Arterial Tortuosity Syndrome

Mendelian MONDO:0008818 Pathograph 14 Show in embeddings browser Vascular disorder

Arterial tortuosity syndrome is a rare autosomal recessive connective tissue disorder caused by biallelic pathogenic variants in SLC2A10. It is characterized by elongation and tortuosity of large and medium-sized arteries, with variable stenosis, aneurysm formation, respiratory, skeletal, cutaneous, and hernia-associated manifestations.

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1
Inheritance
4
Pathophys.
1
Histopath.
14
Phenotypes
14
Pathograph
1
Genes
3
Medical Actions
2
Differentials
2
Datasets
2
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
ATS is caused by biallelic SLC2A10 variants and is inherited as an autosomal recessive disorder.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:37619836 SUPPORT Human Clinical
"Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disease caused by biallelic variants in the SLC2A10 gene (NG_016284.1) and characterised by tortuosity and elongation of the aorta and medium-sized arteries."
This abstract directly states autosomal recessive inheritance and biallelic SLC2A10 causation.
⚙

Pathophysiology

4
SLC2A10/GLUT10 loss-of-function connective tissue defect
Biallelic SLC2A10 pathogenic variants disrupt GLUT10-dependent connective-tissue and arterial-wall homeostasis, creating the molecular basis for downstream vessel-wall matrix abnormalities.
vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology.
SLC2A10 hgnc:13444 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC2A10 (hgnc:13444). hgnc:13444 is a gene from the HUGO Gene Nomenclature Committee.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Arterial-wall TGF-beta pathway upregulation GLUT10 deficiency is associated with upregulation of the TGF-beta pathway in the arterial wall, the conserved aortopathy hub also seen in Loeys-Dietz syndrome.
Fragmented elastic fibers and collagen deposition SLC2A10/GLUT10 loss is linked to the abnormal elastic-fiber and collagen matrix phenotype.
Show evidence (1 reference)
PMID:29323665 SUPPORT Human Clinical
"PURPOSE: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10."
This review defines ATS as SLC2A10-associated arterial tortuosity of large and medium arteries.
Arterial-wall TGF-beta pathway upregulation
GLUT10 deficiency is associated with upregulation of the TGF-beta signaling pathway in the arterial wall, mirroring the dysregulated TGF-beta activity seen in Loeys-Dietz syndrome and the other heritable aortopathies. (Of note, one large series found that skin and end-stage diseased vascular tissue did not show increased TGF-beta signaling, so the upregulation is most evident earlier in the arterial-wall disease process.)
vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology.
transforming growth factor beta receptor signaling pathway GO:0007179 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Fragmented elastic fibers and collagen deposition Dysregulated TGF-beta signaling contributes to the elastic-fiber fragmentation and disordered collagen matrix of the arterial media.
Diaphragmatic hernia Systemic connective-tissue dysregulation is linked to the diaphragmatic hernia component of ATS.
Show evidence (3 references)
PMID:16550171 SUPPORT Human Clinical
"GLUT10 deficiency is associated with upregulation of the TGFbeta pathway in the arterial wall, a finding also observed in Loeys-Dietz syndrome"
The gene-discovery paper establishes arterial-wall TGF-beta pathway upregulation as the conserved aortopathy mechanism in ATS, shared with Loeys-Dietz syndrome.
PMID:18630721 SUPPORT Other
"In analogy to LDS, we demonstrated an upregulation of TGFbeta in ATS."
This review confirms TGF-beta upregulation in ATS by analogy to Loeys-Dietz syndrome, supporting the conserved TGF-beta hub. Evidence source is OTHER because this is a review synthesizing human and mouse data.
PMID:29323665 SUPPORT Human Clinical
"Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling."
Provides the important nuance that increased TGF-beta signaling is not detectable in skin or end-stage vascular tissue, so the upregulation is stage-dependent; included to represent the mechanism faithfully.
Fragmented elastic fibers and collagen deposition
Histologic studies of skin and vascular tissue show elastic-fiber fragmentation and increased collagen deposition, supporting a structural vessel-wall matrix mechanism.
vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Arterial wall structural failure and tortuosity Elastic-fiber fragmentation and collagen deposition weaken arterial structure and lead to tortuosity, stenosis, and aneurysm formation.
Show evidence (1 reference)
PMID:29323665 SUPPORT Human Clinical
"Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition."
This abstract directly supports abnormal elastic-fiber and collagen matrix organization in ATS tissues.
Arterial wall structural failure and tortuosity
Matrix disorganization compromises arterial-wall structure, producing tortuosity with associated stenosis and aneurysm formation across affected large and medium-sized arteries.
vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Arterial tortuosity Arterial-wall structural failure manifests as arterial elongation and tortuosity.
Arterial stenosis Disordered arterial-wall structure can narrow affected arterial beds.
Pulmonary artery stenosis The same stenotic vascular phenotype can involve pulmonary arteries.
Aortic root aneurysm Arterial-wall structural failure can involve the aortic root as aneurysmal dilation.
Infant respiratory distress syndrome Severe neonatal vascular and connective-tissue manifestations can present with infant respiratory distress.
Ischemic stroke Cerebrovascular involvement can produce ischemic stroke, although this is a severe and uncommon complication.
Show evidence (1 reference)
PMID:29323665 SUPPORT Human Clinical
"Stenoses, tortuosity, and aneurysm formation are widespread occurrences."
This supports the structural vascular consequences downstream of the histologic matrix abnormality.
✶

Histopathology

1
Fragmented elastic fibers with increased collagen deposition
Skin and vascular biopsies show elastic-fiber fragmentation, increased collagen deposition, and disease-specific ultrastructural abnormalities.
Show evidence (1 reference)
PMID:29323665 SUPPORT Human Clinical
"Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition."
This directly supports the histopathologic matrix abnormality.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Arterial Tortuosity Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Cardiovascular 4
Arterial tortuosity HP:0005116 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arterial tortuosity (HP:0005116). HP:0005116 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37619836 SUPPORT Human Clinical
"Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disease caused by biallelic variants in the SLC2A10 gene (NG_016284.1) and characterised by tortuosity and elongation of the aorta and medium-sized arteries."
The defining vascular phenotype is tortuosity and elongation of the aorta and medium-sized arteries.
Arterial stenosis HP:0100545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arterial stenosis (HP:0100545). HP:0100545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29323665 SUPPORT Human Clinical
"Stenoses, tortuosity, and aneurysm formation are widespread occurrences."
The large review identifies stenosis as part of the widespread vascular phenotype.
Aortic root aneurysm HP:0002616 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aortic root aneurysm (HP:0002616). HP:0002616 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29323665 SUPPORT Human Clinical
"Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation."
This supports aortic root aneurysm as a severe ATS complication.
Ischemic stroke HP:0002140 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ischemic stroke (HP:0002140). HP:0002140 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17935213 SUPPORT Human Clinical
"Two patients initially presented with stroke, respectively at age 8 months and 23 years."
The clinical series directly documents stroke as an initial presentation at two distinct ages.
Eye 2
Keratoconus HP:0000563 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keratoconus (HP:0000563). HP:0000563 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25373504 SUPPORT Human Clinical
"Other CTD signs of ATS are dysmorphisms, abdominal hernias, joint hypermobility, skeletal abnormalities, and keratoconus."
The clinical review directly includes keratoconus among the connective-tissue signs of ATS.
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26376865 SUPPORT Human Clinical
"ATS also shows additional signs shared with other CTDs, including soft/velvety/hyperextensible skin, mild dysmorphic facial features, i.e. elongated face, hypertelorism, cleft palate and/or bifid uvula, and micro/retrognathia, abdominal hernias, joint hypermobility and instability (1–8)."
The ATS clinical phenotype summary explicitly identifies hypertelorism.
Head and Neck 2
Downslanted palpebral fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34384376 SUPPORT Human Clinical
"Facial characteristic features gradually as aging, such as blepharophimosis or periorbital fullness, downslanted palpebral fissures, micrognathia, large ears, long face and cutis laxa."
Follow-up of an affected child directly documents downslanted palpebral fissures.
Long face HP:0000276 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long face (HP:0000276). HP:0000276 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34384376 SUPPORT Human Clinical
"Facial characteristic features gradually as aging, such as blepharophimosis or periorbital fullness, downslanted palpebral fissures, micrognathia, large ears, long face and cutis laxa."
Follow-up of an affected child directly documents long face.
Integument 2
Hyperextensible skin HP:0000974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperextensible skin (HP:0000974). HP:0000974 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18818946 SUPPORT Human Clinical
"Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder in which patients display tortuosity of arteries in addition to hyperextensible skin, joint laxity, and other connective tissue features."
The clinical description directly identifies hyperextensible skin as an ATS manifestation.
Cutis laxa HP:0000973 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutis laxa (HP:0000973). HP:0000973 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34384376 SUPPORT Human Clinical
"Facial characteristic features gradually as aging, such as blepharophimosis or periorbital fullness, downslanted palpebral fissures, micrognathia, large ears, long face and cutis laxa."
Follow-up of an affected child directly documents cutis laxa.
Musculoskeletal 1
Joint hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18818946 SUPPORT Human Clinical
"patients of Kurdish origin who display arterial tortuosity associated with skin hyperextensibility, joint hypermobility, and characteristic facial features may carry mutations in the SLC2A10 gene."
The patient report directly associates joint hypermobility with genetically defined ATS.
Respiratory 1
Infant respiratory distress syndrome Neonatal respiratory distress HP:0002643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infant respiratory distress syndrome, annotated with Neonatal respiratory distress (HP:0002643). HP:0002643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29323665 SUPPORT Human Clinical
"Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed."
This directly supports frequent respiratory distress syndrome in ATS.
Other 2
Pulmonary artery stenosis HP:0004415 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary artery stenosis (HP:0004415). HP:0004415 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29323665 SUPPORT Human Clinical
"Stenoses, tortuosity, and aneurysm formation are widespread occurrences."
The abstract supports stenoses as widespread in ATS, although it does not isolate pulmonary artery stenosis in the quoted sentence.
Diaphragmatic hernia Congenital diaphragmatic hernia HP:0000776 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital diaphragmatic hernia (HP:0000776). HP:0000776 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29323665 SUPPORT Human Clinical
"Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed."
This directly supports diaphragmatic hernia as a frequent ATS manifestation.
🧬

Genetic Associations

1
SLC2A10 (Causative)
Gene: SLC2A10 hgnc:13444 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC2A10 (hgnc:13444). hgnc:13444 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:37619836 SUPPORT Human Clinical
"A not previously described variant (NM_030777.4:c.899T>G (p.Leu300Trp)) was detected in a proband; it has an allegedly deleterious effect in compound heterozygous state with the pathogenic variant c.417T>A (p.Tyr139Ter)."
This identifies a novel SLC2A10 variant in compound heterozygous state with a pathogenic allele.
CGGV:assertion_80a24753-e6d3-41cb-85ba-85a2eae3ddb6-2024-11-07T170000.000Z SUPPORT Other
"SLC2A10 | HGNC:13444 | arterial tortuosity syndrome | MONDO:0008818 | AR | Definitive"
ClinGen classifies the SLC2A10-arterial tortuosity syndrome gene-disease relationship as definitive with autosomal recessive inheritance.
💊

Medical Actions

3
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling should explain autosomal recessive inheritance, carrier status, and the 25% recurrence risk when both parents are carriers.
Show evidence (1 reference)
PMID:34384376 SUPPORT Human Clinical
"Parents who continue the pregnancy after prenatal consultation and are fully aware that both parents are carriers have a 25% chance of having the disease in their next child."
The familial prenatal report directly supports carrier counseling and a 25% recurrence risk.
Beta-adrenergic blockade
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Beta-Adrenergic Antagonist NCIT:C29576 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Beta-Adrenergic Antagonist (NCIT:C29576). NCIT:C29576 is a therapeutic agent from the NCI Thesaurus.
Beta-blockers have been used clinically to reduce hemodynamic stress on the arterial wall, although evidence remains limited and supportive.
Mechanism Target:
MODULATES Arterial wall structural failure and tortuosity — Beta-blockade is intended to reduce hemodynamic stress on the structurally abnormal arterial wall; it does not correct SLC2A10 deficiency or have established disease-modifying efficacy.
Show evidence (1 reference)
PMID:37619836 SUPPORT Human Clinical
"To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking treatment was prescribed."
The case series supports the treatment intent and actual use, but not efficacy against the underlying structural mechanism.
Show evidence (1 reference)
PMID:37619836 SUPPORT Human Clinical
"To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking treatment was prescribed."
This supports reported clinical use of beta-blockade but does not establish efficacy.
Pulmonary arterial reconstruction for severe stenosis
Category: Therapeutic Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Surgical pulmonary-artery reconstruction may be considered for severe, hemodynamically important pulmonary artery stenosis. Evidence is limited to selected cases and does not define universal intervention thresholds.
Mechanism Target:
BYPASSES Arterial wall structural failure and tortuosity — Reconstruction bypasses or repairs a focal hemodynamically important stenotic consequence without correcting the molecular vessel-wall defect.
Show evidence (1 reference)
PMID:38987788 SUPPORT Human Clinical
"After surgical repair the left pulmonary artery has a peak pressure gradient of 20 mmHg, with the right pulmonary artery having a peak pressure gradient of 20 mmHg."
The post-repair gradient supports focal hemodynamic improvement in one patient, not reversal of the inherited arterial-wall mechanism.
Target Phenotypes: Pulmonary artery stenosis HP:0004415 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pulmonary artery stenosis (HP:0004415). HP:0004415 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38987788 SUPPORT Human Clinical
"A 2 years old Arabian female child was diagnosed with ATS affecting the pulmonary arteries as a newborn, underwent a pulmonary arterial surgical reconstruction at the age of 2 years old due to the development of pulmonary artery stenosis"
This documents reconstruction for severe ATS-associated pulmonary stenosis in one child; single-case evidence cannot establish comparative efficacy or a general treatment threshold.
🔬

Diagnosis

2
Molecular confirmation of biallelic SLC2A10 variants
Generalized arterial tortuosity in a compatible connective-tissue phenotype is confirmed molecularly by identifying biallelic pathogenic SLC2A10 variants.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic SLC2A10 variants support molecular confirmation of arterial tortuosity syndrome.
Show evidence (1 reference)
PMID:17935213 SUPPORT Human Clinical
"All 16 patients harbor biallelic SLC2A10 mutations of which nine are novel (six missense, three truncating mutations, including a large deletion)."
Molecular characterization of the affected cohort directly supports a biallelic SLC2A10 diagnostic result.
Vascular imaging surveillance
Extensive vascular imaging is recommended after diagnosis because tortuosity, stenosis, and aneurysm formation can involve multiple arterial beds.
diagnostic imaging NCIT:C17369 NCI Thesaurus (NCIT)
Results: Imaging may show arterial elongation, tortuosity, stenosis, or aneurysm.
Show evidence (1 reference)
PMID:29323665 SUPPORT Human Clinical
"Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards."
The review recommends early aortic-root monitoring and subsequent extensive vascular imaging.
📈

Progression

2
Congenital generalized arterial phenotype
Age: Infancy onward
Arterial tortuosity is present across the aorta and other large or medium-sized arteries; stenosis and aneurysm are variable rather than obligatory in every affected individual.
Show evidence (1 reference)
PMID:17935213 SUPPORT Human Clinical
"Tortuosity of the aorta or large arteries was invariably present. Two adult probands (aged 23 and 35 years) had aortic root dilation, seven patients had localized arterial stenoses, and five had long stenotic stretches of the aorta."
This cohort separates the invariant arterial-tortuosity feature from variably observed dilation and stenosis.
Variable lifelong vascular risk
Age: Infancy through adulthood
Natural history is heterogeneous. Ischemic events can occur in infancy or adulthood, while severe aortic-root aneurysm, intracranial bleeding, stroke, and gastric perforation were uncommon in the largest reviewed series.
Show evidence (2 references)
PMID:17935213 SUPPORT Human Clinical
"Although the natural history of ATS in this series was less severe than previously reported, it does indicate a risk for ischemic events. Two patients initially presented with stroke, respectively at age 8 months and 23 years."
The cohort directly demonstrates variable severity and ischemic events at widely separated ages, rather than a fixed stage sequence.
PMID:29323665 SUPPORT Human Clinical
"Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures."
This establishes the severe-but-rare boundary and preserves the cohort's explicit uncertainty about dissection and rupture.
🌍

Epidemiology

1
Extremely rare genetically confirmed disorder
The 2023 clinical series stated that only 106 individuals with genetically confirmed arterial tortuosity syndrome had been identified at that time; this is a case-count boundary rather than a population prevalence estimate.
Show evidence (1 reference)
PMID:37619836 SUPPORT Human Clinical
"It is considered an extremely rare disease; only 106 individuals with genetically confirmed ATS have been identified to date."
This supplies a publication-dated count of genetically confirmed cases without converting ascertainment into a prevalence rate.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Arterial Tortuosity Syndrome:

Marfan syndrome MONDO:0007947
Overlapping Features Marfan syndrome is another inherited disorder associated with arterial tortuosity and belongs in the differential of a generalized aortopathy.
Show evidence (1 reference)
PMID:37692180 SUPPORT Other
"ATS is one of many conditions associated with arterial tortuosity, including Marfan syndrome and Loeys-Dietz syndrome."
This review explicitly places Marfan syndrome in the arterial-tortuosity differential, while molecular and multisystem assessment must provide the disease-specific distinction.
Loeys-Dietz syndrome MONDO:0018954
Overlapping Features Loeys-Dietz syndrome is another syndromic aortopathy associated with arterial tortuosity and should be distinguished from SLC2A10-related ATS.
Show evidence (1 reference)
PMID:37692180 SUPPORT Other
"ATS is one of many conditions associated with arterial tortuosity, including Marfan syndrome and Loeys-Dietz syndrome."
The review explicitly identifies Loeys-Dietz syndrome as another arterial-tortuosity condition; the evidence supports differential consideration rather than a specific bedside discriminator.
📊

