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Arterial Tortuosity Syndrome

, MD, PhD, , MD, PhD, and , MD, PhD.

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Clinical characteristics.

Arterial tortuosity syndrome (ATS) is characterized by the following:

  • Severe and widespread arterial tortuosity of the aorta and middle-sized arteries (with an increased risk of aneurysms and dissections) and focal and widespread stenosis which can involve the aorta and/or pulmonary arteries
    The risk for ischemic vascular events involving cerebrovascular circulation and the abdominal arteries is increased. In addition, large veins may be dilated and valvular regurgitation and mitral valve prolapse can occur.
  • Craniofacial involvement with characteristic facies and high palate with dental crowding
  • Soft/doughy skin and other evidence of a generalized connective tissue disorder including skeletal findings (scoliosis, pectus excavatum/carinatum, joint laxity, knee/elbow contractures, arachnodactyly, camptodactyly); inguinal/abdominal wall hernia; sliding hiatal or diaphragmatic hernia; hypotonia; and ocular involvement (myopia, keratoconus)


The diagnosis of ATS is established in a proband with generalized arterial tortuosity and biallelic (homozygous or compound heterozygous) pathogenic variants in SLC2A10.


Treatment of manifestations: Individuals with ATS benefit from a coordinated approach of multidisciplinary specialists in a medical center familiar with ATS or similar conditions. 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. Skeletal manifestations such as scoliosis require management by an orthopedist, and ocular manifestations require management when possible by an ophthalmologist with expertise in connective tissue disorders. Wound healing may be delayed following surgery; thus, stitches should be placed without traction and remain in place ~10 days. A supporting mesh can be used in the surgical repair of hernias to reduce recurrence risk.

Surveillance: Regular cardiovascular follow up (with MRA or CT scan with 3D reconstruction from head to pelvis) starting at birth or at the time of diagnosis. Routine follow-up for: pulmonary manifestations, refractive errors and keratoconus; orthopedic complications, such as scoliosis, especially during periods of rapid growth; possible dental crowding secondary to palatal abnormalities.

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. At conception, each sib of an affected individual has 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 testing for pregnancies at increased risk are possible if the SLC2A10 pathogenic variants in the family are known.


No formal diagnostic criteria have been established for arterial tortuosity syndrome (ATS).

Suggestive Findings

Arterial tortuosity syndrome should be suspected in individuals with severe and widespread arterial tortuosity. Major clinical findings include the following:

Cardiovascular involvement

Craniofacial involvement. Characteristic features are often present and become more prominent with aging (see Figure 1) [Callewaert et al 2008]:

Figure 1.

Figure 1.

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

  • Blepharophimosis or periorbital fullness
  • Downslanted palpebral fissures
  • Convex nasal ridge
  • Midface retrusion
  • Micrognathia
  • Large ears
  • Long face
  • High palate and dental crowding


  • The skin is soft or doughy and is often hyperextensible. Upon stretching, the skin often shows normal recoil.
  • There may be loose skin folds and redundancy as seen in cutis laxa syndromes (see Differential Diagnosis) [Callewaert et al 2008].
  • Scarring is usually normal, but may occasionally be delayed resulting in atrophic scars, especially after surgery [Castori et al 2012].

Other evidence of a generalized connective tissue disorder includes skeletal manifestations (scoliosis, pectus excavatum/carinatum, joint laxity, knee/elbow contractures, arachnodactyly, camptodactyly); inguinal and abdominal wall hernias; sliding hiatal or diaphragmatic hernia; hypotonia; myopia; and/or keratoconus [Callewaert et al 2008]. Joint pain may occur with aging [Castori et al 2012]. Pelvic organ prolapse can occur [Castori et al 2012].

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.

It is appropriate to perform molecular analysis of SLC2A10 in an individual with the following:

  • An elongated aortic arch or arterial tortuosity on vascular imaging (echocardiography, angiography, angio-CT or angio-MRI)
  • A variable combination of craniofacial characteristics (long face, periorbital fullness, convex nasal ridge); soft, hyperextensible skin, cutis laxa; suggestive skeletal manifestations (joint laxity, arachnodactyly, scoliosis, pectus deformity)
  • A family history consistent with autosomal recessive inheritance

One approach to genetic testing is molecular genetic testing of SLC2A10, the only gene in which pathogenic variants are known to cause ATS. Sequence analysis of SLC2A10 is performed first. If only one or no pathogenic variant is found, deletion/duplication analysis should be performed.

