tier 4 View Citations

Arterial tortuosity syndrome. Orphanet encyclopedia, ORPHA: 3342., Albuisson J, et al. (2015) PMID: 25604859, B Callewaert, et al. (2014) NCBI: NBK253404

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown
In a case series of 50 patients from 40 families combined with previous literature reports of 52 patients, for a total cohort of 102 patients (78 probands), the penetrance of various manifestations were reported as:

Ocular:

-Keratoconus = 8/55 (15%)

-Keratoglobus = 2/55 (4%)

-Myopia = 23/53 (43%)

Skeletal:

-Scoliosis = 20/90 (22%)

-Joint laxity = 72/95 (76%)

-Joint pain = 10/69 (26%)

Cardiovascular:

-Aortic tortuosity = 83/90 (92%)

-Tortuosity of other arteries = 73/91 (80%)

-Abnormal implantation of aortic branches = 11/88 (13%)

-Aortic root aneurysm = 14/90 (16%)

-Other arterial aneurysm = 11/87 (13%)

-Arterial dissections = 0/87 (0%)

-Stenosis of the pulmonary arteries = 52/91 (57%)

-Aortic stenosis = 22/90 (24%)

-Other stenosis = 12/81 (15%)

Other manifestations:

-Diaphragmatic hernia = 19/65 (29%)

-Inguinal hernia = 35/92 (38%)

-Respiratory symptoms = 10/67 (15%)

-Urogenital abnormalities = 11/56 (20%)

-Autonomic dysfunction = 10/57 (18%)
Tier 5 View Citations

Beyens A, et al. (2018) PMID: 29323665

Expressivity

ATS is a highly variable disorder ranging from early mortality during infancy to limited manifestations in adulthood.
Tier 3 View Citations

B Callewaert, et al. (2014) NCBI: NBK253404

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Patient Management

To establish extent of disease and needs in an individual diagnosed with ATS, initial evaluation should include echocardiography; MRA or CT scan with 3D reconstruction from head to pelvis; lung function tests and imaging if emphysema is suspected; skeletal radiographs depending on clinical findings; consideration for bone densitometry based on patient history and risk factors; evaluation of the palate and orthodontia; and eye examination by an ophthalmologist with expertise in connective tissue disorders.
Tier 4 View Citations

B Callewaert, et al. (2014) NCBI: NBK253404

Individuals with ATS benefit from a coordinated approach of multidisciplinary specialists in a medical center familiar with ATS or similar conditions.
Tier 4 View Citations

B Callewaert, et al. (2014) NCBI: NBK253404

Although hemodynamic stress on arterial walls can be reduced with use of beta-adrenergic blockers or other medications including angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs) 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, as these medications may confer a risk for renal failure.
Tier 4 View Citations

B Callewaert, et al. (2014) NCBI: NBK253404

While data on the effectiveness of these drugs was not available for ATS, a systematic review of beta blockers, ACEIs, and ARBs in Marfan Syndrome (MFS) concluded that these medications slowed the progression of aortic dilation. Three of the included studies showed that the treatment group’s aortic dilation progressed by roughly 1mm/year less than the non-treatment group, though no information was provided on how this impacted clinical outcomes.
Tier 1 View Citations

Thakur V, et al. (2013) PMID: 23083542

In addition, two randomized trials in patients with MFS reported reductions in aortic root dilation rate with ARB added to beta blockers at three-year follow-up, indicating that treatment with beta blockers and ARB may be more effective than beta blockers alone. In contrast, a double-blind randomized trial found no significant difference between ARB and placebo on aortic root dilation rate at median 3.5-year follow-up, with most patients in both treatment groups also on beta blockers (86%).
Tier 5 View Citations

Groenink M, et al. (2013) PMID: 23999449, Milleron O, et al. (2015) PMID: 25935877, Chiu HH, et al. (2013) PMID: 23321647

Wound healing may be delayed following surgery; thus stitches should be placed without traction and remain in place approximately 10 days.
Tier 4 View Citations

B Callewaert, et al. (2014) NCBI: NBK253404

Aneurysms and focal stenoses are amenable to surgical intervention; however, no data are available on the aortic diameter at which intervention is appropriate. Thus, decision making should also include assessment of the family history or the affected individual’s personal assessment of risk versus benefit.
Tier 4 View Citations

B Callewaert, et al. (2014) NCBI: NBK253404

However, timely repair of aortic aneurysms has been found to prolong survival to that approaching age-matched controls in patients with MFS.
Tier 2 View Citations

Svensson LG, et al. (2013) PMID: 23688839

Limited information is available on the effect of aortic repair on the outcomes of patients with ATS. A case report was identified of a pediatric patient with ATS who underwent successful surgical repair of an ascending aortic aneurysm via hemi-arch and ascending aortic replacement with tube graft. Related to surgical repair of stenosis, 7 patients with ATS (aged 7 months to 10 years) with severe bilateral pulmonary artery stenosis who underwent extensive reconstruction of the pulmonary arterial tree had significant improvement in right ventricular (RV) function prior to hospital discharge and no observed mortality. All patients were alive and asymptomatic with normal RV function after a mean follow-up of 17.6 +/- 9.1 months following surgical reconstruction.
Tier 5 View Citations

