Marfan Syndrome, Loeys–Dietz Syndrome and Heritable Aortopathies

Literature and regulatory information updated: 6 October 2026.

Heritable Thoracic Aortic Disease (HTAD) — Marfan syndrome and other FBN1-related disorders, Loeys–Dietz syndrome (TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, TGFB3, IPO8) and non-syndromic heritable thoracic aortic aneurysm/dissection (ACTA2, MYH11, MYLK, PRKG1, LOX and others)

0. Initial Reference Table

Validity classification according to the ClinGen HTAD panel, reproduced in GeneReviews [2, 26].

1. Introduction

This article addresses heritable diseases of the thoracic aorta, a group of entities whose common denominator is aortic aneurysm or dissection from the root to the diaphragm, with possible coexisting aneurysms and dissections in other arterial territories. Depending on the presence or absence of manifestations in other organs, heritable thoracic aortic disease is divided into syndromic forms — Marfan syndrome, Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome and multisystemic smooth muscle dysfunction syndrome — and non-syndromic forms. The identified genes fall into two functional groups: those encoding structural components of the extracellular matrix (FBN1, COL3A1, MFAP5, BGN, LOX), and those determining the aortic wall's ability to adapt to mechanical load, either through the transforming growth factor beta pathway (TGF-β: TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, SMAD3, SMAD4) or through the vascular smooth muscle cell contractile apparatus (ACTA2, MYH11, MYLK, PRKG1). In a substantial proportion of families, particularly non-syndromic forms, no causal variant is identified, so these families are “heritable”, but not yet, strictly speaking, “genetic” [1].

The history begins in 1896, when the French paediatrician Antoine Bernard-Jean Marfan described a girl with long, slender limbs, which he termed dolichostenomelia [1, 7]. Cardiovascular involvement and the autosomal dominant nature of the disease were recognised only in the mid-1950s, with Victor McKusick's monograph [1, 7]. In 1972, Murdoch and colleagues documented, in an untreated series, a mean age at death of 32 years, mainly from dissection or rupture of the aortic root [27, 28]. In 1991, two articles published in the same issue of Nature linked the syndrome to the fibrillin-1 gene: Lee and colleagues mapped MFS and congenital contractural arachnodactyly to two distinct fibrillin genes, and Dietz and colleagues identified the first de novo pathogenic FBN1 variant [29, 30]. In 2006, Habashi and colleagues demonstrated that losartan prevented aortic aneurysm in a murine MFS model, shifting the therapeutic focus towards TGF-β signalling [31].

Loeys–Dietz syndrome was described in 2005 by Bart Loeys and Harry Dietz in a series of ten families with aggressive arterial aneurysms, arterial tortuosity, hypertelorism and a bifid uvula or cleft palate, caused by TGFBR1 or TGFBR2 variants [32]. In 2006, the same group expanded the spectrum to 52 families and demonstrated that dissection occurred at smaller aortic diameters than in MFS [33]. SMAD3 followed in 2011, in a syndromic form with early osteoarthritis [34]; TGFB2 in 2012 [35, 36]; TGFB3 in 2015 [37]; and, more recently, SMAD2 and IPO8 [3, 38]. In non-syndromic disease, the discovery of MYH11 associated with patent ductus arteriosus (2006), ACTA2 (2007), MYLK (2010) and PRKG1 (2013) established the smooth muscle contractile apparatus as the second pathophysiological axis [39–42].

In 2010, an international panel published the revised Ghent nosology, prioritising aortic root dilatation and ectopia lentis as cardinal manifestations and incorporating the FBN1 molecular result into the diagnostic algorithm [11]. The concept that FBN1 produces a spectrum of opposing phenotypes — “tall” (MFS) and “short” (acromelic dysplasias) — was consolidated with the identification of variants in the fibrillin-1 TB5 domain in acromicric and geleophysic dysplasias in 2011 [43, 44]. In guidelines, heritable aortic disease came to be managed in a “gene-specific” manner in the 2022 American recommendations [12] and the 2024 European recommendations, which for the first time included specific recommendations for LDS, Turner syndrome and Ehlers–Danlos syndrome [13, 45].