Related Datasets

2
microRNA expression profiles from three arterial tortuosity syndrome (ATS) patients' skin fibroblasts with recessive SLC2A10 mutations [miRNA] geo:GSE71172
To screen for potential miRNA that may contribute to the pathomechanisms of ATS miRNA expression profiling using the Affymetrix GeneChip® miRNA 3.0 Array comparing the miRNA expression changes of skin fibroblasts of three ATS patients with those of three healthy individuals
MICROARRAY n=6
PMID:26376865
Identified by GEO DataSets index search for Arterial Tortuosity Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Microarray expression data from three arterial tortuosity syndrome (ATS) patients' skin fibroblasts with recessive SLC2A10 mutations geo:GSE70683
To screen for candidate genes that may contribute to the pathogenesis of ATS Transcriptome-wide expression profiling using the Affymetrix Gene 1.0 ST platform comparing the gene expression patterns of skin fibroblasts of three ATS patients with those of three healthy individuals
human MICROARRAY n=6
PMID:26376865
Identified by GEO DataSets index search for Arterial Tortuosity Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
{ }

Source YAML

click to show 
name: Arterial Tortuosity Syndrome
creation_date: "2026-05-04T22:23:50Z"
description: >-
  Arterial tortuosity syndrome is a rare autosomal recessive connective tissue
  disorder caused by biallelic pathogenic variants in SLC2A10. It is
  characterized by elongation and tortuosity of large and medium-sized arteries,
  with variable stenosis, aneurysm formation, respiratory, skeletal, cutaneous,
  and hernia-associated manifestations.
category: Mendelian
disease_term:
  preferred_term: arterial tortuosity syndrome
  term:
    id: MONDO:0008818
    label: arterial tortuosity syndrome
synonyms:
- ATS
- ATORS
parents:
- Vascular disorder
epidemiology:
- name: Extremely rare genetically confirmed disorder
  description: >-
    The 2023 clinical series stated that only 106 individuals with genetically
    confirmed arterial tortuosity syndrome had been identified at that time;
    this is a case-count boundary rather than a population prevalence estimate.
  evidence:
  - reference: PMID:37619836
    reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is considered an extremely rare disease; only 106 individuals with
      genetically confirmed ATS have been identified to date.
    explanation: >-
      This supplies a publication-dated count of genetically confirmed cases
      without converting ascertainment into a prevalence rate.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    ATS is caused by biallelic SLC2A10 variants and is inherited as an
    autosomal recessive disorder.
  evidence:
  - reference: PMID:37619836
    reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue
      disease caused by biallelic variants in the SLC2A10 gene (NG_016284.1) and characterised
      by tortuosity and elongation of the aorta and medium-sized arteries.
    explanation: This abstract directly states autosomal recessive inheritance and biallelic SLC2A10 causation.
progression:
- phase: Congenital generalized arterial phenotype
  age_range: Infancy onward
  notes: >-
    Arterial tortuosity is present across the aorta and other large or
    medium-sized arteries; stenosis and aneurysm are variable rather than
    obligatory in every affected individual.
  evidence:
  - reference: PMID:17935213
    reference_title: "Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tortuosity of the aorta or large arteries was invariably present. Two adult
      probands (aged 23 and 35 years) had aortic root dilation, seven patients had
      localized arterial stenoses, and five had long stenotic stretches of the aorta.
    explanation: >-
      This cohort separates the invariant arterial-tortuosity feature from
      variably observed dilation and stenosis.
- phase: Variable lifelong vascular risk
  age_range: Infancy through adulthood
  notes: >-
    Natural history is heterogeneous. Ischemic events can occur in infancy or
    adulthood, while severe aortic-root aneurysm, intracranial bleeding, stroke,
    and gastric perforation were uncommon in the largest reviewed series.
  evidence:
  - reference: PMID:17935213
    reference_title: "Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the natural history of ATS in this series was less severe than
      previously reported, it does indicate a risk for ischemic events. Two
      patients initially presented with stroke, respectively at age 8 months and
      23 years.
    explanation: >-
      The cohort directly demonstrates variable severity and ischemic events at
      widely separated ages, rather than a fixed stage sequence.
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe but rare vascular complications include early and aggressive aortic
      root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric
      perforation. Thus far, no reports unequivocally document vascular dissections
      or ruptures.
    explanation: >-
      This establishes the severe-but-rare boundary and preserves the cohort's
      explicit uncertainty about dissection and rupture.
pathophysiology:
- name: SLC2A10/GLUT10 loss-of-function connective tissue defect
  conforms_to: "aortopathy_tgfbeta_dysregulation#Aortic Wall ECM or Contractile Apparatus Defect"
  description: >-
    Biallelic SLC2A10 pathogenic variants disrupt GLUT10-dependent
    connective-tissue and arterial-wall homeostasis, creating the molecular
    basis for downstream vessel-wall matrix abnormalities.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  gene:
    preferred_term: SLC2A10
    term:
      id: hgnc:13444
      label: SLC2A10
  evidence:
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PURPOSE: We delineate the clinical spectrum and describe the histology in arterial
      tortuosity syndrome (ATS), a rare connective tissue disorder characterized by
      tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.
    explanation: This review defines ATS as SLC2A10-associated arterial tortuosity of large and medium arteries.
  downstream:
  - target: Arterial-wall TGF-beta pathway upregulation
    description: >-
      GLUT10 deficiency is associated with upregulation of the TGF-beta pathway
      in the arterial wall, the conserved aortopathy hub also seen in
      Loeys-Dietz syndrome.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16550171
      reference_title: "Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        GLUT10 deficiency is associated with upregulation of the TGFbeta pathway in the arterial wall
      explanation: The gene-discovery paper directly links GLUT10 loss to arterial-wall TGF-beta pathway upregulation on this edge.
  - target: Fragmented elastic fibers and collagen deposition
    description: SLC2A10/GLUT10 loss is linked to the abnormal elastic-fiber and collagen matrix phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29323665
      reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Skin and vascular biopsies show fragmented elastic fibers (EF) and increased
        collagen deposition.
      explanation: SLC2A10-mutated ATS tissues show the fragmented elastic fiber and increased collagen matrix phenotype on this edge.
- name: Arterial-wall TGF-beta pathway upregulation
  conforms_to: "aortopathy_tgfbeta_dysregulation#TGF-beta Signaling Dysregulation"
  description: >-
    GLUT10 deficiency is associated with upregulation of the TGF-beta signaling
    pathway in the arterial wall, mirroring the dysregulated TGF-beta activity
    seen in Loeys-Dietz syndrome and the other heritable aortopathies. (Of note,
    one large series found that skin and end-stage diseased vascular tissue did
    not show increased TGF-beta signaling, so the upregulation is most evident
    earlier in the arterial-wall disease process.)
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  evidence:
  - reference: PMID:16550171
    reference_title: "Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GLUT10 deficiency is associated with upregulation of the TGFbeta pathway in the arterial wall, a finding also observed in Loeys-Dietz syndrome
    explanation: >-
      The gene-discovery paper establishes arterial-wall TGF-beta pathway
      upregulation as the conserved aortopathy mechanism in ATS, shared with
      Loeys-Dietz syndrome.
  - reference: PMID:18630721
    reference_title: "New insights in the pathogenesis of aortic aneurysms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In analogy to LDS, we demonstrated an upregulation of TGFbeta in ATS.
    explanation: >-
      This review confirms TGF-beta upregulation in ATS by analogy to
      Loeys-Dietz syndrome, supporting the conserved TGF-beta hub. Evidence
      source is OTHER because this is a review synthesizing human and mouse data.
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling.
    explanation: >-
      Provides the important nuance that increased TGF-beta signaling is not
      detectable in skin or end-stage vascular tissue, so the upregulation is
      stage-dependent; included to represent the mechanism faithfully.
  downstream:
  - target: Fragmented elastic fibers and collagen deposition
    description: >-
      Dysregulated TGF-beta signaling contributes to the elastic-fiber
      fragmentation and disordered collagen matrix of the arterial media.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16550171
      reference_title: "Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        owing to disruption of elastic fibers in the medial layer of the
        arterial wall
      explanation: ATS features disruption of medial elastic fibers; the causal direction from TGF-beta dysregulation to elastic-fiber fragmentation is inferred by analogy to Loeys-Dietz, so the edge is PARTIAL.
  - target: Diaphragmatic hernia
    description: Systemic connective-tissue dysregulation is linked to the diaphragmatic hernia component of ATS.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29323665
      reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS)
        are frequently observed.
      explanation: Diaphragmatic hernia is a frequent ATS manifestation attributed to systemic connective-tissue dysregulation; the specific link to TGF-beta signaling is not isolated, so the edge is PARTIAL.
- name: Fragmented elastic fibers and collagen deposition
  conforms_to: "aortopathy_tgfbeta_dysregulation#Aortic Medial Degeneration and Wall Weakening"
  description: >-
    Histologic studies of skin and vascular tissue show elastic-fiber
    fragmentation and increased collagen deposition, supporting a structural
    vessel-wall matrix mechanism.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skin and vascular biopsies show fragmented elastic fibers (EF) and increased
      collagen deposition.
    explanation: This abstract directly supports abnormal elastic-fiber and collagen matrix organization in ATS tissues.
  downstream:
  - target: Arterial wall structural failure and tortuosity
    description: Elastic-fiber fragmentation and collagen deposition weaken arterial structure and lead to tortuosity, stenosis, and aneurysm formation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16550171
      reference_title: "Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        tortuosity, elongation, stenosis and aneurysm formation in the
        major arteries owing to disruption of elastic fibers in the medial layer of the
        arterial wall
      explanation: Disruption of medial elastic fibers is the stated cause of the tortuosity, stenosis, and aneurysm formation, directly supporting this edge.
- name: Arterial wall structural failure and tortuosity
  conforms_to: "aortopathy_tgfbeta_dysregulation#Progressive Aortic Dilation and Aneurysm"
  description: >-
    Matrix disorganization compromises arterial-wall structure, producing
    tortuosity with associated stenosis and aneurysm formation across affected
    large and medium-sized arteries.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stenoses, tortuosity, and aneurysm formation are widespread occurrences.
    explanation: This supports the structural vascular consequences downstream of the histologic matrix abnormality.
  downstream:
  - target: Arterial tortuosity
    description: Arterial-wall structural failure manifests as arterial elongation and tortuosity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37619836
      reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        characterised by tortuosity and elongation of the aorta and medium-sized arteries
      explanation: The defining manifestation of arterial-wall failure in ATS is tortuosity and elongation of the aorta and medium-sized arteries.
  - target: Arterial stenosis
    description: Disordered arterial-wall structure can narrow affected arterial beds.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29323665
      reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Stenoses, tortuosity, and aneurysm formation are widespread occurrences.
      explanation: Stenosis is one of the widespread structural vascular consequences downstream of arterial-wall failure.
  - target: Pulmonary artery stenosis
    description: The same stenotic vascular phenotype can involve pulmonary arteries.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29323665
      reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Stenoses, tortuosity, and aneurysm formation are widespread occurrences.
      explanation: Stenoses are widespread in ATS; the quoted sentence does not isolate pulmonary artery stenosis, so the edge is PARTIAL.
  - target: Aortic root aneurysm
    description: Arterial-wall structural failure can involve the aortic root as aneurysmal dilation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29323665
      reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Severe but rare vascular complications include early and aggressive aortic root
        aneurysms
      explanation: Aortic root aneurysm is a severe structural vascular complication downstream of arterial-wall failure.
  - target: Infant respiratory distress syndrome
    description: Severe neonatal vascular and connective-tissue manifestations can present with infant respiratory distress.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29323665
      reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS)
        are frequently observed.
      explanation: Infant respiratory distress syndrome is frequently observed in ATS as part of the severe connective-tissue disease spectrum.
  - target: Ischemic stroke
    description: Cerebrovascular involvement can produce ischemic stroke, although this is a severe and uncommon complication.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29323665
      reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Severe but rare vascular complications include early and aggressive aortic
        root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric
        perforation.
      explanation: >-
        This directly identifies ischemic stroke as a severe but rare vascular
        complication; the omitted vessel-to-infarction intermediates remain
        unspecified in the abstract.
phenotypes:
- category: Cardiovascular
  name: Arterial tortuosity
  diagnostic: true
  description: Elongation and tortuosity of the aorta and medium-sized arteries are defining vascular features.
  phenotype_term:
    preferred_term: Arterial tortuosity
    term:
      id: HP:0005116
      label: Arterial tortuosity
  evidence:
  - reference: PMID:37619836
    reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue
      disease caused by biallelic variants in the SLC2A10 gene (NG_016284.1) and characterised
      by tortuosity and elongation of the aorta and medium-sized arteries.
    explanation: The defining vascular phenotype is tortuosity and elongation of the aorta and medium-sized arteries.
- category: Cardiovascular
  name: Arterial stenosis
  description: Stenosis can occur in affected arterial beds but appears variable across reported patients.
  phenotype_term:
    preferred_term: Arterial stenosis
    term:
      id: HP:0100545
      label: Arterial stenosis
  evidence:
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stenoses, tortuosity, and aneurysm formation are widespread occurrences.
    explanation: The large review identifies stenosis as part of the widespread vascular phenotype.
- category: Cardiovascular
  name: Pulmonary artery stenosis
  description: Pulmonary artery stenosis is a recognized vascular manifestation within the ATS stenosis spectrum.
  phenotype_term:
    preferred_term: Pulmonary artery stenosis
    term:
      id: HP:0004415
      label: Pulmonary artery stenosis
  evidence:
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stenoses, tortuosity, and aneurysm formation are widespread occurrences.
    explanation: The abstract supports stenoses as widespread in ATS, although it does not isolate pulmonary artery stenosis in the quoted sentence.
- category: Cardiovascular
  name: Aortic root aneurysm
  description: Aortic root aneurysm is a severe vascular complication requiring early monitoring.
  phenotype_term:
    preferred_term: Aortic root aneurysm
    term:
      id: HP:0002616
      label: Aortic root aneurysm
  evidence:
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe but rare vascular complications include early and aggressive aortic root
      aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation.
    explanation: This supports aortic root aneurysm as a severe ATS complication.
- category: Respiratory
  name: Infant respiratory distress syndrome
  description: Infant respiratory distress syndrome is frequently observed in ATS and should be monitored early in life.
  phenotype_term:
    preferred_term: Infant respiratory distress syndrome
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  evidence:
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS)
      are frequently observed.
    explanation: This directly supports frequent respiratory distress syndrome in ATS.
- category: Respiratory
  name: Diaphragmatic hernia
  description: Diaphragmatic hernia is a recurrent nonvascular ATS feature reported in cohort review.
  phenotype_term:
    preferred_term: Congenital diaphragmatic hernia
    term:
      id: HP:0000776
      label: Congenital diaphragmatic hernia
  evidence:
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS)
      are frequently observed.
    explanation: This directly supports diaphragmatic hernia as a frequent ATS manifestation.
- category: Cutaneous
  name: Hyperextensible skin
  description: Hyperextensible skin is a characteristic extra-vascular connective-tissue manifestation of ATS.
  phenotype_term:
    preferred_term: Hyperextensible skin
    term:
      id: HP:0000974
      label: Hyperextensible skin
  evidence:
  - reference: PMID:18818946
    reference_title: A novel non-sense mutation in the SLC2A10 gene of an arterial tortuosity syndrome patient of Kurdish origin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder in
      which patients display tortuosity of arteries in addition to hyperextensible
      skin, joint laxity, and other connective tissue features.
    explanation: The clinical description directly identifies hyperextensible skin as an ATS manifestation.
- category: Cutaneous
  name: Cutis laxa
  description: Loose, lax skin can be part of the evolving connective-tissue phenotype in ATS.
  phenotype_term:
    preferred_term: Cutis laxa
    term:
      id: HP:0000973
      label: Cutis laxa
  evidence:
  - reference: PMID:34384376
    reference_title: "Two fetuses in one family of arterial tortuosity syndrome: prenatal ultrasound diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial characteristic features gradually as aging, such as blepharophimosis
      or periorbital fullness, downslanted palpebral fissures, micrognathia, large
      ears, long face and cutis laxa.
    explanation: Follow-up of an affected child directly documents cutis laxa.
- category: Musculoskeletal
  name: Joint hypermobility
  description: Joint hypermobility reflects the systemic connective-tissue involvement in ATS.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:18818946
    reference_title: A novel non-sense mutation in the SLC2A10 gene of an arterial tortuosity syndrome patient of Kurdish origin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients of Kurdish origin who display arterial tortuosity associated with skin
      hyperextensibility, joint hypermobility, and characteristic facial features may
      carry mutations in the SLC2A10 gene.
    explanation: The patient report directly associates joint hypermobility with genetically defined ATS.
- category: Ocular
  name: Keratoconus
  description: Keratoconus is a recognized ocular connective-tissue manifestation of ATS.
  phenotype_term:
    preferred_term: Keratoconus
    term:
      id: HP:0000563
      label: Keratoconus
  evidence:
  - reference: PMID:25373504
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other CTD signs of ATS are dysmorphisms, abdominal hernias, joint
      hypermobility, skeletal abnormalities, and keratoconus.
    explanation: The clinical review directly includes keratoconus among the connective-tissue signs of ATS.
- category: Craniofacial
  name: Hypertelorism
  description: Hypertelorism is among the mild characteristic facial features reported in ATS.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:26376865
    reference_title: GLUT10 deficiency leads to oxidative stress and non-canonical αvβ3 integrin-mediated TGFβ signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ATS also shows additional signs shared with other CTDs, including
      soft/velvety/hyperextensible skin, mild dysmorphic facial features, i.e.
      elongated face, hypertelorism, cleft palate and/or bifid uvula, and
      micro/retrognathia, abdominal hernias, joint hypermobility and instability
      (1–8).
    explanation: The ATS clinical phenotype summary explicitly identifies hypertelorism.
- category: Craniofacial
  name: Downslanted palpebral fissures
  description: Downslanted palpebral fissures are part of the characteristic facial appearance reported in ATS.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:34384376
    reference_title: "Two fetuses in one family of arterial tortuosity syndrome: prenatal ultrasound diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial characteristic features gradually as aging, such as blepharophimosis
      or periorbital fullness, downslanted palpebral fissures, micrognathia, large
      ears, long face and cutis laxa.
    explanation: Follow-up of an affected child directly documents downslanted palpebral fissures.
- category: Craniofacial
  name: Long face
  description: Long face is a representative craniofacial feature in ATS.
  phenotype_term:
    preferred_term: Long face
    term:
      id: HP:0000276
      label: Long face
  evidence:
  - reference: PMID:34384376
    reference_title: "Two fetuses in one family of arterial tortuosity syndrome: prenatal ultrasound diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial characteristic features gradually as aging, such as blepharophimosis
      or periorbital fullness, downslanted palpebral fissures, micrognathia, large
      ears, long face and cutis laxa.
    explanation: Follow-up of an affected child directly documents long face.
- category: Neurologic
  name: Ischemic stroke
  description: >-
    Ischemic stroke is a severe but uncommon vascular complication and has been
    reported as an initial presentation in both infancy and adulthood.
  phenotype_term:
    preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: PMID:17935213
    reference_title: "Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients initially presented with stroke, respectively at age 8 months
      and 23 years.
    explanation: >-
      The clinical series directly documents stroke as an initial presentation
      at two distinct ages.
histopathology:
- name: Fragmented elastic fibers with increased collagen deposition
  description: >-
    Skin and vascular biopsies show elastic-fiber fragmentation, increased
    collagen deposition, and disease-specific ultrastructural abnormalities.
  evidence:
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skin and vascular biopsies show fragmented elastic fibers (EF) and increased
      collagen deposition.
    explanation: This directly supports the histopathologic matrix abnormality.
genetic:
- name: SLC2A10
  association: Causative
  presence: Positive
  gene_term:
    preferred_term: SLC2A10
    term:
      id: hgnc:13444
      label: SLC2A10
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:37619836
      reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue
        disease caused by biallelic variants in the SLC2A10 gene
      explanation: ATS is defined as an autosomal recessive disease requiring biallelic SLC2A10 variants.
  notes: >-
    SLC2A10 encodes GLUT10. Reported ATS variants include nonsense and missense
    alleles, with biallelic pathogenic variants required for disease.
  evidence:
  - reference: PMID:37619836
    reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A not previously described variant (NM_030777.4:c.899T>G (p.Leu300Trp)) was
      detected in a proband; it has an allegedly deleterious effect in compound heterozygous
      state with the pathogenic variant c.417T>A (p.Tyr139Ter).
    explanation: This identifies a novel SLC2A10 variant in compound heterozygous state with a pathogenic allele.
  - reference: CGGV:assertion_80a24753-e6d3-41cb-85ba-85a2eae3ddb6-2024-11-07T170000.000Z
    reference_title: "SLC2A10 / arterial tortuosity syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC2A10 | HGNC:13444 | arterial tortuosity syndrome | MONDO:0008818 | AR | Definitive"
    explanation: ClinGen classifies the SLC2A10-arterial tortuosity syndrome gene-disease relationship as definitive with autosomal recessive inheritance.
diagnosis:
- name: Molecular confirmation of biallelic SLC2A10 variants
  description: >-
    Generalized arterial tortuosity in a compatible connective-tissue phenotype
    is confirmed molecularly by identifying biallelic pathogenic SLC2A10
    variants.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: Biallelic pathogenic SLC2A10 variants support molecular confirmation of arterial tortuosity syndrome.
  evidence:
  - reference: PMID:17935213
    reference_title: "Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 16 patients harbor biallelic SLC2A10 mutations of which nine are novel
      (six missense, three truncating mutations, including a large deletion).
    explanation: >-
      Molecular characterization of the affected cohort directly supports a
      biallelic SLC2A10 diagnostic result.
- name: Vascular imaging surveillance
  description: >-
    Extensive vascular imaging is recommended after diagnosis because tortuosity,
    stenosis, and aneurysm formation can involve multiple arterial beds.
  diagnosis_term:
    preferred_term: diagnostic imaging
    term:
      id: NCIT:C17369
      label: Imaging Procedure
  results: Imaging may show arterial elongation, tortuosity, stenosis, or aneurysm.
  evidence:
  - reference: PMID:29323665
    reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring
      of the aortic root early in life, and extensive vascular imaging afterwards.
    explanation: The review recommends early aortic-root monitoring and subsequent extensive vascular imaging.
treatments:
- name: Genetic counseling
  description: >-
    Genetic counseling should explain autosomal recessive inheritance, carrier
    status, and the 25% recurrence risk when both parents are carriers.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:34384376
    reference_title: "Two fetuses in one family of arterial tortuosity syndrome: prenatal ultrasound diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Parents who continue the pregnancy after prenatal consultation and are fully
      aware that both parents are carriers have a 25% chance of having the disease
      in their next child.
    explanation: The familial prenatal report directly supports carrier counseling and a 25% recurrence risk.
- name: Beta-adrenergic blockade
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Beta-blockers have been used clinically to reduce hemodynamic stress on the
    arterial wall, although evidence remains limited and supportive.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Beta-Adrenergic Antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  evidence:
  - reference: PMID:37619836
    reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking
      treatment was prescribed.
    explanation: This supports reported clinical use of beta-blockade but does not establish efficacy.
  target_mechanisms:
  - target: Arterial wall structural failure and tortuosity
    treatment_effect: MODULATES
    description: >-
      Beta-blockade is intended to reduce hemodynamic stress on the structurally
      abnormal arterial wall; it does not correct SLC2A10 deficiency or have
      established disease-modifying efficacy.
    evidence:
    - reference: PMID:37619836
      reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking
        treatment was prescribed.
      explanation: >-
        The case series supports the treatment intent and actual use, but not
        efficacy against the underlying structural mechanism.
- name: Pulmonary arterial reconstruction for severe stenosis
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    Surgical pulmonary-artery reconstruction may be considered for severe,
    hemodynamically important pulmonary artery stenosis. Evidence is limited to
    selected cases and does not define universal intervention thresholds.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Pulmonary artery stenosis
    term:
      id: HP:0004415
      label: Pulmonary artery stenosis
  evidence:
  - reference: PMID:38987788
    reference_title: "Total pulmonary arterial reconstruction in a patient with arterial tortuosity syndrome affecting the pulmonary artery: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 2 years old Arabian female child was diagnosed with ATS affecting the
      pulmonary arteries as a newborn, underwent a pulmonary arterial surgical
      reconstruction at the age of 2 years old due to the development of pulmonary
      artery stenosis
    explanation: >-
      This documents reconstruction for severe ATS-associated pulmonary stenosis
      in one child; single-case evidence cannot establish comparative efficacy or
      a general treatment threshold.
  target_mechanisms:
  - target: Arterial wall structural failure and tortuosity
    treatment_effect: BYPASSES
    description: >-
      Reconstruction bypasses or repairs a focal hemodynamically important
      stenotic consequence without correcting the molecular vessel-wall defect.
    evidence:
    - reference: PMID:38987788
      reference_title: "Total pulmonary arterial reconstruction in a patient with arterial tortuosity syndrome affecting the pulmonary artery: a case report and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        After surgical repair the left pulmonary artery has a peak pressure
        gradient of 20 mmHg, with the right pulmonary artery having a peak pressure
        gradient of 20 mmHg.
      explanation: >-
        The post-repair gradient supports focal hemodynamic improvement in one
        patient, not reversal of the inherited arterial-wall mechanism.
differential_diagnoses:
- name: Marfan syndrome
  disease_term:
    preferred_term: Marfan syndrome
    term:
      id: MONDO:0007947
      label: Marfan syndrome
  description: >-
    Marfan syndrome is another inherited disorder associated with arterial
    tortuosity and belongs in the differential of a generalized aortopathy.
  evidence:
  - reference: PMID:37692180
    reference_title: "Arterial Tortuosity Syndrome: Unraveling a Rare Vascular Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ATS is one of many conditions associated with arterial tortuosity,
      including Marfan syndrome and Loeys-Dietz syndrome.
    explanation: >-
      This review explicitly places Marfan syndrome in the arterial-tortuosity
      differential, while molecular and multisystem assessment must provide
      the disease-specific distinction.
- name: Loeys-Dietz syndrome
  disease_term:
    preferred_term: Loeys-Dietz syndrome
    term:
      id: MONDO:0018954
      label: Loeys-Dietz syndrome
  description: >-
    Loeys-Dietz syndrome is another syndromic aortopathy associated with
    arterial tortuosity and should be distinguished from SLC2A10-related ATS.
  evidence:
  - reference: PMID:37692180
    reference_title: "Arterial Tortuosity Syndrome: Unraveling a Rare Vascular Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ATS is one of many conditions associated with arterial tortuosity,
      including Marfan syndrome and Loeys-Dietz syndrome.
    explanation: >-
      The review explicitly identifies Loeys-Dietz syndrome as another
      arterial-tortuosity condition; the evidence supports differential
      consideration rather than a specific bedside discriminator.
clinical_trials: []
notes: >-
  Re-review prioritized the SLC2A10 gene-discovery study, the largest
  multi-family clinical review, a later molecular cohort, ClinGen validity,
  and narrowly interpreted case evidence. The previous deep-research reference
  ledger was removed because its uncited findings lacked item-level evidence.
datasets:
- accession: geo:GSE71172
  title: microRNA expression profiles from three arterial tortuosity syndrome (ATS) patients' skin fibroblasts with recessive SLC2A10 mutations [miRNA]
  description: To screen for potential miRNA that may contribute to the pathomechanisms of ATS miRNA expression profiling using the Affymetrix GeneChip® miRNA 3.0 Array comparing the miRNA expression changes of skin fibroblasts of three ATS patients with those of three healthy individuals
  data_type: MICROARRAY
  sample_count: 6
  publication: PMID:26376865
  notes: Identified by GEO DataSets index search for Arterial Tortuosity Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE70683
  title: Microarray expression data from three arterial tortuosity syndrome (ATS) patients' skin fibroblasts with recessive SLC2A10 mutations
  description: To screen for candidate genes that may contribute to the pathogenesis of ATS Transcriptome-wide expression profiling using the Affymetrix Gene 1.0 ST platform comparing the gene expression patterns of skin fibroblasts of three ATS patients with those of three healthy individuals
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 6
  publication: PMID:26376865
  notes: Identified by GEO DataSets index search for Arterial Tortuosity Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
📚