Cine N, et al. (2011) PMID: 21441255, Al-Khaldi A, et al. (2011) PMID: 21704298

Preconception counseling should include possible pregnancy-associated risks to the mother (mainly aortic root dilation and dissection) and recommendation to discontinue medications with possible teratogenic effects (e.g., ACEIs, angiotensin II receptor 1 antagonists [ATIIR1] such as losartan, and anticoagulant therapy) and to begin therapy with beta-blockers. As is common practice in management in MFS, elective aortic repair using a valve-sparing procedure (if possible) could be performed prior to conception when the aortic root diameter reaches 45 mm. Peripartum intensive monitoring is advised. Pregnancies should be followed by a high-risk obstetrician and a cardiologist familiar with this or related conditions. Increased surveillance of the aortic root and previously detected aneurysms during pregnancy and following delivery is recommended because of the increased risk for progressive dilation. Echocardiography is suggested every two to three months from conception until six months post-partum. Delivery should be planned in a center with experience with this or related conditions. It is currently unclear if vaginal delivery or caesarean section is preferable. No data are available on risk for pregnancy-associated uterine rupture (as is seen in Loeys-Dietz syndrome and Ehlers-Danlos syndrome, vascular type). Prenatal and postnatal physiotherapy can minimize risk for pelvic organ prolapse.
Tier 4 View Citations

B Callewaert, et al. (2014) NCBI: NBK253404

Overall, the obstetric aspects of ATS have not been elucidated. Of 5 cases reported, 4 had successful pregnancies with uncomplicated deliveries, suggesting that pregnancy can be safely handled with multidisciplinary management including close maternal and fetal surveillance.
Tier 5 View Citations

Ritelli M, et al. (2014) PMID: 25373504

Surveillance

Annual echocardiogram is recommended if no aortic root dilation, and, in the presence of aortic root dilation, echocardiogram should be performed at least every 6 months.
Tier 2 View Citations

Pyeritz RE, et al. (2012) PMID: 22237449

Annual magnetic resonance angiography of the head, neck, thorax, abdomen, and pelvis is recommended.
Tier 2 View Citations

Pyeritz RE, et al. (2012) PMID: 22237449

In the case of pulmonary hypertension secondary to pulmonary artery stenosis, regular echocardiographic follow-up should be initiated
Tier 4 View Citations

B Callewaert, et al. (2014) NCBI: NBK253404

Increased vigilance for emphysema is appropriate
Tier 4 View Citations

B Callewaert, et al. (2014) NCBI: NBK253404

Routine follow-up for refractive errors and keratoconus, when possible with an ophthalmologist with an expertise in connective tissue disorders, is recommended.
Tier 4 View Citations

B Callewaert, et al. (2014) NCBI: NBK253404

Circumstances to Avoid

Patients with ATS should avoid the following: contact sports, competitive sports, and isometric exercise; scuba diving; agents stimulating the cardiovascular system, including routine use of decongestants; tobacco; and sun tanning (which may lead to premature skin aging).
Tier 4 View Citations

B Callewaert, et al. (2014) NCBI: NBK253404

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Nature of Intervention

The nature of intervention includes regular surveillance imaging, including imaging with radiation exposure. Treatment of manifestations include surgery and pharmacotherapy. Pharmacotherapy does pose a potential risk to fetal development, meaning alternative therapies would need to be considered during pregnancy.
Context: Adult
View Citations

B Callewaert, et al. (2014) NCBI: NBK253404, Pyeritz RE, et al. (2012) PMID: 22237449

A literature review of case studies suggests that complications have not been observed during cardiovascular surgery in ATS patients, and the risk of fatal events should be similar to the general population.
Context: Adult
View Citations

Ritelli M, et al. (2014) PMID: 25373504

Chance to Escape Clinical Detection

Because adults can present with cardiovascular complications and no previous sign of disease, there is a chance to escape clinical detection.
Context: Adult
Tier 4 View Citations

Albuisson J, et al. (2015) PMID: 25604859

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Gene Condition Associations
OMIM Identifier Primary MONDO Identifier Additional MONDO Identifiers
SLC2A10 208050 0008818

References List

Al-Khaldi A, Mohammed Y, Tamimi O, Alharbi A. (2011) Early outcomes of total pulmonary arterial reconstruction in patients with arterial tortuosity syndrome. The Annals of thoracic surgery. 92(2):698-704; discussion 704.

Albuisson J, Moceri P, Flori E, Belli E, Gronier C, Jeunemaitre X. (2015) Clinical utility gene card for: Arterial tortuosity syndrome. European journal of human genetics : EJHG. 23(10).