An alternate approach to genetic testing is use of a multigene panel that includes SLC2A10 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Summary of Molecular Genetic Testing Used in Arterial Tortuosity Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
SLC2A10Sequence analysis 225/29 3
Deletion/duplication analysis 42/29 5

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Coucke et al [2006], Bottio et al [2007], Drera et al [2007b], Callewaert et al [2008], Faiyaz-Ul-Haque et al [2008], Allen et al [2009], Faiyaz-Ul-Haque et al [2009], Ritelli et al [2009], Zaidi et al [2009b], Castori et al [2012], Moceri et al [2013], Takahashi et al [2013]. Note: Faiyaz-Ul-Haque et al [2008] reported the same pathogenic variant in ten related family members from Qatar. For clarity and in order not to bias the numbers of affected families, the authors consider these ten families to be related to a single proband.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Two probands were found to harbor a deletion of exon 4 of SLC2A10 (c.1411+480_1547+299del) [Callewaert et al 2008]

Clinical Characteristics

Clinical Description

Arterial tortuosity syndrome (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].

Presenting findings. 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, often prompting an echocardiogram that reveals aortic abnormalities.

More rarely, pulsatile carotid arteries or sudden arterial dissections are the initial presenting symptom.

Few reports mention cardiorespiratory failure as the initial presentation during infancy or young childhood.

Rare patients have been identified initially in adulthood, with joint aches and premature aging as the main presenting features.

Cardiovascular involvement. The cardiovascular system is the major source of morbidity and mortality. Cardiovascular manifestations include congenital widespread tortuosity of the large and middle-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]. Arterial aneurysms and dissections 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 older individuals.

Pulmonary artery stenosis may result in pulmonary hypertension.

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

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]. It is likely that 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.

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

Skeletal. 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 (3/15) and ranges from mild to severe; it can be progressive, mostly during periods of fast growth. Pes planus with hindfoot valgus may be present.

Osteopenia has been observed in rare cases [unpublished data].

Generalized connective tissue disorder. Patients often present with joint hypermobility and are at risk for sprains and luxations. Adults are at increased risk for joint pain and fatigue [Castori et al 2012].

Affected women are more prone to prolapse of the bladder, uterus, and rectum, especially following childbirth [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 2009a].

Respiratory involvement. Severe early-onset emphysema has been reported following an episode of bronchiolitis in one proband compound heterozygous for the SLC2A10 pathogenic variants c.417T>A and c.692G>A [Takahashi et al 2013].

Eye. Keratoconus has been reported in three affected individuals, one of whom also had keratoglobus, deep corneal opacification, and diffuse corneal thinning [Hasler et al 2011]. Ectopia lentis has not been described. It is unclear whether myopia and astigmatism occur more frequently than in the general population.

Genotype-Phenotype Correlations

No clinically significant genotype-phenotype correlations have emerged.


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].


No reliable estimates of prevalence exist. Arterial tortuosity syndrome (ATS) is considered rare (<1:1000 000 live births). However, some authors suggest that it maybe 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.

Differential Diagnosis

The following disorders should be considered in the differential diagnosis of arterial tortuosity syndrome (ATS).

EFEMP2-related cutis laxa (autosomal recessive cutis laxa type 1B [ARCL1B]) is characterized by cutis laxa and systemic involvement, most commonly arterial tortuosity, aneurysms and stenosis; retrognathia; joint laxity; and arachnodactyly. Severity ranges from perinatal lethality as a result of cardiopulmonary failure to manifestations limited to the vascular and craniofacial systems. Differentiation of ATS from EFEMP2-related cutis laxa is difficult as both skin and arterial findings overlap; however:

  • Focal stenosis at the aortic isthmus is more common in EFEMP2-related cutis laxa than in ATS [Hucthagowder et al 2006, Renard et al 2010];
  • EFEMP2-related cutis laxa often presents with a more aggressive arterial phenotype with fast progression to aneurysms; AND
  • The typical facial characteristics found in ATS (including blepharophimosis, a convex nasal ridge, and a long face) are often absent in EFEMP2-related cutis laxa.

Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus).

  • Approximately 75% of individuals with LDS type I have craniofacial manifestations (widely spaced eyes, cleft uvula/palate, craniosynostosis), findings not usually not seen in individuals with ATS.
  • Arterial tortuosity is often present in LDS, but to a lesser degree than in ATS.
  • Individuals with LDS present more frequently with an aneurysm of the aortic root than individuals with ATS.

Heterozygous pathogenic variants in TGFBR1, TGFBR2, SMAD3, and TGFB2 have been associated with Loeys-Dietz syndrome [Loeys et al 2006, van de Laar et al 2011, Lindsay et al 2012]. LDS is inherited in an autosomal dominant manner.