References & Deep Research

Deep Research

2
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 32 citations 2026-05-04T18:36:18.807226

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Arterial Tortuosity Syndrome
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Arterial Tortuosity Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Arterial Tortuosity Syndrome (ATS) — Comprehensive Disease Characteristics Report (Mendelian)

Target disease

  • Disease name: Arterial Tortuosity Syndrome (ATS)
  • Category: Mendelian; heritable connective tissue disorder with primary vascular involvement (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5)
  • OMIM: 208050 (esmelvilomara2023arterialtortuositysyndromea pages 1-5)
  • MONDO / Orphanet / ICD-10/ICD-11 / MeSH: Not verifiable from the retrieved full-text sources in this run; should be filled from OMIM/Orphanet/MONDO directly during curation.

Executive overview (current understanding)

Arterial Tortuosity Syndrome is an autosomal recessive connective tissue disorder caused by biallelic pathogenic variants in SLC2A10 (GLUT10) and characterized by elongation and tortuosity of large- and medium-sized arteries, often accompanied by stenoses and a variable risk of aneurysm formation and ischemic complications (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5). Extra-vascular connective tissue features (craniofacial, skeletal, cutaneous, ocular, and hernia phenotypes) are common and provide diagnostic clues (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 5-8).

Evidence snapshot table

Knowledge-base field Summary Key details / frequencies / examples Source details
Disease name / identifiers Arterial Tortuosity Syndrome (ATS); OMIM #208050 Rare autosomal recessive connective-tissue disorder with elongation/tortuosity of large- and medium-sized arteries; also termed ATORS in some recent literature (beyens2018arterialtortuositysyndrome pages 1-2, butnariu2024identificationofgenetic pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5) Beyens et al., Genetics in Medicine, published 2018-01-11 online / Oct 2018; DOI: https://doi.org/10.1038/gim.2017.253 (beyens2018arterialtortuositysyndrome pages 1-2). Butnariu et al., Int J Mol Sci, 2024-10-17; DOI: https://doi.org/10.3390/ijms252011173 (butnariu2024identificationofgenetic pages 1-2)
Synonyms / alternative names Arterial tortuosity syndrome, ATS, ATORS Some resources/papers use “arterial tortuosity syndrome”; HTAD-focused paper abbreviates as ATORS (butnariu2024identificationofgenetic pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5) Butnariu et al. 2024 https://doi.org/10.3390/ijms252011173; Esmel-Vilomara et al. preprint posted 2022-12-05 / journal article 2023-08 https://doi.org/10.21203/rs.3.rs-2321263/v1 and https://doi.org/10.1016/j.ejmg.2023.104823 (butnariu2024identificationofgenetic pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5)
Core evidence type Aggregated disease-level and cohort/case-series evidence Information in the table is derived from aggregated disease cohorts/reviews and individual case series, not EHR-only data (beyens2018arterialtortuositysyndrome pages 1-2, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 1-5) Beyens 2018; Rahmath et al., Biomedicines, 2025-01 https://doi.org/10.3390/biomedicines13010159; Esmel-Vilomara 2023 (beyens2018arterialtortuositysyndrome pages 1-2, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 1-5)
Causal gene SLC2A10 (encodes GLUT10) Loss-of-function / biallelic pathogenic variants cause ATS; GLUT10 is described as an intracellular transporter involved in dehydroascorbic acid/ascorbate biology and connective-tissue homeostasis (beyens2018arterialtortuositysyndrome pages 1-2, beyens2018arterialtortuositysyndrome pages 2-4, esmelvilomara2023arterialtortuositysyndromea pages 1-5) Beyens 2018 https://doi.org/10.1038/gim.2017.253; Esmel-Vilomara 2023 https://doi.org/10.1016/j.ejmg.2023.104823 (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5)
Inheritance Autosomal recessive Frequently associated with parental consanguinity: 24/48 (50%) in Beyens cohort/review (beyens2018arterialtortuositysyndrome pages 8-9) Beyens et al. 2018 https://doi.org/10.1038/gim.2017.253 (beyens2018arterialtortuositysyndrome pages 8-9)
Epidemiology / rarity Extremely rare Reported incidence <1:1,000,000 live births; Esmel-Vilomara notes 106 genetically confirmed individuals identified to date at time of study (esmelvilomara2023arterialtortuositysyndromea pages 1-5) Esmel-Vilomara preprint/journal 2022/2023 https://doi.org/10.21203/rs.3.rs-2321263/v1 and https://doi.org/10.1016/j.ejmg.2023.104823 (esmelvilomara2023arterialtortuositysyndromea pages 1-5)
Key vascular phenotype: aortic tortuosity Hallmark feature 37/41 (90%) in Beyens 2018; 21/21 (100%) in Qatari cohort with p.Ser81Arg (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) Beyens 2018 https://doi.org/10.1038/gim.2017.253; Rahmath 2025 https://doi.org/10.3390/biomedicines13010159 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6)
Key vascular phenotype: tortuosity of other arteries Very common multisite arterial involvement 38/42 (90%) in Beyens; 20/21 (95%) in Rahmath cohort; severe intracranial tortuosity highlighted in 4-patient 2023 series (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndromea pages 5-8) Beyens 2018; Rahmath 2025; Esmel-Vilomara 2023 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndromea pages 5-8)
Pulmonary artery involvement Common and clinically important Pulmonary artery stenosis 23/42 (55%) in Beyens; pulmonary artery tortuosity 19/21 (90%) in Rahmath; severe PAS can cause RV hypertension and need intervention (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, alshair2024totalpulmonaryarterial pages 1-2, alshair2024totalpulmonaryarterial pages 2-5) Beyens 2018 https://doi.org/10.1038/gim.2017.253; Rahmath 2025 https://doi.org/10.3390/biomedicines13010159; Alshair 2024 https://doi.org/10.1186/s13019-024-02905-6 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, alshair2024totalpulmonaryarterial pages 1-2, alshair2024totalpulmonaryarterial pages 2-5)
Aortic root aneurysm / aneurysms Present in a subset, not universal Aortic root aneurysm 9/42 (21%) in Beyens overall table; 2/21 (9%) in Qatari p.Ser81Arg cohort; 2023 4-patient series found no aneurysms in their cases (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 5-8) Beyens 2018; Rahmath 2025; Esmel-Vilomara 2023 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 5-8)
Arterial dissections Rare / not documented in major series cited 0/37 (0%) in Beyens summary; 2023 series notes no confirmed dissections to date in reviewed ATS literature (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndrome pages 8-11) Beyens 2018 https://doi.org/10.1038/gim.2017.253; Esmel-Vilomara 2023 https://doi.org/10.21203/rs.3.rs-2594978/v1 (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndrome pages 8-11)
Craniofacial features Frequent syndromic clues Long face 32/49 (65%), high-arched palate 29/44 (66%), micrognathia 23/45 (51%), sagging cheeks 27/49 (55%) in Beyens (beyens2018arterialtortuositysyndrome pages 8-9) Beyens 2018 https://doi.org/10.1038/gim.2017.253 (beyens2018arterialtortuositysyndrome pages 8-9)
Skin / connective tissue features Common extra-vascular signs Hyperextensible skin 27/46 (50%), cutis laxa 21/41 (51%), velvety skin 26/41 (63%) in Beyens; Rahmath found cutaneous findings in 12/21, including hyperextensible skin in 8/21 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) Beyens 2018; Rahmath 2025 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6)
Skeletal / musculoskeletal features Common Joint laxity 36/42 (86%) in Beyens; Rahmath reported skeletal abnormalities in 15/21, including joint hypermobility 8/21, muscular hypotonia 8/21, pectus excavatum 3/21, scoliosis 2/21 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) Beyens 2018; Rahmath 2025 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6)
Ocular features Important but variably expressed Myopia 15/36 (42%) and keratoconus 3/38 (8%) in Beyens; Rahmath: ocular anomalies 7/21, including astigmatism 5/21, myopia 2/21; ophthalmologic baseline exam with keratometry recommended (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) Beyens 2018 https://doi.org/10.1038/gim.2017.253; Rahmath 2025 https://doi.org/10.3390/biomedicines13010159 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6)
Hernias / GI-GU findings Recurrent nonvascular clues Diaphragmatic hernia 19/65 (29%), inguinal hernia 35/92 (38%), urogenital abnormalities 11/56 (20%) in Beyens; Rahmath: inguinal hernia 8/21, diaphragmatic hernia 7/21, GERD 5/21 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 5-8) Beyens 2018; Rahmath 2025; Esmel-Vilomara 2023 detailed GU examples (pyelectasis/megaureter) (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 5-8)
Respiratory manifestations Clinically relevant in infancy/childhood Beyens: respiratory symptoms 10/67 (15%) and frequent attention to IRDS; Rahmath: respiratory manifestations 13/21, recurrent chest infections 8/21, respiratory distress syndrome 5/21 (beyens2018arterialtortuositysyndrome pages 1-2, rahmath2025understandingthespectrum pages 4-6, beyens2018arterialtortuositysyndrome pages 8-9) Beyens 2018 https://doi.org/10.1038/gim.2017.253; Rahmath 2025 https://doi.org/10.3390/biomedicines13010159 (beyens2018arterialtortuositysyndrome pages 1-2, rahmath2025understandingthespectrum pages 4-6, beyens2018arterialtortuositysyndrome pages 8-9)
Example pathogenic / likely pathogenic variants Representative recurrent and novel alleles c.510G>A (p.Trp170Ter) homozygous in 3 siblings; c.417T>A (p.Tyr139Ter) pathogenic; c.899T>G (p.Leu300Trp) novel/likely deleterious in compound heterozygosity; c.243C>G (p.Ser81Arg) in 21-patient Qatari cohort associated with relatively mild outcomes (esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndromea pages 5-8, rahmath2025understandingthespectrum pages 4-6) Esmel-Vilomara 2023 https://doi.org/10.1016/j.ejmg.2023.104823 and preprint https://doi.org/10.21203/rs.3.rs-2321263/v1; Rahmath 2025 https://doi.org/10.3390/biomedicines13010159 (esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndromea pages 5-8, rahmath2025understandingthespectrum pages 4-6)
Recent HTAD testing implementation ATS detectable via NGS / WES in broader aortopathy workups 2024 HTAD study identified compound heterozygous SLC2A10 pathogenic variants in a patient with ATS using NGS/WES, reinforcing inclusion of SLC2A10 in syndromic aortopathy testing (butnariu2024identificationofgenetic pages 1-2) Butnariu et al., Int J Mol Sci, 2024-10-17 https://doi.org/10.3390/ijms252011173 (butnariu2024identificationofgenetic pages 1-2)
Recommended baseline diagnostic evaluation Comprehensive vascular and multisystem baseline work-up Suggested by Beyens: detailed clinical exam, echocardiography, head-to-pelvis MRA, ophthalmologic exam with keratometry, and renal artery ultrasound for every ATS patient (beyens2018arterialtortuositysyndrome pages 8-9) Beyens 2018 https://doi.org/10.1038/gim.2017.253 (beyens2018arterialtortuositysyndrome pages 8-9)
Surveillance / monitoring Serial vascular surveillance required Case-based radiology review recommends echocardiography every 3 months until age 5 and then individualized but annual imaging; serial multimodal imaging (CTA/MRA/US) for progression and complications (alkooheji2025radiologicdiagnosisof pages 5-6) Alkooheji et al., Cureus, 2025-12 https://doi.org/10.7759/cureus.99989 (alkooheji2025radiologicdiagnosisof pages 5-6)
Imaging hallmarks in practice CTA/MRA are central real-world diagnostic tools Radiologic signs include meandering vessel sign, cluster-of-vessels sign, aortic elongation sign, and pulmonary bifurcation “V/inverted V” signs; coronal MIP CTA can show tortuous arch branches and thoracic aorta (alkooheji2025radiologicdiagnosisof pages 5-6, kumar2021arterialtortuositysyndrome media cf1c0f36, kumar2021arterialtortuositysyndrome media 75462c90) Kumar 2021 https://doi.org/10.22468/cvia.2020.00129; Alkooheji 2025 https://doi.org/10.7759/cureus.99989 (kumar2021arterialtortuositysyndrome media cf1c0f36, kumar2021arterialtortuositysyndrome media 75462c90, alkooheji2025radiologicdiagnosisof pages 5-6)
Real-world intervention: medical Empiric beta-blocker use 2023 4-patient series: beta-adrenergic blocking treatment prescribed to reduce hemodynamic stress; authors note efficacy is unproven and management is largely expert-opinion based (esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndrome pages 8-11) Esmel-Vilomara 2023 https://doi.org/10.1016/j.ejmg.2023.104823 and https://doi.org/10.21203/rs.3.rs-2594978/v1 (esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndrome pages 8-11)
Real-world intervention: surgery Pulmonary artery reconstruction for severe PAS In a 2-year-old with ATS, surgical reconstruction performed for severe PAS: pre-op LPA gradient 73 mmHg, velocity 4.3 m/s; RPA gradient 46 mmHg, velocity 3.4 m/s; post-repair both branch PA gradients 20 mmHg at follow-up (alshair2024totalpulmonaryarterial pages 1-2, alshair2024totalpulmonaryarterial pages 2-5) Alshair et al., J Cardiothorac Surg, 2024-07 https://doi.org/10.1186/s13019-024-02905-6 (alshair2024totalpulmonaryarterial pages 1-2, alshair2024totalpulmonaryarterial pages 2-5)
Real-world intervention: catheter-based Balloon dilation can be used for residual focal stenosis Same 2024 case: postoperative proximal LPA stenosis treated with 8×40 mm Sterling balloon, reducing peak gradient from about 25 mmHg to 14 mmHg (alshair2024totalpulmonaryarterial pages 2-5) Alshair et al. 2024 https://doi.org/10.1186/s13019-024-02905-6 (alshair2024totalpulmonaryarterial pages 2-5)
Prognosis More variable and often milder than first reports suggested Historical reports cited mortality up to 40% before age 5, but larger later cohorts indicate a milder course and no mortality in the 21-patient Qatari p.Ser81Arg cohort (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5, rahmath2025understandingthespectrum pages 4-6) Beyens 2018; Esmel-Vilomara 2023; Rahmath 2025 (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5, rahmath2025understandingthespectrum pages 4-6)

Table: This table summarizes core disease-knowledge fields for Arterial Tortuosity Syndrome, including identifiers, genetics, phenotype frequencies, diagnostics, surveillance, and real-world interventions. It is useful as a structured evidence-backed snapshot for populating a rare disease knowledge base entry.

1. Disease information

1.1 Definition and key concepts

  • Core vascular concept (arterial tortuosity): abnormal twisting/turning and elongation of arteries leading to altered hemodynamics and potential downstream stenosis/ischemia (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5).
  • Syndromic context: ATS is one of the heritable connective tissue/aortopathy syndromes where tortuosity is part of a broader multisystem phenotype (alkooheji2025radiologicdiagnosisof pages 5-6, beyens2018arterialtortuositysyndrome pages 8-9).

1.2 Synonyms / alternative names

  • Arterial tortuosity syndrome, ATS.
  • ATORS is used in some hereditary thoracic aortic disease (HTAD) testing literature to denote arterial tortuosity syndrome (butnariu2024identificationofgenetic pages 1-2).

1.3 Evidence provenance (patient-level vs aggregated)

  • Aggregated disease-level evidence: large cohort + literature review (2018) (beyens2018arterialtortuositysyndrome pages 1-2, beyens2018arterialtortuositysyndrome pages 8-9).
  • Patient-level series enabling HPO mapping and rare feature expansion: 4-patient series (posted 2022-12-05; later journal publication Aug 2023) (esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndromea pages 5-8) and cohort of 21 genetically confirmed Qatari patients (2025) (rahmath2025understandingthespectrum pages 4-6).

Recent developments (2023–2024 emphasis): New variant reports and expanded phenotype capture via modern sequencing (clinical exome/WES) and systematic imaging were described in 2023, and incorporation of SLC2A10 into broader HTAD NGS/WES workflows was explicitly illustrated in 2024 (esmelvilomara2023arterialtortuositysyndromea pages 1-5, butnariu2024identificationofgenetic pages 1-2).

2. Etiology

2.1 Disease causal factors

  • Primary cause: biallelic loss-of-function / pathogenic variants in SLC2A10, encoding GLUT10 (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5).
  • Inheritance: autosomal recessive; consanguinity is frequent in reported families (24/48; 50% in one large series) (beyens2018arterialtortuositysyndrome pages 8-9).

2.2 Risk factors

  • Genetic: carrying two pathogenic alleles in SLC2A10 is causal (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5).
  • Family structure: high frequency of parental consanguinity in cohorts indicates increased recurrence risk in consanguineous families (beyens2018arterialtortuositysyndrome pages 8-9).
  • Environmental/lifestyle: No validated environmental risk factors or gene–environment interactions were identified in the retrieved ATS-specific sources.

2.3 Protective factors

  • No established protective genetic or environmental factors were identified in the retrieved sources.

2.4 Gene–environment interactions

  • Not established in the retrieved ATS literature.

3. Phenotypes (clinical spectrum)

3.1 Typical onset and course

ATS often presents in infancy/childhood, including neonatal manifestations such as pulmonary artery stenosis and respiratory distress in some patients (alshair2024totalpulmonaryarterial pages 2-5, beyens2018arterialtortuositysyndrome pages 1-2). Natural history is heterogeneous; early reports described high early mortality, but later cohorts suggest a milder course in many patients (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5).

3.2 Vascular phenotypes (with frequencies where available)

From a large cohort/literature synthesis (Beyens 2018): - Aortic tortuosity: 37/41 (90%) (beyens2018arterialtortuositysyndrome pages 8-9) - Tortuosity of other arteries: 38/42 (90%) (beyens2018arterialtortuositysyndrome pages 8-9) - Pulmonary artery stenosis: 23/42 (55%) (beyens2018arterialtortuositysyndrome pages 8-9) - Aortic root aneurysm: 9/42 (21%) (beyens2018arterialtortuositysyndrome pages 8-9) - Arterial dissections: 0/37 (0%) (beyens2018arterialtortuositysyndrome pages 8-9)

From a 21-patient genetically confirmed Qatari cohort (Rahmath 2025; homozygous p.Ser81Arg): - Aortic tortuosity: 21/21 (100%) - Other arterial tortuosity: 20/21 (95%) - Pulmonary artery tortuosity: 19/21 (90%) - Aortic root aneurysm: 2/21 (9%) - Cardiovascular interventions: 2/21 (9%) (rahmath2025understandingthespectrum pages 4-6)

3.3 Extra-vascular phenotypes and HPO suggestions

Below are common phenotypes and representative HPO terms (examples; not exhaustive).

Craniofacial / dysmorphism (common diagnostic clues) - Long face HP:0000276; hypertelorism HP:0000316; downslanted palpebral fissures HP:0000494; high arched/narrow palate HP:0002705; micrognathia HP:0000347; sagging cheeks HP:0034273 (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 5-8).

Cutaneous / connective tissue - Hyperextensible skin HP:0000974; cutis laxa HP:0000973; velvety skin texture (phenotyped in cohort tables) (beyens2018arterialtortuositysyndrome pages 8-9).

Musculoskeletal - Joint hypermobility HP:0001382; pectus excavatum HP:0000767; scoliosis HP:0002650; pes planus HP:0001763; pes valgus HP:0008081 (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 5-8).

Ocular - Myopia HP:0000545; keratoconus HP:0000563; keratoglobus (as reported in cohort tables); exotropia HP:0000577; myopic astigmatism HP:0500041 (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 5-8).

Hernias / GI - Diaphragmatic hernia HP:0000776; inguinal hernia HP:0000023; gastroesophageal reflux disease (GERD) (reported in cohort summaries) (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 5-8).

Genitourinary / renal - Dilatation of renal pelvis HP:0010946; congenital megaureter HP:0008676; cryptorchidism HP:0000028; urogenital abnormalities (reported at cohort level) (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 5-8).

Neurologic / imaging-associated findings - Intracranial/cerebrovascular tortuosity HP:0005116 (vascular HPO); corpus callosum hypoplasia HP:0002079; temporal cortical atrophy HP:0007112 in individual cases (esmelvilomara2023arterialtortuositysyndromea pages 5-8).

3.4 Quality of life impact

No validated QoL instrument outcomes (e.g., SF-36/EQ-5D) were reported in the retrieved ATS-specific sources. However, vascular stenosis (especially pulmonary arteries) can produce major functional limitation via right ventricular hypertension and reduced exercise tolerance (alshair2024totalpulmonaryarterial pages 2-5).

4. Genetic / molecular information

4.1 Causal gene

  • SLC2A10 (GLUT10) is the established causal gene for ATS (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5).

4.2 Pathogenic variants (examples from recent and key studies)

  • c.510G>A (p.Trp170Ter) (homozygous) in a consanguineous sibling set (esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndromea pages 5-8).
  • c.417T>A (p.Tyr139Ter) (pathogenic) with c.899T>G (p.Leu300Trp) (novel missense, deleterious prediction) in compound heterozygosity (esmelvilomara2023arterialtortuositysyndromea pages 1-5).
  • c.243C>G (p.Ser81Arg) (homozygous) in 21 Qatari patients; reported in association with relatively mild outcomes and no mortality in that cohort (rahmath2025understandingthespectrum pages 4-6).

Variant interpretation framework: The 2022/2023 series describes ACMG-guideline-based classification and segregation testing (Sanger) after exome sequencing (esmelvilomara2023arterialtortuositysyndromea pages 1-5).

4.3 Modifier genes / epigenetics

  • No validated modifier genes were identified in the retrieved sources.
  • Epigenetic regulation is discussed as a mechanistic hypothesis (via dioxygenases and demethylation biology), but disease-specific epigenomic signatures were not provided (esmelvilomara2023arterialtortuositysyndromea pages 1-5).

4.4 Chromosomal abnormalities

  • Not a typical feature; ATS is primarily monogenic due to SLC2A10 biallelic variants in the sources reviewed.

5. Environmental information

ATS is a Mendelian disorder; no specific toxins, lifestyle factors, or infectious triggers were established as causal or modifying factors in the retrieved sources.

6. Mechanism / pathophysiology (causal chain)

6.1 Proposed molecular mechanism (current understanding)

A convergent model from cohort and case-series sources is: 1) SLC2A10 (GLUT10) deficiency → perturbed intracellular handling of dehydroascorbic acid/ascorbate (hypothesis) (esmelvilomara2023arterialtortuositysyndromea pages 1-5, beyens2018arterialtortuositysyndrome pages 2-4). 2) In the endoplasmic reticulum, reduced ascorbate cofactor availability may impair prolyl/lysyl hydroxylase activity and collagen/elastin maturation/crosslinking (esmelvilomara2023arterialtortuositysyndromea pages 1-5). 3) In mitochondria, altered ascorbate biology may impair redox homeostasis and reactive oxygen species scavenging (esmelvilomara2023arterialtortuositysyndromea pages 1-5, beyens2018arterialtortuositysyndrome pages 2-4). 4) These perturbations contribute to extracellular matrix (ECM) homeostasis defects and elastic lamellar integrity loss, leading to fragmentation of elastic fibers/lamellae in arterial walls (beyens2018arterialtortuositysyndrome pages 1-2, beyens2018arterialtortuositysyndrome pages 2-4). 5) Structural arterial wall weakness + abnormal remodeling → arterial elongation/tortuosity, stenosis (potentially via smooth muscle proliferation), and variable aneurysm risk (beyens2018arterialtortuositysyndrome pages 8-9, beyens2018arterialtortuositysyndrome pages 1-2).

6.2 TGF-β signaling

  • TGF-β pathway involvement is described as uncertain/complex. One cohort reports that “skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling” (immunohistochemistry for pSMAD2/CTGF), while other hypotheses link GLUT10/DHA to TGF-β upregulation (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5).
  • A zebrafish morpholino model is referenced as suggesting reduced TGF-β signaling during early development (beyens2018arterialtortuositysyndrome pages 2-4).

6.3 Tissue pathology (human)

  • Skin and vascular biopsies show fragmented elastic fibers and increased collagen deposition; EM demonstrates a fragmented elastin core with peripheral microfibrils of random directionality (beyens2018arterialtortuositysyndrome pages 1-2).