ARTERIAL TORTUOSITY SYNDROME; ATS. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 208050, (2016) World Wide Web URL: http://omim.org/

Arterial tortuosity syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=3342

B Callewaert, A De Paepe, P Coucke. Arterial Tortuosity Syndrome. (2014) . In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK253404/

Beyens A, Albuisson J, Boel A, Al-Essa M, Al-Manea W, Bonnet D, Bostan O, Boute O, Busa T, Canham N, Cil E, Coucke PJ, Cousin MA, Dasouki M, De Backer J, De Paepe A, De Schepper S, De Silva D, Devriendt K, De Wandele I, Deyle DR, Dietz H, Dupuis-Girod S, Fontenot E, Fischer-Zirnsak B, Gezdirici A, Ghoumid J, Giuliano F, Diez NB, Haider MZ, Hardin JS, Jeunemaitre X, Klee EW, Kornak U, Landecho MF, Legrand A, Loeys B, Lyonnet S, Michael H, Moceri P, Mohammed S, Muino-Mosquera L, Nampoothiri S, Pichler K, Prescott K, Rajeb A, Ramos-Arroyo M, Rossi M, Salih M, Seidahmed MZ, Schaefer E, Steichen-Gersdorf E, Temel S, Uysal F, Vanhomwegen M, Van Laer L, Van Maldergem L, Warner D, Willaert A, Collins TR, Taylor A, Davis EC, Zarate Y, Callewaert B. (2018) Arterial tortuosity syndrome: 40 new families and literature review. Genetics in medicine : official journal of the American College of Medical Genetics. 20(1530-0366):1236-1245.

Chiu HH, Wu MH, Wang JK, Lu CW, Chiu SN, Chen CA, Lin MT, Hu FC. (2013) Losartan added to beta-blockade therapy for aortic root dilation in Marfan syndrome: a randomized, open-label pilot study. Mayo Clinic proceedings. 88(3):271-6.

Cine N, Basaran M, Guzelmeric F, Sunar H. (2011) Repair of ascending aortic aneurysm in a patient with arterial tortuosity syndrome. Interactive cardiovascular and thoracic surgery. 12(6):1051-3.

Groenink M, den Hartog AW, Franken R, Radonic T, de Waard V, Timmermans J, Scholte AJ, van den Berg MP, Spijkerboer AM, Marquering HA, Zwinderman AH, Mulder BJ. (2013) Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. European heart journal. 34(45):3491-500.

Milleron O, Arnoult F, Ropers J, Aegerter P, Detaint D, Delorme G, Attias D, Tubach F, Dupuis-Girod S, Plauchu H, Barthelet M, Sassolas F, Pangaud N, Naudion S, Thomas-Chabaneix J, Dulac Y, Edouard T, Wolf JE, Faivre L, Odent S, Basquin A, Habib G, Collignon P, Boileau C, Jondeau G. (2015) Marfan Sartan: a randomized, double-blind, placebo-controlled trial. European heart journal. 36(32):2160-6.

Pyeritz RE. (2012) Evaluation of the adolescent or adult with some features of Marfan syndrome. Genetics in medicine : official journal of the American College of Medical Genetics. 14(1):171-7.

Ritelli M, Chiarelli N, Dordoni C, Reffo E, Venturini M, Quinzani S, Monica MD, Scarano G, Santoro G, Russo MG, Calzavara-Pinton P, Milanesi O, Colombi M. (2014) 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. BMC medical genetics. 15(1471-2350):122.

Svensson LG, Adams DH, Bonow RO, Kouchoukos NT, Miller DC, O'Gara PT, Shahian DM, Schaff HV, Akins CW, Bavaria JE, Blackstone EH, David TE, Desai ND, Dewey TM, D'Agostino RS, Gleason TG, Harrington KB, Kodali S, Kapadia S, Leon MB, Lima B, Lytle BW, Mack MJ, Reardon M, Reece TB, Reiss GR, Roselli EE, Smith CR, Thourani VH, Tuzcu EM, Webb J, Williams MR. (2013) Aortic valve and ascending aorta guidelines for management and quality measures. The Annals of thoracic surgery. 95(6 Suppl):S1-66.

Thakur V, Rankin KN, Hartling L, Mackie AS. (2013) A systematic review of the pharmacological management of aortic root dilation in Marfan syndrome. Cardiology in the young. 23(4):568-81.

Early Rule-Out Summary

This topic did not pass the early rule out stage due to insufficient evidence for actionability. Thus, this topic did not move forward for a full evidence curation and summary report. This topic may be reconsidered if additional evidence becomes available.

Findings of Early Rule-Out Assessment

  1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
  2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?

    3. a. Patient Management

    b. Surveillance or Screening

    c. Circumstances to Avoid

  3. Is there an intervention that is initiated during childhood (<18 years of age) in an undiagnosed child with the genetic condition?
  4. Does the disease present outside of the neonatal period?
  5. Is this condition an important health problem?
  6. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?