FBLN5-related cutis laxa and LTBP4-related cutis laxa (autosomal recessive cutis laxa type IA and type IC) are two closely related entities characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective disorder such as inguinal hernias and hollow viscus diverticula (e.g., intestine, bladder). Occasionally, supravalvular aortic stenosis is observed. Pulmonary emphysema or gastrointestinal ruptures are often the cause of death. Individuals with FBLN5- and LTBP4-related cutis laxa do not have the arterial tortuosity seen in individuals with ATS [Callewaert et al 2013].

Occipital horn syndrome (OHS, ATP7A-related related cutis laxa) is characterized by "occipital horns," distinctive wedge-shaped calcifications at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. Occipital horns may be clinically palpable or observed on skull radiographs. Individuals with OHS also have lax skin and joints, bladder diverticula, inguinal hernias, and vascular tortuosity, mainly of the cerebral vasculature. Intellect is normal or slightly reduced. The skeletal and urogenital features of OHS are distinctive. Caused by a pathogenic variant in ATP7A, OHS is inherited in an X-linked manner.

Ehlers-Danlos syndrome (EDS). Individuals with EDS present with generalized joint hypermobility, variable skin and internal organ manifestations.

  • In EDS, hypermobility type (EDS type III) generalized joint hypermobility results in repetitive joint luxations and chronic musculoskeletal pain. These manifestations occur with soft and hyperextensible skin, and autonomic dysfunction, but not arterial tortuosity. Two reports mention arterial tortuosity syndrome in patients previously misdiagnosed with EDS hypermobility type, one of whom was homozygous for the SLC2A10 pathogenic variant c.1411+1G>A [Allen et al 2009] and one of whom was homozygous for the SLC2A10 pathogenic variant c.685C>T [Castori et al 2012].
    Haploinsufficiency of tenascin-X (encoded by TNXB) has been associated with EDS, hypermobility type in a small subset of affected individuals. Inheritance is autosomal dominant.
  • Ehlers-Danlos syndrome, vascular type (EDS type IV) is characterized by thin, translucent skin; atrophic scars, easy bruising; characteristic facial appearance (in some individuals); and arterial, intestinal, and/or uterine fragility. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in the majority of adults identified to have EDS type IV. However, arterial tortuosity is absent in individuals with EDS type IV and the skin and craniofacial features are usually distinctive.
    Heterozygous pathogenic variants in COL3A1 are associated with EDS type IV. Inheritance is autosomal dominant.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with arterial tortuosity syndrome (ATS), the following evaluations are recommended:

  • Echocardiography. Aortic root measurements must be interpreted based on consideration of normal values for age and body size [Roman et al 1989].
  • MRA or CT scan with 3D reconstruction from head to pelvis to evaluate arterial tortuosity and identify arterial aneurysms and/or stenoses throughout the arterial tree
  • Lung function test and imaging (radiographs, CT-scan) when emphysema is suspected
  • Skeletal radiographs depending on the clinical findings (e.g., scoliosis).
  • Consideration of bone densitometry based on patient history (fractures), sex, habits (smoking, alcohol consumption, sedentary life style) and age
  • Evaluation of the palate to identify patients with a highly arched palate, bifid uvula, or cleft palate who may be at risk for orthodontic complications including dental crowding (see Surveillance). Patients with bifid uvula and cleft palate may be at risk for feeding difficulties.
  • Eye examination by an ophthalmologist with expertise in connective tissue disorders that includes: refraction and correction of refractive errors, especially in young children at risk for amblyopia; specific assessment for keratoconus, keratoglobus, and corneal thinning
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Individuals with ATS benefit from a coordinated approach of multidisciplinary specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon. If feasible, individuals with ATS should be managed in a medical center familiar with this condition.

Cardiovascular. In managing the cardiovascular features of ATS the following should be kept in mind:

  • Clinical history studies are limited.
  • Vascular disease is widespread and requires repeated imaging of the complete arterial tree from head to pelvis by MRA or CTA.
  • It is currently not known whether arterial dissections or thrombosis is the main cause of ischemic events.

As is common practice in the treatment of Marfan syndrome and Loeys-Dietz syndrome, hemodynamic stress on the arterial wall can be reduced through 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, when titrated to effect. While ATIIR1 antagonists may have an additional beneficial effect by attenuating TGFβ signaling in the arterial wall, the role of TGFβ signaling in ATS is unclear (see Molecular Genetic Pathogenesis). Importantly, 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.

Aneurysms and focal stenoses are amenable to surgical intervention.