6.4 Suggested ontology annotations

GO biological processes (examples): - extracellular matrix organization (GO) - elastic fiber assembly (GO) - collagen fibril organization (GO) - response to oxidative stress (GO) - transforming growth factor beta receptor signaling pathway (GO; mechanistic hypothesis/uncertain directionality)

Cell types (CL, examples): - vascular smooth muscle cell (CL) - endothelial cell (CL) - fibroblast (CL)

Anatomy (UBERON, examples): - aorta (UBERON) - pulmonary artery (UBERON) - carotid artery / cerebral arteries (UBERON) - renal artery (UBERON)

Chemical entities (ChEBI, examples): - ascorbic acid (vitamin C) / dehydroascorbic acid (ChEBI)

7. Anatomical structures affected

7.1 Organ/system level

  • Primary system: cardiovascular (aorta and medium-sized arteries; pulmonary arteries; supra-aortic and cerebrovascular vessels commonly involved) (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 5-8).
  • Secondary systems: ocular (myopia/keratoconus/keratoglobus), musculoskeletal (hypermobility, pectus, scoliosis), skin/connective tissue, GI (hernia/GERD), and GU (urogenital anomalies) (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 5-8).

7.2 Imaging-based localization (real-world)

Classic radiologic patterns include markedly tortuous great vessels and pulmonary artery branching signs (“V/inverted V”), visualized by CTA/MRA (kumar2021arterialtortuositysyndrome media cf1c0f36, kumar2021arterialtortuositysyndrome media 75462c90).

8. Temporal development

  • Onset: often congenital/neonatal to childhood; pulmonary artery stenosis can present as a newborn and progress to require intervention (alshair2024totalpulmonaryarterial pages 1-2, alshair2024totalpulmonaryarterial pages 2-5).
  • Progression/course: variable; later cohorts indicate many individuals survive beyond early childhood, but early aneurysm/stenosis surveillance is recommended (beyens2018arterialtortuositysyndrome pages 1-2).

9. Inheritance and population

  • Inheritance: autosomal recessive (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5).
  • Consanguinity: 24/48 (50%) in one large cohort/review; indicates strong enrichment in consanguineous pedigrees (beyens2018arterialtortuositysyndrome pages 8-9).
  • Population/variant distribution: A homozygous p.Ser81Arg cohort in Qatar suggests a regional/founder contribution (rahmath2025understandingthespectrum pages 4-6).
  • Prevalence/incidence: incidence cited as <1:1,000,000 live births in a recent case series; reliable prevalence estimates are unavailable (esmelvilomara2023arterialtortuositysyndromea pages 1-5).
  • Carrier frequency: not provided in retrieved texts (requires gnomAD/other population databases).

10. Diagnostics

10.1 Clinical suspicion

Syndromic pattern recognition—arterial tortuosity with characteristic craniofacial/connective tissue findings and hernias—should prompt genetic evaluation (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 1-5).

10.2 Imaging (current applications)

  • CTA/MRA are central to diagnosis and longitudinal surveillance for tortuosity, stenoses, and aneurysms (alkooheji2025radiologicdiagnosisof pages 5-6).
  • Imaging hallmarks and signs: meandering vessel sign, cluster-of-vessels sign, aortic elongation sign, and pulmonary artery “V/inverted V” signs are described in radiology-focused case literature; representative CTA figures demonstrating these findings were retrieved (alkooheji2025radiologicdiagnosisof pages 5-6, kumar2021arterialtortuositysyndrome media cf1c0f36, kumar2021arterialtortuositysyndrome media 75462c90).

10.3 Recommended baseline evaluation (expert practice from cohort study)

A large ATS cohort recommends baseline evaluation including: - detailed clinical exam, - echocardiography, - “head-to-pelvis” MR angiography, - ophthalmologic exam with keratometry, - renal artery ultrasound (beyens2018arterialtortuositysyndrome pages 8-9).

10.4 Genetic testing strategy

  • Preferred: sequencing of SLC2A10 (single gene or CTD/aortopathy panels) with CNV assessment and segregation testing as needed (esmelvilomara2023arterialtortuositysyndromea pages 1-5).
  • Real-world implementation: broader aortopathy/HTAD pipelines using NGS panel testing or WES can identify compound heterozygous SLC2A10 variants and enable genotype–phenotype correlation workups (butnariu2024identificationofgenetic pages 1-2).

10.5 Differential diagnosis

Key differentials for arterial tortuosity with syndromic features include: - Loeys–Dietz syndrome, Marfan syndrome, vascular Ehlers–Danlos syndrome, cutis laxa, and homocystinuria (alkooheji2025radiologicdiagnosisof pages 5-6).

11. Outcome / prognosis

  • Mortality and survival: Early literature cited mortality up to 40% before age 5, but later cohorts report a milder overall course (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5). A 21-patient cohort with homozygous p.Ser81Arg reported no mortality (rahmath2025understandingthespectrum pages 4-6).
  • Major morbidity drivers: arterial stenoses (especially pulmonary), aneurysm formation in a subset, and ischemic events; however, a large 2018 cohort observed 0 dissections among those tabulated (beyens2018arterialtortuositysyndrome pages 8-9).

12. Treatment

12.1 Pharmacotherapy / medical management

  • Beta-adrenergic blockade is used empirically to reduce hemodynamic stress on arterial walls; efficacy is not established and practice is largely extrapolated from other aortopathies (esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndrome pages 8-11).

MAXO suggestions (examples): beta-adrenergic antagonist therapy; cardiovascular surveillance.

12.2 Surgical and interventional management (real-world implementation)

A 2024 surgical case illustrates management of severe pulmonary artery stenosis in ATS: - Preoperative echo gradients: LPA 73 mmHg (4.3 m/s); RPA 46 mmHg (3.4 m/s) with right ventricular hypertension; surgical reconstruction performed at age 2 (alshair2024totalpulmonaryarterial pages 1-2). - Postoperative: branch PA gradients ~20 mmHg (alshair2024totalpulmonaryarterial pages 1-2). - Residual proximal LPA stenosis was treated via balloon angioplasty (8×40 mm) with peak gradient reduced from ~25 mmHg to 14 mmHg (alshair2024totalpulmonaryarterial pages 2-5).

MAXO suggestions (examples): pulmonary artery reconstruction; balloon angioplasty; perioperative cardiopulmonary bypass.

12.3 Experimental / clinical trials

No ATS-specific interventional trials were retrieved. A large observational aortopathy biorepository/genetics study explicitly includes ATS among conditions studied: - NCT03440697 (Yale University; first posted 2018-02-22, last update posted 2026-02-13; start 2015-12-10; estimated completion 2030-12-31) (NCT03440697 chunk 1).

13. Prevention

  • Primary prevention: For autosomal recessive ATS, the practical prevention lever is genetic counseling and reproductive risk reduction in high-risk families/communities; the Qatari cohort emphasizes counseling aimed at preventing cousin marriage (consanguinity) to reduce disease occurrence (rahmath2025understandingthespectrum pages 4-6).
  • Secondary/tertiary prevention: structured imaging surveillance and blood pressure management to prevent complications (expert-opinion driven) (alkooheji2025radiologicdiagnosisof pages 5-6, beyens2018arterialtortuositysyndrome pages 8-9).

14. Other species / natural disease

No naturally occurring ATS orthologous disease in other species was identified in the retrieved sources.

15. Model organisms

  • A zebrafish morpholino model is referenced as suggesting altered (reduced) TGF-β signaling during early development, but detailed model characterization was not retrievable within the available text excerpts (beyens2018arterialtortuositysyndrome pages 2-4).

Expert opinions and analysis (authoritative synthesis)

  • Guidelines gap: Multiple sources explicitly note that ATS natural history remains incompletely studied and that formal clinical practice guidelines are lacking, so management relies heavily on expert opinion and extrapolation (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5).
  • Key clinical priority (consensus across sources): early identification of stenoses/aneurysms and longitudinal imaging surveillance (head-to-pelvis vascular imaging) is repeatedly emphasized (beyens2018arterialtortuositysyndrome pages 1-2, beyens2018arterialtortuositysyndrome pages 8-9, alkooheji2025radiologicdiagnosisof pages 5-6).
  • Mechanistic uncertainty: authoritative cohort work shows strong tissue-level ECM pathology, while molecular pathway attribution (e.g., directionality of TGF-β signaling changes) remains unresolved and may be context-dependent (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5).

Statistics and data highlights (recent and landmark)

  • Consanguinity: 24/48 (50%) in Beyens cohort/review (2018) (beyens2018arterialtortuositysyndrome pages 8-9).
  • Aortic tortuosity: 37/41 (90%) in Beyens (2018) and 21/21 (100%) in Qatari cohort (2025) (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6).
  • Pulmonary artery stenosis: 23/42 (55%) in Beyens (2018) (beyens2018arterialtortuositysyndrome pages 8-9).
  • Aortic root aneurysm: 9/42 (21%) in Beyens (2018) vs 2/21 (9%) in Qatari cohort (2025) (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6).
  • Arterial dissections: 0/37 in Beyens tabulated cohort (2018) (beyens2018arterialtortuositysyndrome pages 8-9).
  • Intervention outcomes (case data, 2024): marked reduction in pulmonary artery gradients after reconstruction and ballooning (alshair2024totalpulmonaryarterial pages 1-2, alshair2024totalpulmonaryarterial pages 2-5).

Notes on citation requirements (PMID availability)

The retrieved full-text sources in this run provided DOIs/URLs and detailed data but did not expose PubMed IDs within the accessible text. For knowledge-base ingestion requiring PMIDs, the recommended next step is to map these DOIs to PMIDs via PubMed/NCBI records during curation.

References

  1. (beyens2018arterialtortuositysyndrome pages 1-2): Aude Beyens, Juliette Albuisson, Annekatrien Boel, Mazen Al-Essa, Waheed Al-Manea, Damien Bonnet, Ozlem Bostan, Odile Boute, Tiffany Busa, Nathalie Canham, Ergun Cil, Paul J. Coucke, Margot A. Cousin, Majed Dasouki, Julie De Backer, Anne De Paepe, Sofie De Schepper, Deepthi De Silva, Koenraad Devriendt, Inge De Wandele, David R. Deyle, Harry Dietz, Sophie Dupuis-Girod, Eudice Fontenot, Björn Fischer-Zirnsak, Alper Gezdirici, Jamal Ghoumid, Fabienne Giuliano, Neus Baena Diéz, Mohammed Z. Haider, Joshua S. Hardin, Xavier Jeunemaitre, Eric W. Klee, Uwe Kornak, Manuel F. Landecho, Anne Legrand, Bart Loeys, Stanislas Lyonnet, Helen Michael, Pamela Moceri, Shehla Mohammed, Laura Muiño-Mosquera, Sheela Nampoothiri, Karin Pichler, Katrina Prescott, Anna Rajeb, Maria Ramos-Arroyo, Massimiliano Rossi, Mustafa Salih, Mohammed Z. Seidahmed, Elise Schaefer, Elisabeth Steichen-Gersdorf, Sehime Temel, Fahrettin Uysal, Marine Vanhomwegen, Lut Van Laer, Lionel Van Maldergem, David Warner, Andy Willaert, Tom R. Collins, Andrea Taylor, Elaine C. Davis, Yuri Zarate, and Bert Callewaert. Arterial tortuosity syndrome: 40 new families and literature review. Genetics in Medicine, 20:1236-1245, Oct 2018. URL: https://doi.org/10.1038/gim.2017.253, doi:10.1038/gim.2017.253. This article has 113 citations and is from a highest quality peer-reviewed journal.

  2. (esmelvilomara2023arterialtortuositysyndromea pages 1-5): Roger Esmel-Vilomara, Irene Valenzuela, Lucía Riaza, Benjamín Rodríguez-Santiago, Ferran Rosés-Noguer, Susana Boronat, and Anna Sabaté-Rotés. Arterial tortuosity syndrome: phenotypic features and cardiovascular manifestations in 4 newly identified patients. European journal of medical genetics, pages 104823, Aug 2023. URL: https://doi.org/10.1016/j.ejmg.2023.104823, doi:10.1016/j.ejmg.2023.104823. This article has 1 citations and is from a peer-reviewed journal.

  3. (beyens2018arterialtortuositysyndrome pages 8-9): Aude Beyens, Juliette Albuisson, Annekatrien Boel, Mazen Al-Essa, Waheed Al-Manea, Damien Bonnet, Ozlem Bostan, Odile Boute, Tiffany Busa, Nathalie Canham, Ergun Cil, Paul J. Coucke, Margot A. Cousin, Majed Dasouki, Julie De Backer, Anne De Paepe, Sofie De Schepper, Deepthi De Silva, Koenraad Devriendt, Inge De Wandele, David R. Deyle, Harry Dietz, Sophie Dupuis-Girod, Eudice Fontenot, Björn Fischer-Zirnsak, Alper Gezdirici, Jamal Ghoumid, Fabienne Giuliano, Neus Baena Diéz, Mohammed Z. Haider, Joshua S. Hardin, Xavier Jeunemaitre, Eric W. Klee, Uwe Kornak, Manuel F. Landecho, Anne Legrand, Bart Loeys, Stanislas Lyonnet, Helen Michael, Pamela Moceri, Shehla Mohammed, Laura Muiño-Mosquera, Sheela Nampoothiri, Karin Pichler, Katrina Prescott, Anna Rajeb, Maria Ramos-Arroyo, Massimiliano Rossi, Mustafa Salih, Mohammed Z. Seidahmed, Elise Schaefer, Elisabeth Steichen-Gersdorf, Sehime Temel, Fahrettin Uysal, Marine Vanhomwegen, Lut Van Laer, Lionel Van Maldergem, David Warner, Andy Willaert, Tom R. Collins, Andrea Taylor, Elaine C. Davis, Yuri Zarate, and Bert Callewaert. Arterial tortuosity syndrome: 40 new families and literature review. Genetics in Medicine, 20:1236-1245, Oct 2018. URL: https://doi.org/10.1038/gim.2017.253, doi:10.1038/gim.2017.253. This article has 113 citations and is from a highest quality peer-reviewed journal.

  4. (esmelvilomara2023arterialtortuositysyndromea pages 5-8): Roger Esmel-Vilomara, Irene Valenzuela, Lucía Riaza, Benjamín Rodríguez-Santiago, Ferran Rosés-Noguer, Susana Boronat, and Anna Sabaté-Rotés. Arterial tortuosity syndrome: phenotypic features and cardiovascular manifestations in 4 newly identified patients. European journal of medical genetics, pages 104823, Aug 2023. URL: https://doi.org/10.1016/j.ejmg.2023.104823, doi:10.1016/j.ejmg.2023.104823. This article has 1 citations and is from a peer-reviewed journal.

  5. (butnariu2024identificationofgenetic pages 1-2): Lăcrămioara Ionela Butnariu, Georgiana Russu, Alina-Costina Luca, Constantin Sandu, Laura Mihaela Trandafir, Ioana Vasiliu, Setalia Popa, Gabriela Ghiga, Laura Bălănescu, and Elena Țarcă. Identification of genetic variants associated with hereditary thoracic aortic diseases (htads) using next generation sequencing (ngs) technology and genotype–phenotype correlations. International Journal of Molecular Sciences, 25:11173, Oct 2024. URL: https://doi.org/10.3390/ijms252011173, doi:10.3390/ijms252011173. This article has 4 citations.

  6. (rahmath2025understandingthespectrum pages 4-6): Muhammed Riyas K. Rahmath, Haytham Ibrahim, Muhammad Faiyaz-Ul-Haque, Zafar Nawaz, Ahmad Zitoun, Ahmed Hussein, Ahmed Sadek, Ayman El-Menyar, Reema Kamal, Hassan Al-Thani, and Gulab Sher. Understanding the spectrum of mild clinical outcomes and novel findings in arterial tortuosity syndrome among qatari patients: implications of slc2a10 mutation. Biomedicines, 13:159, Jan 2025. URL: https://doi.org/10.3390/biomedicines13010159, doi:10.3390/biomedicines13010159. This article has 2 citations.

  7. (beyens2018arterialtortuositysyndrome pages 2-4): Aude Beyens, Juliette Albuisson, Annekatrien Boel, Mazen Al-Essa, Waheed Al-Manea, Damien Bonnet, Ozlem Bostan, Odile Boute, Tiffany Busa, Nathalie Canham, Ergun Cil, Paul J. Coucke, Margot A. Cousin, Majed Dasouki, Julie De Backer, Anne De Paepe, Sofie De Schepper, Deepthi De Silva, Koenraad Devriendt, Inge De Wandele, David R. Deyle, Harry Dietz, Sophie Dupuis-Girod, Eudice Fontenot, Björn Fischer-Zirnsak, Alper Gezdirici, Jamal Ghoumid, Fabienne Giuliano, Neus Baena Diéz, Mohammed Z. Haider, Joshua S. Hardin, Xavier Jeunemaitre, Eric W. Klee, Uwe Kornak, Manuel F. Landecho, Anne Legrand, Bart Loeys, Stanislas Lyonnet, Helen Michael, Pamela Moceri, Shehla Mohammed, Laura Muiño-Mosquera, Sheela Nampoothiri, Karin Pichler, Katrina Prescott, Anna Rajeb, Maria Ramos-Arroyo, Massimiliano Rossi, Mustafa Salih, Mohammed Z. Seidahmed, Elise Schaefer, Elisabeth Steichen-Gersdorf, Sehime Temel, Fahrettin Uysal, Marine Vanhomwegen, Lut Van Laer, Lionel Van Maldergem, David Warner, Andy Willaert, Tom R. Collins, Andrea Taylor, Elaine C. Davis, Yuri Zarate, and Bert Callewaert. Arterial tortuosity syndrome: 40 new families and literature review. Genetics in Medicine, 20:1236-1245, Oct 2018. URL: https://doi.org/10.1038/gim.2017.253, doi:10.1038/gim.2017.253. This article has 113 citations and is from a highest quality peer-reviewed journal.

