Table 3.

Genes of Interest in the Differential Diagnosis of Arterial Tortuosity Syndrome

Gene(s)DiffDx DisorderMOIClinical Features of DiffDx DisorderDistinguishing Clinical Features
ACTA2
(BGN)
COL3A1
FBN1
(FOXE3)
(HCN4)
LOX
(MAT2A)
(MFAP5)
MYH11
MYLK
PRKG1
SMAD3
TGFB2
(TGFB3)
TGFBR1
TGFBR2 1		Heritable thoracic aortic disease (HTAD; familial thoracic aortic aneurysms) 1ADAortic root dilatation may be isolated or assoc w/other vascular & nonvascular features, incl marfanoid skeletal features as seen in ATS. 1Though some of these thoracic aortic aneurysm syndromes may present w/mild tortuosity, severe tortuosity is usually absent, & stenosis is rare (except in ACTA2-HTAD).
ALDH18A1 ALDH18A1 cutis laxa (ARCL3A: OMIM 219150; ADCL3: OMIM 616603)AR
AD 2		Intracerebral AT (no widespread AT); ID; chorea-athetosis; corneal clouding or cataract; intrauterine growth restriction; some degree of cutis laxaATS is not assoc w/ID, chorea-athetosis, corneal clouding, or cataract.
ATP7A Occipital horn syndrome (OHS) (See ATP7A Copper Transport Disorders.)XLOccipital horns 3 (may be clinically palpable or observed on skull radiographs); lax skin & joints; bladder diverticula; inguinal hernias; vascular tortuosity (mainly of cerebral vasculature)Skeletal & urogenital features of OHS are distinctive.
BGN BGN-associated aortic aneurysm syndrome 4XLClinical features significantly overlap w/Marfan syndrome & LDS: early-onset aortic root dilatation & dissection, widely spaced eyes, joint hypermobility, contractures, bifid uvula, & pectus deformities
  • Persons w/BGN-assoc aortic aneurysm syndrome may share craniofacial manifestations (widely spaced eyes, cleft uvula/palate, & craniosynostosis) w/persons w/LDS, findings less frequently seen in persons w/ATS.
  • AT is rarely present in BGN-assoc aortic aneurysm syndrome, and to a lesser degree than in ATS.
  • Persons w/BGN-assoc aortic aneurysm syndrome present more frequently w/aneurysm of aortic root than persons w/ATS.
COL3A1
TNXB 		Hypermobile EDS (hEDS), TNXB-related classical-like EDS, & vascular EDS (vEDS)AD AR 5
  • hEDS: generalized joint hypermobility → repetitive joint luxations & chronic musculoskeletal pain; soft & hyperextensible skin; autonomic dysfunction
  • vEDS: thin, translucent skin; atrophic scars, easy bruising; characteristic facial appearance (in some persons); arterial, intestinal, &/or uterine fragility
  • Vascular dissection or rupture, GI perforation, or organ rupture are presenting signs in most adults w/vEDS.
  • AT is absent in persons w/hEDS & vEDS. 6
  • Skin & craniofacial features in vEDS are usually distinctive.
EFEMP2 EFEMP2 cutis laxa (ARCL1B)AR
  • Cutis laxa & systemic involvement, most commonly AT, aneurysms, & stenosis; retrognathia; joint laxity; arachnodactyly
  • Severity ranges from perinatal lethality (due to cardiopulmonary failure) to manifestations limited to vascular & craniofacial systems
  • Focal stenosis at aortic isthmus is more common in ARCL1B than in ATS. 7
  • ARCL1B often presents w/more aggressive arterial phenotype w/rapid progression to aneurysms.
  • Typical facial characteristics of ATS (e.g., blepharophimosis, convex nasal ridge, & long face) are often absent in ARCL1B.
EMILIN1 EMILIN1-related cutis laxa 8Cutis laxa, AT, aortic root aneurysms
  • Osteopenia w/neonatal fractures
  • Typical facial characteristics of ATS are absent
FBLN5
LTBP4 		FBLN5 cutis laxa & LTBP4 cutis laxaAR
AD 9
  • Cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, & other evidence of generalized connective disorder incl inguinal hernias & hollow viscus diverticula (e.g., intestine, bladder)
  • Supravalvar aortic stenosis occasionally observed
  • Pulmonary emphysema or GI ruptures are often cause of death.
Persons w/FBLN5 cutis laxa & LTBP4 cutis laxa do not have the AT seen in persons w/ATS. 10
FBN1 Marfan syndrome ADAortic root aneurysm; long bone overgrowth; scoliosis; lens subluxation
  • Persons w/Marfan syndrome do not show manifest AT.
  • Lens subluxation is not present in ATS.
FKBP1
PLOD1 		Kyphoscoliotic EDS (See FKBP14-kEDS & PLOD1-kEDS.)ARAortic root aneurysm; vascular rupture; scoliosis; corneal thinning; ocular rupture; joint hypermobility; skin fragility
  • Persons w/kEDS do not present w/manifest tortuosity.
  • Ocular fragility (a feature of PLOD1-kEDS) is not seen in ATS.
SMAD2
SMAD3
TGFB2
TGFB3
TGFBR1
TGFBR2 		Loeys-Dietz syndrome (LDS)AD
  • Vascular findings (cerebral, thoracic, & abdominal arterial aneurysms, &/or dissections)
  • Skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus)
  • Persons w/LDS may have craniofacial manifestations (widely spaced eyes, cleft uvula/palate, craniosynostosis), findings usually not seen w/ATS.
  • AT is often present in LDS but more often in ATS.
  • Persons w/LDS present more frequently w/aneurysm of aortic root than persons w/ATS.