  • For aortic root aneurysms, a valve-sparing procedure that precludes the need for chronic anticoagulation can be used. 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.
  • For focal stenoses of the aorta and aortic branches, surgery, catheterization, or a hybrid of the two (transcatheter-surgical procedure) may be used [Santoro et al 2008, Vicchio et al 2008].

Pulmonary artery stenosis resulting in pulmonary hypertension may be treated by catheterization and/or surgery.

Skeletal. Bone overgrowth and ligamentous laxity can lead to severe problems (including progressive scoliosis) and should be managed by an orthopedist. Surgical stabilization of the spine may be required.

At the patient's discretion, orthotics may be used for severe pes planus.

Pectus excavatum can be severe; rarely, surgical intervention is medically (rather than cosmetically) indicated.

Eye. The ocular manifestations of ATS should be managed by an ophthalmologist with expertise in connective tissue disorders. Careful and aggressive refraction and visual correction is essential, and evaluation of keratoconus is necessary.


  • Hernias may recur after surgical repair. A supporting mesh can be used in the surgical repair to minimize recurrence risk.
  • Careful postoperative evaluation of (surgical) wounds is necessary as wound healing may be delayed. Note that stitches should avoid traction and should remain in place for approximately ten days.
  • Emphysema is treated symptomatically. Of note, positive pressure ventilation may cause emphysematous changes to progress.
  • Individuals with ATS can and should remain active with aerobic activities (e.g., swimming) performed in moderation.


The following are appropriate:

  • Regular cardiovascular follow up with echocardiography, and MRI- angiography or CT scan with 3D reconstructions from head to pelvis starting at birth or at the time of diagnosis, and repeated at regular intervals depending on the initial findings and the disease course. Under stable conditions (in the absence of aneurysms, stenosis, or dilatation of the aortic root), echocardiography could be performed on a yearly basis and MRI angiography or CT scan at least every three years in older children and adults.
    Pulmonary hypertension may develop secondary to pulmonary artery stenosis, requiring regular echocardiographic follow-up.
  • Pulmonary follow up. Increased vigilance for emphysema is appropriate
  • Routine follow-up for refractive errors and keratoconus, when possible with an ophthalmologist with expertise in connective tissue disorders
  • Evaluation for orthopedic complications especially during periods of rapid growth (first two years of life and during puberty), e.g., serial radiographs to evaluate for progression of scoliosis
  • Orthodontic follow-up, especially during eruption of permanent dentition because of the increased risk of dental crowding secondary to palatal abnormalities

Agents/Circumstances to Avoid

Avoid the following:

  • Contact sports, competitive sports, and isometric exercise
  • Scuba diving because of pressure differences and the need for positive pressure ventilation
  • Agents that stimulate the cardiovascular system including routine use of decongestants
  • Use of tobacco, which increases cardiovascular risk and the likelihood of premature skin aging
  • Sun tanning, which increases the likelihood of premature skin aging

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 institution of surveillance and preventive measures.

  • If the SLC2A10 pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
  • If the pathogenic variants in the family are not known, at-risk sibs should be evaluated for signs of the disorder (clinically and with echocardiography or more elaborative vascular imaging, as clinical symptoms may be very subtle) to clarify their genetic status.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Data on the management of women with arterial tortuosity syndrome during pregnancy and delivery are limited with only three pregnancies reported (in 2 women) to date. All pregnancies had a good outcome; however, one woman experienced pelvic organ prolapse following the vaginal delivery of her first child [Castori et al 2012]. The other woman, who delivered without complications at 34 weeks' gestation by elective cesarean section, was started on acetylsalicylic acid to prevent thromboembolic events eight days post partum [Allen et al 2009].

Preconception counseling should include possible pregnancy-associated risks to the mother and medication-associated risks to the fetus.

The risks to the mother are mainly those of aortic root dilatation and dissection. As is common practice in management in Marfan syndrome, elective aortic repair using a valve-sparing procedure (if possible) could be performed prior to conception when the aortic root diameter reaches 45 mm.

Currently, no data are available on a possible risk for pregnancy-associated uterine rupture (as is seen in Loeys-Dietz syndrome and EDS, vascular type). Prenatal and postnatal physiotherapy can minimize the risk for pelvic organ prolapse.

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 dilatation. 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 whether caesarean section or vaginal delivery is preferable.

Medication-associated risks to the fetus. The effects of angiotensin-converting enzyme inhibitors (ACE-I) on the fetus in the first trimester of pregnancy are incompletely understood; however, use in the second and third trimesters of pregnancy can lead to fetal death and damage. Angiotensin II receptor 1 antagonists (ATIIR1) such as losartan are thought to lead to similar fetal effects as ACE-I, including fetal damage, oligohydramnios, and fetal death, if taken during the second and/or third trimesters of pregnancy.