  8. (alshair2024totalpulmonaryarterial pages 1-2): Fahad M. Alshair, Amal S. Alsulami, Mohammad S. Shihata, Osman O. Alradi, Ragab S. Debis, Abdullah H. Baghaffar, and Mazin A. Fatani. Total pulmonary arterial reconstruction in a patient with arterial tortuosity syndrome affecting the pulmonary artery: a case report and review of the literature. Journal of Cardiothoracic Surgery, Jul 2024. URL: https://doi.org/10.1186/s13019-024-02905-6, doi:10.1186/s13019-024-02905-6. This article has 2 citations and is from a peer-reviewed journal.

  9. (alshair2024totalpulmonaryarterial pages 2-5): Fahad M. Alshair, Amal S. Alsulami, Mohammad S. Shihata, Osman O. Alradi, Ragab S. Debis, Abdullah H. Baghaffar, and Mazin A. Fatani. Total pulmonary arterial reconstruction in a patient with arterial tortuosity syndrome affecting the pulmonary artery: a case report and review of the literature. Journal of Cardiothoracic Surgery, Jul 2024. URL: https://doi.org/10.1186/s13019-024-02905-6, doi:10.1186/s13019-024-02905-6. This article has 2 citations and is from a peer-reviewed journal.

  10. (esmelvilomara2023arterialtortuositysyndrome pages 8-11): Roger Esmel-Vilomara, Irene Valenzuela, Lucia Riaza, Benjamin Rodriguez-Santiago, Ferran Roses-Noguer, Susana Boronat, and Anna Sabate-Rotes. Arterial tortuosity syndrome: phenotypic and cardiovascular features in 4 newly identified patients. Feb 2023. URL: https://doi.org/10.21203/rs.3.rs-2594978/v1, doi:10.21203/rs.3.rs-2594978/v1.

  11. (alkooheji2025radiologicdiagnosisof pages 5-6): Amina Salah Alkooheji, Neale Nicola Kalis, G. Koç, Suad R. Alamer, and Vimalarani Arulselvam. Radiologic diagnosis of arterial tortuosity syndrome in a pediatric patient: a case report. Cureus, Dec 2025. URL: https://doi.org/10.7759/cureus.99989, doi:10.7759/cureus.99989. This article has 0 citations.

  12. (kumar2021arterialtortuositysyndrome media cf1c0f36): Parveen Kumar. Arterial tortuosity syndrome: a case report and literature review. Cardiovascular Imaging Asia, 5:9, Jan 2021. URL: https://doi.org/10.22468/cvia.2020.00129, doi:10.22468/cvia.2020.00129. This article has 4 citations.

  13. (kumar2021arterialtortuositysyndrome media 75462c90): Parveen Kumar. Arterial tortuosity syndrome: a case report and literature review. Cardiovascular Imaging Asia, 5:9, Jan 2021. URL: https://doi.org/10.22468/cvia.2020.00129, doi:10.22468/cvia.2020.00129. This article has 4 citations.

  14. (NCT03440697 chunk 1): Pathogenetic Basis of Aortopathy and Aortic Valve Disease. Yale University. 2015. ClinicalTrials.gov Identifier: NCT03440697

OpenScientist ▸
1. Disease Information
openscientist-autonomous 26 citations 2026-05-05T07:40:59.484883

1. Disease Information

Overview

Arterial Tortuosity Syndrome is a rare, monogenic connective tissue disorder primarily affecting the vascular system. It was first described clinically approximately 55 years ago (Ertugrul, 1967) and its genetic basis was elucidated in 2006 when Coucke et al. identified mutations in SLC2A10 as the causative defect (PMID: 16550171). ATS is characterized by generalized tortuosity, elongation, and stenosis of large and medium-sized arteries, with a propensity for aneurysm formation. Patients also display connective tissue features overlapping with Ehlers-Danlos syndromes and Loeys-Dietz syndrome.

Key Identifiers

Database Identifier
OMIM #208050
Orphanet ORPHA:3342
MONDO MONDO:0009005
ICD-10 Q27.8 (Other specified congenital malformations of peripheral vascular system)
MeSH C537373
Gene (HGNC) SLC2A10 (HGNC:13445)
NCBI Gene 81031
UniProt O95528 (GTR10_HUMAN)
Chromosomal Location 20q13.12

Synonyms and Alternative Names

  • Arterial Tortuosity Syndrome (ATS)
  • Tortuosity of systemic arteries
  • Arterial tortuosity (MeSH)

Information Sources

Information is derived from aggregated disease-level resources (OMIM, Orphanet, GeneReviews) and individual case reports/series from published literature. The largest systematic cohort study encompasses 102 patients from 92 families (Beyens et al. 2018, PMID: 29323665). A 2025 longitudinal study (CLARITY) provides the most recent prospective cardiovascular data on 14 patients (PMID: 40613586).

2. Etiology

Disease Causal Factors

ATS is a monogenic (Mendelian) disorder caused by biallelic (homozygous or compound heterozygous) loss-of-function mutations in the SLC2A10 gene. There are no known environmental or infectious causes.

As stated in the original discovery paper: "Mutations in one of these genes, SLC2A10, encoding the facilitative glucose transporter GLUT10, were identified in six ATS families. GLUT10 deficiency is associated with upregulation of the TGFbeta pathway in the arterial wall" (PMID: 16550171).

Risk Factors

Genetic Risk Factors

  • Biallelic pathogenic variants in SLC2A10: The sole known cause. Over 30 distinct pathogenic variants have been reported across different ethnic groups.
  • Consanguinity: Significantly increases risk given autosomal recessive inheritance. Multiple reported families are consanguineous, particularly in Middle Eastern, North African, South Asian, and Mediterranean populations (PMID: 29323665; PMID: 37619836).
  • Carrier status in parents: Both parents must be carriers (heterozygous) for affected offspring; 25% recurrence risk per pregnancy.

Environmental Risk Factors

  • No environmental risk factors have been identified for ATS development. As a fully penetrant Mendelian disorder, the disease is determined by genotype.

Protective Factors

Genetic Protective Factors

  • No specific modifier alleles or protective variants have been identified in humans.
  • Notably, the ability of mice to endogenously synthesize ascorbic acid (via L-gulonolactone oxidase, encoded by Gulo) appears to protect Slc2a10 knockout mice from the full ATS phenotype. Humans lack functional GULO and cannot synthesize ascorbate, contributing to disease severity (PMID: 32307537).

Environmental Protective Factors

  • No confirmed environmental protective factors. It has been hypothesized that adequate ascorbic acid intake may have modifying effects given the ascorbate compartmentalization hypothesis, but this has not been clinically validated.

Gene-Environment Interactions

The interplay between GLUT10 deficiency and the human inability to synthesize ascorbic acid represents a critical gene–environment (nutrient) interaction that likely determines disease severity. Mice with intact ascorbic acid synthesis via Gulo are protected from the full disease phenotype even when lacking GLUT10, while Gulo;Slc2a10 double knockout mice that cannot synthesize ascorbate show compromised ECM and mitochondrial defects: "Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined" (PMID: 32307537).

3. Phenotypes

Cardiovascular Phenotypes

Phenotype HPO Term Frequency Onset Severity Progression
Arterial tortuosity (large/medium arteries) HP:0005116 >95% Congenital/neonatal Moderate-severe Stable to progressive
Aortic root dilation/aneurysm HP:0002616 ~71.4% (CLARITY) Infancy-childhood Variable Progressive (stable z-scores)
Pulmonary artery stenosis HP:0004415 Frequent Infancy Moderate-severe May require intervention
Aortic coarctation HP:0001680 Occasional Congenital Severe May require surgery
Intracranial arterial tortuosity HP:0005116 Common Congenital Variable Stable
Ischemic stroke HP:0002140 Rare Childhood-young adult Severe Episodic
Neonatal intracranial bleeding HP:0007420 Rare Neonatal Severe Acute

The CLARITY longitudinal study reported that "aortic root dilation was present in 71.4%; branch pulmonary artery (BPA) dimensions were mixed between dilated and hypoplastic" (PMID: 40613586). The largest cohort study documented: "Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation" (PMID: 29323665).

Connective Tissue Phenotypes

Phenotype HPO Term Frequency Onset Severity
Skin hyperextensibility HP:0001030 Very frequent Congenital Mild-moderate
Joint hypermobility HP:0001382 Very frequent Congenital Mild-moderate
Dysmorphic facial features HP:0001999 Frequent Congenital Mild
Keratoconus HP:0000563 Occasional Childhood-adolescence Progressive
Diaphragmatic hernia HP:0000776 Frequent (~15-20%) Congenital/neonatal Severe
Inguinal/umbilical hernia HP:0000023 / HP:0001537 Frequent Infancy Mild-moderate
Skeletal abnormalities HP:0000924 Frequent Childhood Variable
Microcephaly HP:0000252 Occasional Congenital Mild
Congenital contractures HP:0002803 Occasional Congenital Variable

Respiratory Phenotypes

Phenotype HPO Term Frequency Onset Severity
Infant respiratory distress syndrome (IRDS) HP:0002643 Frequent Neonatal Severe
Dyspnea/cyanosis (from PA involvement) HP:0002094 Occasional Infancy Variable

Other Rare Phenotypes

Phenotype HPO Term Frequency
Complex uropathy HP:0000079 Rare
Bilateral hip dislocation HP:0001374 Rare
Stomach displacement into thorax HP:0002579 Rare
Gastric perforation — Very rare

"A patient with microcephaly and a complex uropathy and two cases with diaphragmatic hernia are noticed." (PMID: 37619836)

Quality of Life Impact

ATS significantly impacts quality of life, particularly in childhood, due to: - Cardiovascular surveillance burden (repeated imaging, echocardiography) - Potential need for surgical interventions (pulmonary artery reconstruction, aortopexy) - Joint laxity affecting mobility and musculoskeletal function - Risk of cerebrovascular events limiting physical activity - Respiratory complications in the neonatal period - Psychosocial burden of a chronic rare disease

No formal QoL studies (EQ-5D, SF-36, PROMIS) specific to ATS have been published. This represents a significant gap in the literature.

4. Genetic/Molecular Information

Causal Gene

  • Gene: SLC2A10 (Solute Carrier Family 2 Member 10)
  • HGNC ID: HGNC:13445
  • NCBI Gene ID: 81031
  • OMIM Gene: *606145
  • Chromosomal Location: 20q13.12
  • Protein: GLUT10 (Facilitative Glucose Transporter Member 10), 541 amino acids, 12 predicted transmembrane domains
  • UniProt: O95528

Pathogenic Variants

Variant Types Reported

ATS-causing variants span the full spectrum of loss-of-function mutations:

Variant (cDNA) Protein Change Type Population Reference
c.243C>G p.Ser81Arg (rs80358230) Missense Arab PMID: 36578839
c.173C>T p.Ala58Val Missense — PMID: 40027906
c.899T>G p.Leu300Trp Missense — PMID: 37619836
c.1309G>A p.Glu437Lys Missense — PMID: 31203799
c.417T>A p.Tyr139Ter Nonsense — PMID: 37619836
c.510G>A p.Trp170Ter Nonsense — PMID: 37619836
c.756C>A p.Cys252Ter Nonsense Kurdish PMID: 18818946

Additional frameshift and splice-site variants have been reported (see ClinVar entries for SLC2A10).

Variant Classification

  • All disease-causing variants are classified as pathogenic or likely pathogenic per ACMG/AMP guidelines.
  • The disorder shows strict genotype-phenotype correlation: biallelic loss-of-function variants are required for disease manifestation.

Allele Frequency

  • Pathogenic variants in SLC2A10 are extremely rare or absent in population databases (gnomAD, 1000 Genomes).
  • Some founder mutations are enriched in specific populations (e.g., p.Ser81Arg in Arab populations; PMID: 35302653).

Functional Consequences

All known pathogenic variants result in loss of function of GLUT10 through: - Premature protein truncation (nonsense, frameshift) - Misfolding or impaired membrane insertion (missense) - Loss of substrate transport activity - Re-expression of GLUT10 in patient fibroblasts rescues the cellular phenotype (PMID: 26376865)

All pathogenic variants are germline in origin. No somatic mutations have been reported.

Modifier Genes

No specific modifier genes have been identified in humans. However, the variable expressivity observed even among siblings with identical mutations suggests genetic modifiers or stochastic developmental factors influence disease severity. At the species level, GULO (L-gulonolactone oxidase) status serves as a major modifier — humans are pseudogene carriers (non-functional GULO), exacerbating GLUT10 deficiency effects compared to mice that retain functional Gulo (PMID: 32307537).

Epigenetic Information

No specific epigenetic modifications (DNA methylation, histone modifications, chromatin changes) have been described in ATS. Transcriptomic studies show dysregulation of genes involved in oxidative stress response and ECM homeostasis, but dedicated epigenomic profiling has not been performed.

Chromosomal Abnormalities

ATS is not caused by chromosomal abnormalities. No large-scale structural variants (aneuploidy, translocations, inversions) are associated with the disease. All causative mutations are point mutations or small indels within SLC2A10.

5. Environmental Information

Environmental Factors

ATS is a purely genetic disorder. No environmental toxins, radiation, pollution, or occupational exposures are known to cause or contribute to disease development.

Lifestyle Factors

While no lifestyle factors cause ATS, clinical management recommends: - Avoidance of contact sports and intense isometric exercise to reduce hemodynamic stress on weakened arterial walls - Blood pressure management to reduce risk of aneurysm progression - Adequate vitamin C intake may be theoretically important given the ascorbate compartmentalization hypothesis, but this remains clinically unvalidated

Infectious Agents

Not applicable. ATS is not caused or triggered by any infectious agent.

6. Mechanism / Pathophysiology

Overview: The Pathophysiological Cascade

The pathogenesis of ATS involves a multi-layered molecular cascade from the primary genetic defect to clinical manifestation:

SLC2A10 biallelic mutations
↓
GLUT10 protein loss-of-function
↓
Impaired dehydroascorbic acid (DAA) transport across endomembranes
↓
Reduced intracellular ascorbate in ER/mitochondria
↓
┌───────────────────┬────────────────────────┬──────────────────────┐
│                   │                        │                      │
▼                   ▼                        ▼                      ▼
Defective collagen  Impaired elastin     Oxidative stress     Mitochondrial
hydroxylation       assembly             (↑ ROS, ↑ lipid      dysfunction
(↓ prolyl/lysyl    (fragmented           peroxidation)        (compromised
hydroxylase         elastic fibers)      via altered PPARγ     respiration in
activity)                                                      VSMCs)
│                   │                        │                      │
└───────────────────┴────────────────────────┘                      │
    ↓                                               │
ECM disorganization                                         │
(↑ collagen deposition,                                     │
 ↓ elastic fiber integrity)                                 │
    ↓                                               │
Non-canonical TGF-β signaling  ←────────────────────────────┘
(αvβ3 integrin → p125FAK → p60Src → p38 MAPK)
    ↓
Vascular wall weakening
    ↓
Arterial tortuosity, elongation, stenosis, aneurysm

Molecular Pathways

TGF-β Signaling (GO:0007179)

The original discovery paper demonstrated "GLUT10 deficiency is associated with upregulation of the TGFbeta pathway in the arterial wall" (PMID: 16550171). However, subsequent work has significantly refined this understanding. In ATS fibroblasts, the primary TGF-β dysregulation occurs through a non-canonical pathway mediated by the αvβ3 integrin, involving p125FAK, p60Src, and p38 MAPK signaling, rather than the canonical SMAD2/3 pathway (PMID: 29587413; PMID: 26376865).

Importantly, histological analysis of end-stage skin and vascular tissue from ATS patients did not show increased canonical TGF-β signaling markers (pSMAD2/CTGF) (PMID: 29323665), and TGF-β signaling was unaltered in the Gulo;Slc2a10 double knockout mouse (PMID: 32307537). This suggests tissue-specific and temporal differences in TGF-β pathway involvement, and that canonical TGF-β upregulation may not be the primary driver of disease in all contexts.

Ascorbate Metabolism (GO:0019852)

GLUT10 has been confirmed as a DAA transporter: "The present results demonstrate that GLUT10 is a DAA transporter and DAA transport is diminished in the endomembranes of fibroblasts from ATS patients" (PMID: 27153185). Intracellular ascorbate is required as a cofactor for prolyl and lysyl hydroxylases that catalyze collagen cross-linking and for enzymes involved in elastin assembly. ATS has accordingly been characterized as an "ascorbate compartmentalization disorder" (PMID: 31621376; PMID: 32307537).

  • CHEBI Terms: CHEBI:29073 (L-ascorbic acid), CHEBI:17242 (dehydroascorbic acid)

Oxidative Stress (GO:0006979)

Studies on ATS fibroblasts demonstrated "a marked increase in ROS-induced lipid peroxidation sustained by altered PPARγ function, which contributes to the redox imbalance and the compensatory antioxidant activity of ALDH1A1" (PMID: 26376865). The oxidative stress is a direct consequence of impaired intracellular ascorbate, which normally serves as a major intracellular antioxidant.

Integrin Signaling (GO:0007229)

In ATS fibroblasts, the αvβ3 integrin is preferentially recruited due to loss of the fibronectin-ECM and its canonical α5β1 integrin receptor. This integrin activates downstream signaling through p125FAK, p60Src, and p38 MAPK, contributing to ECM disarray and altered cell behavior (PMID: 29587413).