AD = autosomal dominant; AR = autosomal recessive; AT = arterial tortuosity; ATS = arterial tortuosity syndrome; DiffDx = differential diagnosis; EDS = Ehlers-Danlos syndrome; GI = gastrointestinal; ID = intellectual disability; LDS = Loeys-Dietz syndrome; MOI = mode of inheritance; XL = X-linked

1.

Renard et al [2018] discussed the clinical validity of genes associated with heritable thoracic aortic aneurysm and dissection (FTAAD). Genes in ( )s were recently associated with FTAAD and require further confirmation. Of note, this paper mentions SLC2A10 as a "potentially diagnostic gene for FTAAD," meaning that identification of biallelic SLC2A10 pathogenic variants may allow diagnosis of the cause of thoracic aortic enlargement, but that pathogenic variants in SLC2A10 are primarily causative of other clinical features and are not associated with a significant risk of progression to aortic dissection.

2.

ALDH18A1-related cutis laxa can be inherited in an autosomal recessive or autosomal dominant manner; the autosomal recessive form is more severe.

3.

"Occipital horns" are distinctive wedge-shaped calcifications at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone.

4.
5.

Hypermobile EDS is inherited in an autosomal dominant manner (the molecular basis of hEDS is unknown). TNXB-related classical-like EDS is inherited in an autosomal recessive manner. Vascular EDS is associated with pathogenic variants in COL3A1 and is almost always inherited in an autosomal dominant manner (rare examples of biallelic inheritance have been reported).

6.

Two reports mention arterial tortuosity syndrome in individuals previously misdiagnosed with EDS hypermobility type, one of whom was homozygous for the SLC2A10 pathogenic variant c.1411+1G>A [Allen et al 2009] and one of whom was homozygous for the SLC2A10 pathogenic variant c.685C>T [Castori et al 2012].

7.
8.
9.

LTBP4-related cutis laxa is inherited in an autosomal recessive manner. FBLN5 cutis laxa can be inherited in an autosomal recessive or (less commonly) autosomal dominant manner.

10.

From: Arterial Tortuosity Syndrome

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