Epidemiology and clinical burden

Estimated MFS prevalence ranges from 1:3,000–5,000 (CARDIO) to 1:5,000–1:10,000 (GeneReviews), without ethnic or sex predilection, and approximately 25% of cases result from de novo variants [1, 4]. In the Danish national registry, which retrospectively applied the 2010 nosology to 1,628 people with a suspected diagnosis, 412 cases were confirmed, with a maximum prevalence of 6.5/100,000 in 2014, median annual incidence of 0.19/100,000 and median age at diagnosis of 19 years [8, 46]. Median life expectancy increased by at least 30 years with prophylactic surgery and medical treatment, but a recent population study showed a median age at death of 50 years, 8 to 13 years below the general population [1]. MFS is associated with a hazard ratio (HR) of approximately 200 for aortic disease [1].

For LDS, exact prevalence is unknown and estimated at 1:50,000 [3]. Non-syndromic HTAD is frequent among patients with thoracic aortic aneurysm: up to 20% of patients with aneurysm or type A dissection without connective tissue disease have an affected first-degree relative, and the younger the proband, the greater the probability of familial clustering [1]. Even so, a genetic cause is identified in only 20% to 30% of non-syndromic families [2].

2. Molecular Genetics and Pathophysiology

2.1. FBN1 and fibrillin-1

The FBN1 gene, at 15q21.1, encodes fibrillin-1, a glycoprotein of 2,871 amino acids and approximately 320 kDa [1]. The MANE Select reference transcript, NM_000138.5, has 66 exons, the first of which is non-coding, that is, 65 coding exons (exons 2 to 66) [47]; the literature before 2017 and OMIM number the exons from the first coding exon (NM_000138.4), so that, for example, “exon 64” in those sources corresponds to exon 65 of MANE [47]. The protein consists of 47 cysteine-rich epidermal growth factor-like domains (EGF-like), 43 of which contain a calcium-binding consensus sequence (cbEGF domains), and seven 8-cysteine domains homologous to latent TGF-β-binding proteins (TB/8-cys) [1, 44]. Fibrillin molecules polymerise into 10–12 nm microfibrils, which serve as a template for elastin deposition in elastic tissues (aorta, lung, skin) and provide tensile strength in non-elastic tissues, such as the ciliary zonule suspending the lens, tendons and the cornea [1, 44]. The C terminus of profibrillin is cleaved by furin, releasing asprosin, a glycogenic hormone whose deficiency has been implicated in Marfan–lipodystrophy syndrome [44, 48].

Approximately 2,000 pathogenic FBN1 variants have been described, most private to each family [1]. Missense variants creating or eliminating a cysteine residue or altering residues in the calcium-binding consensus sequence of cbEGF domains are the most frequent; these are followed by nonsense variants, splicing variants with exon skipping and, more rarely, small deletions [1, 4]. Sequencing detects 90% to 93% of variants in patients with classic MFS, and deletion/duplication analysis adds approximately 5% [4]. Two mechanisms coexist: a dominant negative effect, in which mutant fibrillin interferes with assembly of microfibrils from normal protein, and haploinsufficiency, in which the mutant allele is not expressed [1, 4].

Genotype–phenotype correlations in MFS

There are no definitive genotype–phenotype correlations, but some generalisations have clinical value (Table 1) [1, 4]. The French cohort of 1,575 probands and relatives showed that premature termination codon variants (PTC, haploinsufficient) are associated with shorter life expectancy, higher lifetime risk of an aortic event, higher risk of severe scoliosis and less need for ectopia lentis surgery, whereas in-frame variants with cysteine loss are more severe overall and those adding cysteine have the highest frequency of ectopia lentis surgery [49]. In the COMPARE trial substudy, losartan reduced root dilatation only in patients with haploinsufficient variants [50]. A systematic review with meta-analysis published in 2025 (17 studies, 11 meta-analysed, more than 6,000 adults, all observational) estimated, for haploinsufficient versus dominant negative variants, a relative risk of aortic presentation of 2.62 (95% CI 1.90–3.61) and, among missense variants, 2.21 (95% CI 1.18–4.15) for substitutions involving cysteine; splicing variants, traditionally grouped with haploinsufficient variants, had a risk closer to missense variants [51]. Between-study heterogeneity was moderate to high (I² 50–76%), so these estimates guide surveillance but do not replace individual assessment of diameter, growth and family history [51].