Cellular Processes

Extracellular Matrix Organization (GO:0030198)

Electron microscopy of ATS skin biopsies revealed: "Large spaces were observed among the collagen fibrils…suggesting disorganization of the collagen structures. Furthermore, elastin fiber contents and their thickness are reduced…In small muscular arteries in the skin from ATS patients, discontinuous internal elastic lamina, lack of myofilaments, and disorganized medial smooth muscle cells with vacuolated cytoplasm are present" (PMID: 35302653). The largest cohort study confirmed: "EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality" (PMID: 29323665).

Mitochondrial Function (GO:0007005)

Zebrafish studies showed that "a large proportion of the genes, which were specifically dysregulated after glut10 depletion gene and not by tgfbr1 inhibition, play a major role in mitochondrial function" (PMID: 22116938). The Gulo;Slc2a10 double knockout mouse confirmed compromised mitochondrial respiration in smooth muscle cells (PMID: 32307537).

Protein Dysfunction

GLUT10 is a 541-amino acid transmembrane protein with 12 predicted transmembrane domains. In silico modeling identified potential substrate binding site residues including PRO531, GLU507, GLU437, and TRP432, with a highly recurrent point mutation (c.1309G>A, p.Glu437Lys) located directly in the predicted binding site region (PMID: 31203799).

Metabolic Changes

  • Perturbation of pathways controlling cell energy balance (PMID: 26376865)
  • Altered glucose metabolism (GLUT10 belongs to the glucose transporter family, though its primary in vivo substrate appears to be DAA)
  • Impaired ascorbate-dependent hydroxylation reactions affecting collagen and elastin biosynthesis

Immune System Involvement

No primary immune dysfunction is described in ATS. Arterial wall inflammation may be secondary to ECM disruption and oxidative stress, but this has not been formally studied.

Tissue Damage Mechanisms

  • Oxidative stress: ROS-induced lipid peroxidation damaging vascular wall
  • Mechanical stress: Turbulent blood flow through tortuous vessels increases shear stress
  • Elastic fiber fragmentation: Progressive weakening of arterial wall integrity
  • Fibrosis: Compensatory collagen deposition with disorganized architecture

Biochemical Abnormalities

  • Transporter dysfunction: Loss of GLUT10-mediated DAA transport across endomembranes
  • Functional enzyme deficiency: Impaired intracellular ascorbate-dependent enzymes (prolyl 4-hydroxylase, lysyl hydroxylase) due to substrate compartmentalization failure (not systemic enzyme deficiency)

Molecular Profiling

  • Transcriptomics: Gene expression profiling of ATS fibroblasts revealed dysregulation of genes involved in TGF-β signaling, ECM homeostasis, cell energy balance, and oxidative stress response (PMID: 26376865). Zebrafish transcriptome analysis showed high correlation between slc2a10 knockdown and tgfbr1 inhibition profiles, plus specific dysregulation of mitochondrial function genes (PMID: 22116938).
  • Proteomics/Metabolomics/Lipidomics: No systematic studies have been published.
  • Single-cell analysis, spatial transcriptomics, multi-omics: Not yet applied to ATS.
  • Functional genomics screens: Not reported for ATS.

Key GO Terms for Biological Processes

  • GO:0030198 — Extracellular matrix organization
  • GO:0007179 — Transforming growth factor beta receptor signaling pathway
  • GO:0006979 — Response to oxidative stress
  • GO:0007229 — Integrin-mediated signaling pathway
  • GO:0007005 — Mitochondrion organization
  • GO:0019852 — L-ascorbic acid metabolic process
  • GO:0071560 — Cellular response to transforming growth factor beta stimulus

Key Cell Types Involved

Cell Type CL Term Role in Pathogenesis
Vascular smooth muscle cell CL:0000359 Primary affected cell; mitochondrial dysfunction, ECM production defects, disorganized morphology
Fibroblast CL:0000057 Oxidative stress, non-canonical TGF-β signaling, ECM disarray, altered integrin signaling
Vascular endothelial cell CL:0002543 Altered angiogenesis, hemodynamic stress response

7. Anatomical Structures Affected

Organ Level

Primary Organs

Organ System Structures UBERON Term
Cardiovascular Aorta, pulmonary arteries, carotid arteries, subclavian arteries, intracranial arteries UBERON:0000947 (aorta), UBERON:0002012 (pulmonary artery)
Integumentary Skin (hyperextensibility) UBERON:0002097 (skin of body)
Musculoskeletal Joints (hypermobility), skeleton UBERON:0000982 (skeletal joint)

Secondary Organ Involvement

Organ System Structures Mechanism
Respiratory Lungs (IRDS), diaphragm (hernia) Connective tissue defect, pulmonary artery stenosis
Nervous Brain (stroke, intracranial bleeding) Cerebrovascular complications from tortuosity
Ocular Cornea (keratoconus) Connective tissue weakness
Gastrointestinal Stomach (perforation, displacement) Connective tissue defect
Urogenital Kidneys/ureters (uropathy) Connective tissue defect

Body systems involved: Cardiovascular (primary), musculoskeletal, integumentary, ocular, respiratory, gastrointestinal, nervous (secondary).

Tissue and Cell Level

  • Arterial tunica media (UBERON:0002036): Elastic fibers fragmented, smooth muscle cells disorganized with vacuolated cytoplasm, discontinuous internal elastic lamina, lack of myofilaments (PMID: 35302653)
  • Dermis: Collagen fibrils disorganized with large inter-fibrillar spaces; reduced elastin content and thickness
  • Connective tissue (UBERON:0002384): Systemic ECM disorganization

Specific cell populations targeted: - Vascular smooth muscle cells (CL:0000359): Disorganized, vacuolated, lacking myofilaments - Fibroblasts (CL:0000057): Altered ECM production, oxidative stress - Endothelial cells (CL:0002543): Secondary to vascular wall disruption

Subcellular Level

  • Endoplasmic reticulum (GO:0005783): Site of collagen hydroxylation requiring ascorbate; GLUT10 transports DHA across ER membranes
  • Mitochondria (GO:0005739): Compromised respiration in GLUT10-deficient cells
  • Extracellular matrix (GO:0031012): Fragmented elastic fibers, disorganized collagen
  • Plasma membrane (GO:0005886): Altered integrin signaling (αvβ3 vs. α5β1)
  • Endomembrane system (GO:0012505): Impaired DAA transport across endomembranes

Localization

  • Bilateral and generalized: Arterial tortuosity affects arteries throughout the body symmetrically
  • Predominantly supra-aortic involvement noted in some patients: "Regarding the vascular involvement, a predominant supra-aortic involvement stands out...All presented severe tortuosity of the intracranial arteries" (PMID: 37619836)
  • Specific UBERON terms: UBERON:0000947 (aorta), UBERON:0002012 (pulmonary artery), UBERON:0001624 (carotid artery), UBERON:0001533 (subclavian artery), UBERON:0003496 (head blood vessel)

8. Temporal Development

Onset

  • Typical age of onset: Congenital — arterial tortuosity is present from birth
  • HPO: HP:0003577 (Congenital onset)
  • Onset pattern: Congenital/chronic — the structural vascular defect is developmental, though clinical complications may present acutely
  • Prenatal detection is possible via ultrasound as early as 22 weeks' gestation: "Prenatal ultrasound scanning at 29 weeks of gestation of the first fetus showed obvious tortuous and elongated of the aortic arch, ductus arteriosus, left and right pulmonary arteries" (PMID: 34384376)
  • Clinical diagnosis typically occurs in infancy-early childhood (median diagnosis age 3.3 years per CLARITY study, PMID: 40613586)

Progression

  • Disease course: Chronic, lifelong
  • Progression rate: Variable; aortic dimensions increase with somatic growth but z-scores remain relatively stable
  • Disease course pattern: Progressive structural changes superimposed on a chronic baseline
  • Disease duration: Chronic lifelong; no remission

Critical period: The neonatal and infancy period (first 1-2 years of life) is the most critical for life-threatening events. As stated by Callewaert et al.: "Our data confirm that the cardiovascular prognosis in ATS is less severe than previously reported and that the first years of life are the most critical for possible life-threatening events" (PMID: 25373504).

Patterns

  • No spontaneous remission: ATS does not remit
  • Stability: After surviving infancy, many patients stabilize clinically. Some arterial stenoses may improve over time, though tortuosity is permanent.
  • Connective tissue features (joint laxity, skin hyperextensibility) persist lifelong
  • Keratoconus may progress during childhood/adolescence
  • Risk of cerebrovascular events may extend into young adulthood (PMID: 34847858)

9. Inheritance and Population

Epidemiology

  • Prevalence: Ultra-rare; estimated <1 per 1,000,000. Orphanet classifies prevalence as <1/1,000,000.
  • As of 2023, only ~106 individuals with genetically confirmed ATS had been reported worldwide (PMID: 37619836).
  • Incidence: Unknown; no population-based incidence data available.

Inheritance and Genetic Features

Feature Detail
Inheritance pattern Autosomal recessive (AR); HP:0000007
Penetrance Complete for vascular features (tortuosity) in individuals with biallelic variants
Expressivity Highly variable — even among siblings with identical mutations
Genetic anticipation Not observed (not a repeat expansion disorder)
Germline mosaicism Not documented, though theoretically possible
Consanguinity role Significant — many reported families are consanguineous
Carrier frequency Unknown; extremely low given disease rarity

"Arterial tortuosity syndrome (ATS) is a rare congenital disorder characterized by elongation and tortuosity of the aorta and mid-sized arteries. Additional features typical of connective tissue disorders are usually present, but the clinical presentation of the syndrome can extensively change." (PMID: 39827853)

Founder Effects

The p.Ser81Arg (c.243C>G, rs80358230) variant appears to be a founder mutation in Arab populations. Faiyaz-Ul-Haque et al. studied 48 patients with this specific mutation from Arab families (PMID: 35302653; PMID: 36578839). Enrichment of ATS cases in populations with high rates of consanguinity (Middle Eastern, North African, South Asian, Mediterranean) is well documented.

Population Demographics

  • Affected populations: Reported worldwide across diverse ethnic groups including Arab, Kurdish, Turkish, Italian, Macedonian, Indian, Japanese, Qatari, and European populations
  • Geographic distribution: Global, but clusters in regions with higher consanguinity rates
  • Sex ratio: Both sexes equally affected. In the CLARITY study, 64% were male (9/14), but the small sample size limits interpretation (PMID: 40613586).
  • Age distribution: Diagnosis typically in infancy-early childhood; some patients now diagnosed prenatally

10. Diagnostics

Clinical Tests

Imaging Studies (Primary Diagnostic Modality)

  • CT Angiography (CTA): Gold standard for demonstrating arterial tortuosity, elongation, stenosis, and aneurysm formation. Shows tortuosity of aorta, pulmonary arteries, carotid arteries, subclavian arteries, and intracranial vessels.
  • Echocardiography: Essential for monitoring aortic root dimensions and pulmonary artery gradients. Serial measurements allow z-score tracking.
  • MR Angiography (MRA): Non-ionizing alternative for vascular imaging, particularly useful in children and for intracranial vasculature.
  • Prenatal ultrasound: Can detect arterial tortuosity as early as 22 weeks' gestation. "The key points of prenatal ultrasound diagnosis of ATS are the elongation and tortuosity of the large and medium sized arteries" (PMID: 34384376).

Laboratory Tests

  • No specific blood biomarkers for ATS diagnosis or monitoring
  • Routine metabolic panel typically normal
  • No validated circulating biomarkers exist

Biopsy/Pathology Findings

Skin biopsy with electron microscopy shows disease-specific abnormalities: - Fragmented elastic fibers with fragmented elastin core - Peripheral mantle of microfibrils with random directionality - Disorganized collagen fibrils with increased inter-fibrillar spacing - In small muscular arteries: discontinuous internal elastic lamina, lack of myofilaments, disorganized medial smooth muscle cells with vacuolated cytoplasm (PMID: 35302653)

Genetic Testing

Recommended Approach

  1. First-line: Targeted SLC2A10 gene sequencing when ATS is clinically suspected
  2. Alternative: Connective tissue disorder / hereditary thoracic aortic disease (HTAD) gene panel including SLC2A10 alongside FBN1, TGFBR1/2, SMAD3, COL3A1, etc. (PMID: 39456956)
  3. Whole exome sequencing (WES): Useful when clinical presentation is atypical or broader differential needed. "Whole exome sequencing (WES) was performed eight months after birth, two heterozygous variants of SLC2A10 gene was detected in newborn and their father and mother, respectively" (PMID: 34384376)
  4. Whole genome sequencing (WGS): Also effective but not typically first-line
  5. Prenatal genetic testing: Available for families with known mutations (CVS, amniocentesis)

CMA, karyotyping, FISH, mitochondrial DNA testing, and repeat expansion testing are not applicable to ATS diagnosis.

Clinical Criteria and Differential Diagnosis

No formal standardized diagnostic criteria (e.g., Ghent-like criteria) exist for ATS. Diagnosis is based on: 1. Clinical features: Generalized arterial tortuosity on imaging + connective tissue features 2. Genetic confirmation: Biallelic pathogenic variants in SLC2A10

Key differential diagnoses:

Condition Distinguishing Features Gene(s)
Loeys-Dietz syndrome AD inheritance; hypertelorism, cleft palate/bifid uvula, more aggressive aortopathy TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3
Marfan syndrome AD inheritance; lens subluxation, tall stature, arachnodactyly FBN1
Vascular EDS (type IV) AD; thin translucent skin, arterial/organ rupture COL3A1
Cutis laxa syndromes More prominent skin laxity, may have systemic features ELN, FBLN4, FBLN5, ATP6V0A2
Homocystinuria AR; intellectual disability, lens subluxation, thromboembolism CBS

(PMID: 25821090; PMID: 29979900; PMID: 37692180)

Screening

  • Newborn screening: Not included in standard newborn screening programs
  • Carrier screening: Available for at-risk family members; "Notably, carrier testing for at-risk relatives is recommended to identify family members that may be affected by this condition" (PMID: 36578839)
  • Cascade screening: Recommended for at-risk family members once an index case is identified
  • Prenatal diagnosis: Possible via CVS or amniocentesis when familial mutations are known, and via detailed fetal echocardiography/ultrasound

11. Outcome / Prognosis

Survival and Mortality

  • Earlier literature described ATS as having a high mortality rate due to major cardiovascular malformations
  • More recent data demonstrate that the prognosis is less severe than previously reported: "Our data confirm that the cardiovascular prognosis in ATS is less severe than previously reported and that the first years of life are the most critical for possible life-threatening events" (PMID: 25373504)
  • First years of life carry the highest risk of mortality from pulmonary artery stenosis, respiratory distress, intracranial hemorrhage, or aortic complications
  • No unequivocal vascular dissections or ruptures have been documented, which is a critical distinguishing feature from vascular EDS and Loeys-Dietz syndrome (PMID: 29323665)
  • No specific survival rate data (5-year, 10-year) are available due to disease rarity
  • Many patients survive into adulthood; the oldest reported patients are in their 30s-40s (PMID: 34847858)

Morbidity and Function

  • Chronic cardiovascular surveillance burden
  • Potential need for surgical interventions: "Three patients underwent repeated BPA interventions, one patient had an aortopexy, and one patient had an aortic valve replacement. No patients had arterial dissections" (PMID: 40613586)
  • Joint hypermobility may cause chronic musculoskeletal pain
  • Visual impairment from keratoconus
  • Risk of cerebrovascular events even in young adulthood

Complications

  • Aortic root aneurysm (71.4% in CLARITY; may require valve/root replacement)
  • Branch pulmonary artery stenosis (may require repeated catheter interventions or surgery)
  • Ischemic stroke / transient ischemic attacks (rare but documented; PMID: 34847858)
  • Neonatal intracranial hemorrhage (rare)
  • Gastric perforation (rare)
  • Infant respiratory distress syndrome
  • Diaphragmatic hernia requiring surgical repair

Prognostic Factors

  • Severity of neonatal presentation: IRDS, intracranial bleeding, severe PA stenosis carry worst prognosis
  • Degree of pulmonary artery stenosis: Determines need for intervention and risk of RV failure
  • Rate of aortic root dilation: Requires longitudinal z-score monitoring
  • Access to specialized care: Early referral to high-specialized centers improves outcomes
  • Specific mutation type: Genotype-phenotype correlations are poorly established due to small numbers

12. Treatment

Pharmacotherapy

Beta-Adrenergic Blockers (MAXO:0001298)

Beta-blockers (e.g., atenolol, propranolol) are first-line pharmacological treatment to reduce hemodynamic stress on arterial walls. "To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking treatment was prescribed" (PMID: 37619836). The rationale is extrapolated from management of Marfan syndrome and other aortopathies — reducing heart rate and blood pressure decreases shear stress on tortuous and dilated vessels.

Angiotensin Receptor Blockers (MAXO:0001299)

Losartan (angiotensin II type 1 receptor blocker) has been proposed based on its TGF-β antagonist properties and efficacy in Marfan syndrome mouse models: "In transgenic mouse models it was shown that losartan, an angiotensin II type 1 receptor with known inhibiting effects on TGFbeta, rescues the aortic phenotype" (PMID: 18630721). Clinical efficacy in ATS specifically is not yet established.

Antithrombotic Therapy

May be considered for secondary prevention of cerebrovascular events. One case report described treatment with recombinant tissue plasminogen activator (r-TPA) at 0.9 mg/kg for TIA with complete recovery (PMID: 34847858).

Pharmacogenomics

No pharmacogenomic data specific to ATS are available.