  • Ideally, women with ATS who are planning a pregnancy should transition to a different antihypertensive medication (e.g., a beta-blocker) prior to conception.
  • Women with ATS who become pregnant while taking an ACE-I or an ATIIR1 should be transitioned to a different antihypertensive medication as soon as the pregnancy is recognized.

Women undergoing a non-valve sparing aortic root replacement before pregnancy should be advised of the risk associated with anticoagulant therapy during pregnancy.

Therapies Under Investigation

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Arterial tortuosity syndrome (ATS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one SLC2A10 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has 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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of an SLC2A10 pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with ATS are obligate heterozygotes (carriers) for a pathogenic variant in SLC2A10.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC2A10 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SLC2A10 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for ATS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Arterial Tortuosity Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Arterial Tortuosity Syndrome (View All in OMIM)


Molecular Genetic Pathogenesis

SLC2A10 encodes GLUT10, a member of the class III facilitative glucose transporter family. The transporter is located intracellularly; however, neither the exact localization nor the transported substances have been clarified with certainty. Using immunohistochemistry, different authors have detected GLUT10 in the nuclear membrane, the mitochondria, and/or the endoplasmic reticulum [Coucke et al 2006, Lee et al 2010]. The localization may differ among different cell types or physiologic states.

In vitro studies demonstrated transport of both glucose and dehydroascorbic acid [Dawson et al 2001, Lee et al 2010]. Some authors suggest that GLUT10 transports DHA into the endoplasmic reticulum or mitochondria [Lee et al 2010].

Analysis of end-stage diseased arteries showed increased TGFβ signaling, similar to that observed in related disorders including Loeys-Dietz syndrome and FBLN4-related cutis laxa [Loeys et al 2005, Renard et al 2010]. However, studies in a zebrafish model show reduced signaling in early developmental stages. Furthermore, mitochondrial dysfunction was shown in this model [Willaert et al 2012].

Gene structure. SLC2A10 comprises five exons and produces a single 4241 bp transcript, which in turn encodes a protein of 541 amino acid residues. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Most pathogenic variants are recurrent (c.243C>G, c.1334delG, c.685C>T, c.1276G>T, c.1411+480_1547+299del, c.394C>T, c.692G>A, and c.756C>A), and founder effects have been shown for some [Callewaert et al 2008].

Table 2.

SLC2A10 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.243C>G 1, 2, 3p.Ser81Arg 1, 2, 3NM_030777​.3
c.394C>T 4p.Arg132Trp 4
c.417T>A 5p.Tyr139Ter 5
c.685C>T 4, 6, 7p.Arg229Ter 4, 6
c.692G>A 4, 5p.Arg231Gln 4, 5
c.756C>A 5, 8p.Cys252Ter 5, 8
c.1276G>T 4p.Gly426Trp 4
c.1334delG 1, 4p.Gly445fsTer40 1, 4
c.1411+480_c.1547+299del 4p.Gly471_Arg515delTerfs 4

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


For additional variants, see Table 3 (pdf).

Normal gene product. The solute carrier family 2, facilitated glucose transporter member 10 protein consists of 541 amino acids. It is a membrane bound transporter protein with 12 transmembrane domains (TMD). It has a small hydrophilic loop with between TDM 6 and 7, and a large exofacial loop between TDM 9 and 10, containing potential N-hydroxylation sites.

Abnormal gene product. Pathogenic variants lead to loss of function of the protein. About half of all currently known pathogenic variants are expected to result in absent protein due to nonsense-mediated decay. Missense variants are expected to interfere with the transporter function. Most of the missense variants are localized on the TMD or the endofacial site of the protein.


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Chapter Notes

Author Notes

University of Ghent Center for Medical Genetics

Bert Callewaert is a clinical geneticist and an investigator at the Center for Medical Genetics of the Ghent University Hospital. His main research interest focuses on connective tissue disorders including the arterial tortuosity syndrome, cutis laxa syndromes, congenital contractural arachnodactyly, Ehlers-Danlos syndromes and familial thoracic aortic aneurysms.

Paul Coucke and Anne De Paepe are respectively supervisor of the connective tissue laboratory and head of the department at the Center for Medical Genetics.


Bert Callewaert is a senior clinical investigator of the Fund for Scientific Research-Flanders. This research is sponsored by a Methusalem grant from the Ghent University (BOF 08/01M01108)

Revision History

  • 13 November 2014 (me) Review posted live
  • 14 February 2014 (bc) Original submission
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