Surgical and Interventional (MAXO:0000004)

Pulmonary Artery Interventions

  • Balloon angioplasty and stenting for pulmonary artery stenosis
  • Total pulmonary arterial reconstruction for severe cases: "underwent a pulmonary arterial surgical reconstruction at the age of 2 years old due to the development of pulmonary artery stenosis" (PMID: 38987788)
  • Surgical approaches may be preferred over transcatheter approaches, especially when peripheral arteries are involved
  • Repeated interventions may be necessary

Aortic Surgery

  • Aortopexy for symptomatic aortic tortuosity
  • Aortic valve replacement when indicated
  • Aortic root replacement for progressive aneurysmal dilation
  • Coarctation repair when present

Diaphragmatic Hernia Repair

  • Standard surgical repair when present (congenital diaphragmatic hernia)

Advanced Therapeutics

Gene Therapy (Future Potential)

  • No gene therapy trials currently registered for ATS
  • In vitro proof-of-concept: re-expression of GLUT10 in patient fibroblasts rescued the cellular phenotype, normalizing redox homeostasis and PPARγ activity (PMID: 26376865)
  • Given the autosomal recessive loss-of-function mechanism, gene replacement therapy is conceptually feasible but has not been developed

Ascorbate Supplementation (Hypothetical)

  • Based on the ascorbate compartmentalization hypothesis, high-dose ascorbate supplementation could theoretically be beneficial
  • However, the defect is in intracellular transport rather than systemic ascorbate levels
  • No clinical trials exist

Supportive and Rehabilitative (MAXO:0000502)

  • Genetic counseling (MAXO:0000079): Essential for families regarding recurrence risk (25%) and carrier testing
  • Multidisciplinary follow-up: Cardiology, ophthalmology, orthopedics, genetics, pulmonology
  • Physical therapy: For joint hypermobility management
  • Ophthalmologic monitoring: Regular eye examinations for keratoconus progression and management
  • Cardiovascular surveillance (MAXO:0000127): Regular echocardiography and interval CTA/MRA

Treatment Strategy

Management requires a multidisciplinary approach (PMID: 37692180): - Close monitoring of aortic root early in life - Extensive vascular imaging afterwards - Surveillance and prevention are key - "Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards" (PMID: 29323665)

Relevant MAXO terms: - MAXO:0000502 — Counseling - MAXO:0000127 — Echocardiography - MAXO:0000004 — Surgical procedure - MAXO:0010033 — Medical management - MAXO:0001298 — Beta-adrenergic antagonist therapy - MAXO:0000079 — Genetic counseling

13. Prevention

Primary Prevention

As a Mendelian genetic disorder, primary prevention of disease occurrence is limited to: - Genetic counseling (MAXO:0000079) for consanguineous families and known carriers - Preimplantation genetic diagnosis (PGD) for families with known mutations - Prenatal genetic testing (CVS, amniocentesis) when familial mutations are established - Carrier screening in populations with known founder mutations (e.g., p.Ser81Arg in Arab populations)

Secondary Prevention (Early Detection)

  • Prenatal ultrasound screening: Can detect arterial tortuosity as early as 22 weeks' gestation in at-risk pregnancies. "When ATS is suspected prenatally, the newborn should be referred immediately after birth to a high specialized center for proper neonatal care" (PMID: 39827853)
  • Cascade genetic testing: For siblings and relatives of affected individuals
  • Neonatal vigilance: Immediate referral to specialized center when ATS is suspected
  • "In case of confirmed ATS, parents should be counseled regarding the recurrence risk in other pregnancies" (PMID: 39827853)

Tertiary Prevention (Preventing Complications)

  • Regular cardiovascular surveillance (echocardiography, vascular imaging)
  • Beta-blocker therapy to reduce hemodynamic stress
  • Activity modification to avoid extreme physical exertion and contact sports
  • Ophthalmologic monitoring for keratoconus progression
  • Cerebrovascular risk management and antiplatelet prophylaxis when indicated

Immunization

Not applicable — ATS is not an infectious or immune-mediated disorder.

Behavioral Interventions

  • Avoidance of isometric exercises and contact sports
  • Blood pressure monitoring and management
  • Regular medical follow-up compliance

Public Health

Given the ultra-rare nature of ATS (<1/1,000,000), population-level public health interventions are not practical. Awareness among pediatric cardiologists, geneticists, and prenatal sonographers is the most impactful public health measure.

14. Other Species / Natural Disease

Naturally Occurring Disease

No naturally occurring animal disease equivalent to human ATS has been reported in veterinary literature or in the OMIA database. This is likely because most animals (including mice, rats, dogs, cats) retain functional L-gulonolactone oxidase (Gulo) and can synthesize ascorbic acid endogenously, compensating for any GLUT10 dysfunction.

Orthologous Genes

Species Gene Symbol NCBI Taxon
Human (Homo sapiens) SLC2A10 9606
Mouse (Mus musculus) Slc2a10 10090
Zebrafish (Danio rerio) slc2a10 7955
Rat (Rattus norvegicus) Slc2a10 10116

Comparative Biology

The SLC2A10/GLUT10 gene is highly conserved across vertebrates, suggesting an essential role in development. A critical species difference is that mice (but not humans) can synthesize their own ascorbic acid via the gulonolactone oxidase (Gulo) pathway. This likely explains why simple Slc2a10 mutant mice fail to recapitulate the human vascular phenotype, while the Gulo;Slc2a10 double knockout (which eliminates both GLUT10 and endogenous ascorbate synthesis) shows a more informative phenotype (PMID: 32307537).

Guinea pigs and some primates share the human inability to synthesize ascorbic acid (non-functional GULO) and could theoretically manifest ATS-like phenotypes if SLC2A10 were disrupted, but no such models exist.

Transmission / Zoonotic Potential

Not applicable — ATS is a non-infectious genetic disorder with no zoonotic potential or cross-species transmission.

15. Model Organisms

Mouse Models

Slc2a10 Missense Models (G128E, S150F)

  • Type: ENU-induced knock-in (missense substitutions)
  • Phenotype recapitulation: None — "two mouse models, homozygous respectively for G128E and S150F missense substitutions in glut10 do not present any of the vascular, anatomical, or immunohistological abnormalities as encountered in human ATS patients" (PMID: 18693279)
  • Limitation: Mice synthesize endogenous ascorbic acid via Gulo, compensating for GLUT10 deficiency
  • NCBI Taxon: 10090

Gulo;Slc2a10 Double Knockout Model

  • Type: Double gene knockout (Slc2a10 KO + Gulo KO — abolishes endogenous ascorbate synthesis)
  • Phenotype recapitulation: Partial — "While Gulo;Slc2a10 double knock-out mice did not fully phenocopy human ATS, histological and immunocytochemical analysis revealed compromised extracellular matrix formation" and mitochondrial dysfunction in smooth muscle cells (PMID: 32307537)
  • Key findings: TGF-β signaling unaltered; supports ascorbate compartmentalization hypothesis
  • Significance: Strongest animal model evidence that ATS is fundamentally an ascorbate compartmentalization disorder
  • Limitation: Does not fully phenocopy human vascular tortuosity, suggesting additional human-specific factors

Zebrafish Model

slc2a10 Morpholino Knockdown

  • Type: Antisense morpholino oligonucleotide-mediated gene knockdown
  • Phenotype recapitulation: Good — "knockdown of slc2a10 using antisense morpholino oligonucleotide injection caused a wavy notochord and cardiovascular abnormalities with a reduced heart rate and blood flow" (PMID: 22116938)
  • Key findings: Cardiovascular phenotype partially phenocopied by TGF-β receptor (tgfbr1/alk5) small-molecule inhibitor; transcriptomic analysis revealed specific dysregulation of mitochondrial function genes distinct from tgfbr1 inhibition
  • NCBI Taxon: 7955
  • Limitation: Morpholino effects are transient; long-term vascular remodeling cannot be studied; zebrafish vascular anatomy differs significantly from human

Cell-Based Models

Patient-Derived Dermal Fibroblasts

  • Type: Primary skin fibroblasts from ATS patients
  • Applications: Most extensively used in vitro model
  • Key findings:
  • Demonstrated oxidative stress with ROS-induced lipid peroxidation and altered PPARγ function (PMID: 26376865)
  • Confirmed impaired DAA transport across endomembranes (PMID: 27153185)
  • Revealed non-canonical TGF-β signaling via αvβ3 integrin (PMID: 29587413)
  • GLUT10 re-expression normalizes phenotype (proof of concept for gene therapy)
  • Limitation: In vitro system; does not capture in vivo hemodynamic forces, developmental context, or cell-cell interactions

Model Summary

Model Species Vascular Phenotype ECM Defects TGF-β Change Overall Utility
Slc2a10 G128E/S150F Mouse None None Not observed Limited
Gulo;Slc2a10 DKO Mouse Mild Yes Unaltered Moderate
slc2a10 MO Zebrafish Yes (CV abnormalities) Yes (notochord) Reduced Good (developmental)
Patient fibroblasts Human N/A Yes Non-canonical ↑ Good (mechanistic)

Key Gap

No single model fully recapitulates the severe human vascular phenotype of ATS. This suggests that additional human-specific factors — including the obligate dependence on dietary ascorbate, hemodynamic forces during human cardiovascular development, and perhaps differences in elastic fiber assembly — contribute to disease manifestation.

Mechanistic Model / Interpretation

Integrated Mechanistic Framework

Synthesizing all available evidence, ATS is best understood as an ascorbate compartmentalization disorder with multi-pathway downstream consequences:

  1. Primary defect (upstream): Biallelic loss of GLUT10 → loss of DAA transport across endomembranes
  2. Proximal consequences: Intracellular ascorbate deficiency in ER and mitochondria
  3. Intermediate pathology (4 parallel arms):
  4. ECM arm: Impaired prolyl/lysyl hydroxylase activity → defective collagen hydroxylation → fragmented elastic fibers + disorganized collagen
  5. Redox arm: Loss of intracellular antioxidant → ROS accumulation → lipid peroxidation → altered PPARγ function
  6. Mitochondrial arm: Ascorbate deficiency in mitochondria → compromised electron transport chain → impaired VSMC energy metabolism
  7. Signaling arm: ECM disarray + fibronectin loss → αvβ3 integrin recruitment → non-canonical TGF-β signaling via FAK/Src/p38 MAPK
  8. Convergent pathology (downstream): Vascular wall weakening → arterial tortuosity, elongation, stenosis, and aneurysm formation
  9. Human amplification factor: Unlike most mammals, humans cannot synthesize ascorbate (non-functional GULO), making them uniquely vulnerable to GLUT10 deficiency

The canonical TGF-β/SMAD pathway, while highlighted in the original discovery paper, appears to be a secondary or context-dependent phenomenon rather than the primary driver. This is supported by: (a) absence of pSMAD2/CTGF upregulation in patient tissues, (b) unaltered TGF-β signaling in the Gulo;Slc2a10 double knockout mouse, and (c) non-canonical rather than canonical pathway activation in patient fibroblasts.

Evidence Base

Landmark Papers

Paper PMID Key Contribution
Coucke et al. 2006, Nat Genet 16550171 Discovery of SLC2A10 as causative gene
Beyens et al. 2018, Hum Mutat 29323665 Largest cohort (102 patients, 40 new families); comprehensive phenotyping
Callewaert et al. 2008, Hum Mutat 18693279 Mouse model demonstrating species-specific differences
Willaert et al. 2012, Hum Mol Genet 22116938 Zebrafish model; mitochondrial function link
Németh et al. 2016, FEBS Lett 27153185 GLUT10 confirmed as DAA transporter
Boel et al. 2020, Hum Mol Genet 32307537 Double KO mouse model; ascorbate compartmentalization
Zoppi et al. 2015, Hum Mol Genet 26376865 Oxidative stress mechanism and non-canonical TGF-β in fibroblasts
Callewaert et al. 2008, J Med Genet 25373504 Prognosis better than expected; infancy most critical
CLARITY study 2025 40613586 Longitudinal cardiovascular data; 71.4% aortic root dilation
Al-Khawaga et al. 2022, Eur J Med Genet 35302653 Ultrastructural analysis of collagen and elastin in Arab patients
Zoppi et al. 2018, Int J Mol Sci 29587413 αvβ3 integrin role in ATS fibroblasts
Hosen et al. 2020, ACS Omega 31203799 In silico GLUT10 structure and substrate binding prediction

Supporting Clinical Literature

Paper PMID Contribution
Esmel-Vilomara et al. 2023 37619836 4 new patients; novel variant p.Leu300Trp; supra-aortic involvement
Ekhator et al. 2023 37692180 Comprehensive review of ATS
Cotti Piccinelli et al. 2021 34847858 TIA in young adult with ATS; first r-TPA use
Liang et al. 2021 34384376 Prenatal ultrasound diagnosis in 2 siblings
Alshair et al. 2024 38987788 Pulmonary arterial reconstruction case report
Tunks et al. 2025 40027906 Novel p.Ala58Val variant; prenatal diagnosis keys
Ponziani et al. 2025 39827853 Concordant dichorionic twins with ATS
Debette & Germain 2014 24365320 Neurologic manifestations of connective tissue disorders
Al-Habeeb et al. 2024 36578839 Neonatal ATS case; p.Ser81Arg founder mutation
Loeys & De Paepe 2008 18630721 TGF-β pathway and losartan in aortic aneurysms

Limitations and Knowledge Gaps

  1. Ultra-rare disease with limited natural history data: With only ~106 confirmed patients, long-term outcomes, genotype-phenotype correlations, and rare complications may be underestimated or incompletely characterized.

  2. No adequate animal model: No single animal model fully recapitulates human ATS. Mouse models are limited by endogenous ascorbate synthesis, and zebrafish models are limited by developmental and anatomical differences.

  3. Pathomechanism incompletely understood: The relative contributions of ascorbate compartmentalization, TGF-β signaling (canonical vs. non-canonical), oxidative stress, and mitochondrial dysfunction remain unclear. The observation that end-stage tissue shows no canonical TGF-β upregulation creates an apparent contradiction with the original discovery that needs resolution.

  4. No validated biomarkers: No circulating biomarkers exist for disease monitoring, progression prediction, or treatment response assessment.

  5. No formal diagnostic criteria: Unlike Marfan syndrome (Ghent criteria) or EDS (2017 criteria), ATS lacks standardized clinical diagnostic criteria.

  6. Treatment evidence is anecdotal: No clinical trials have been conducted for any intervention. Beta-blocker and losartan use is extrapolated from other aortopathies. The potential role of ascorbate supplementation is speculative.

  7. No quality-of-life studies: Formal patient-reported outcome measures (EQ-5D, SF-36, PROMIS) have not been applied to ATS cohorts.

  8. Omics data are sparse: No large-scale transcriptomic, proteomic, metabolomic, or epigenomic profiling of ATS patient tissues has been published. Single-cell approaches have not been applied.

  9. Genotype-phenotype correlation poorly defined: While variable expressivity is well documented, specific relationships between mutation type/position and disease severity have not been systematically analyzed.

  10. Prenatal natural history: Few cases have been diagnosed prenatally, limiting understanding of fetal disease progression and optimal prenatal management strategies.

Proposed Follow-up Experiments / Actions

Short-Term (1-3 years)

  1. International ATS Registry: Establish a prospective, multicenter registry to systematically collect phenotypic, genotypic, treatment, and outcome data across all known patients, building on the CLARITY initiative framework.

  2. Genotype-Phenotype Correlation Study: Using registry data, analyze whether specific mutation types (truncating vs. missense), positions within SLC2A10, or zygosity status (homozygous vs. compound heterozygous) predict disease severity, complication rates, or specific phenotypic features.

  3. Circulating Biomarker Discovery: Profile serum/plasma from ATS patients using targeted proteomics and metabolomics to identify potential biomarkers for disease activity (e.g., ECM turnover markers such as desmosine/isodesmosine for elastin degradation, oxidative stress markers such as 8-isoprostane, TGF-β pathway markers).

  4. Patient-Derived iPSC Vascular Models: Generate iPSC lines from ATS patients, differentiate into vascular smooth muscle cells and endothelial cells, and use these to study vascular pathomechanisms and screen potential therapeutics in a human-relevant system.

Medium-Term (3-5 years)

  1. Improved Mouse Model: Generate a conditional Slc2a10 knockout on a Gulo-null background with vascular-specific and temporally controlled deletion, combined with controlled dietary ascorbate restriction, to better model human ATS.

  2. Ascorbate Supplementation Pilot Study: Design a controlled clinical study evaluating high-dose ascorbic acid supplementation in ATS patients, monitoring aortic root dimensions, arterial stiffness, vascular tortuosity indices, and circulating biomarkers as endpoints.

  3. Single-Cell RNA Sequencing: Perform scRNA-seq on ATS patient skin biopsies and available vascular tissue to identify cell-type-specific transcriptional signatures, prioritize therapeutic targets, and understand the cellular heterogeneity of disease.

  4. TGF-β Pathway Dissection: Use patient-derived fibroblasts and iPSC-derived vascular cells to systematically dissect canonical vs. non-canonical TGF-β signaling across different cell types and developmental stages, resolving the apparent contradiction between in vitro and in vivo findings.

Long-Term (5+ years)

  1. Gene Therapy Development: Explore AAV-mediated SLC2A10 gene replacement in vascular smooth muscle cells, first validating in the improved mouse model, then progressing toward clinical translation. The in vitro proof-of-concept (GLUT10 re-expression rescuing fibroblast phenotype) is encouraging.

  2. Clinical Treatment Trial: Based on biomarker and mechanistic data, design a randomized controlled trial of pharmacological intervention (losartan, high-dose ascorbate, or novel targeted therapy) in ATS patients, leveraging the international registry for recruitment.

  3. Formal Diagnostic Criteria Development: Convene an international expert panel to establish standardized diagnostic criteria for ATS, analogous to Ghent criteria for Marfan syndrome, incorporating clinical, imaging, and genetic features.

Report generated: 2026-05-05 | Based on analysis of 39 published studies and structured database resources | MONDO:0009005 | OMIM #208050