Table 1. Main genotype–phenotype correlations in MFS caused by FBN1 variants [1, 4, 49]

Pathophysiology of FBN1 aortopathy

Fibrillin-1 has at least three roles in aneurysm pathogenesis: structural, in elastic fibre composition; regulatory, in TGF-β bioavailability; and mechanotransductive [1]. The classic structural theory, which attributed disease to fragility of tissues with defective microfibrils, explains aneurysm, ectopia lentis and dural ectasia, but not excessive bone growth, craniofacial features or myxomatous degeneration of the mitral valve [1]. In murine models, defective fibrillin compromises the connection between elastic fibres and endothelial and smooth muscle cells, triggering abortive matrix remodelling, overproduction of metalloproteinases 2 and 9, inflammatory infiltration, intimal hyperplasia, elastic fibre calcification and structural collapse of the wall [1]. Because fibrillin-1 is homologous to LTBP proteins, which maintain TGF-β in a latent matrix complex, its deficiency was proposed to release active TGF-β; increased signalling was demonstrated in the lung, mitral valve, skeletal muscle, dura mater and ascending aorta, and neutralisation prevented emphysema, myxomatous degeneration and aneurysm in animals [1, 4, 31]. However, a mouse in which the LTBP-binding site was deleted (Fbn1H1Δ) did not develop MFS, so increased TGF-β signalling is now understood as a common final pathway, probably secondary to altered mechanotransduction between matrix, integrins and cytoskeleton [1]. Histology shows elastic fibre fragmentation, elastin loss and accumulation of amorphous matrix in the media, findings that do not distinguish MFS from other aneurysm causes [4].

2.2. Non-Marfan FBN1 disorders: the paradigm of opposing phenotypes

Different FBN1 variants cause diseases with opposing skeletal and cardiovascular phenotypes (Table 2) [44]. “Tall” fibrillinopathies include MFS and, through FBN2, congenital contractural arachnodactyly; “short” fibrillinopathies include Weill–Marchesani syndrome, geleophysic and acromicric dysplasias and stiff skin syndrome [4, 44]. Variants in acromicric and geleophysic dysplasias cluster in exons 41 and 42, encoding the fibrillin-1 TB5 domain [43, 52]. Stiff skin syndrome, a congenital form of scleroderma, results from variants in the TB4 domain, which contains fibrillin-1's only integrin-binding RGD motif [44, 53]. These phenotypes should not be managed as MFS, although overlap exists: thoracic aortic aneurysm with cervical dissection has been described in a three-generation family with FBN1-related Weill–Marchesani syndrome, and TB5 domain variants have also been found in MFS patients [5, 54].

Table 2. FBN1 fibrillinopathies — “tall” and “short” phenotypes [4, 5, 44, 52, 55]

2.3. Loeys–Dietz syndrome genes and the “TGF-β paradox”

LDS is caused by heterozygous variants in six TGF-β pathway genes and, in a recessive form, by biallelic IPO8 variants (Table 3) [3]. TGFBR1 and TGFBR2 variants are mostly missense variants at conserved residues encoding the receptors' intracellular serine–threonine kinase domain; there are no clinical differences between the two genes [1]. Nonsense or frameshift variants are rare in these genes, and complete TGFBR1 or TGFBR2 deletions have been described in people without aortic involvement, suggesting that the mutant receptor must reach the cell surface, bind its ligand and be unable to propagate the signal (“functional haploinsufficiency”); consequently, small in-frame deletions tend to cause LDS, unlike out-of-frame deletions [3]. SMAD3 shows truncating and missense variants, the latter clustered in the MH2 domain, and TGFB2/TGFB3 show loss-of-function missense, frameshift, nonsense and splicing variants [1]. Missense TGFB2 and TGFB3 variants affecting the RKKR consensus sequence or cytokine domain, and SMAD2/SMAD3 variants in the MH2 domain, are more likely to be pathogenic; in TGFBR1, extracellular domain variants and those causing haploinsufficiency do not cause LDS, and variation in the length of the exon 1 alanine repeat (rs11466445) is benign [3].

All LDS genes are essential to TGF-β signalling and, although variants cause molecular loss of function, aortic tissue shows a paradoxical increase in signalling: nuclear accumulation of phosphorylated SMAD2 and increased expression of TGF-β-dependent products such as collagen and CTGF (CCN2) [1, 3]. In animal models, adjacent cell types in the arterial wall differ in susceptibility to loss of function; in more vulnerable cells, attempted compensation increases ligand secretion, hyperactivating signalling in neighbouring cells, and selective attenuation of TGF-β in smooth muscle cells derived from the cardiac neural crest prevents aneurysm [3]. Histology shows elastic fibre fragmentation, elastin loss, excess collagen and more diffuse medial degeneration than in MFS, present even in young children and without inflammation, pointing to a primary elastogenesis defect [3].

Table 3. Loeys–Dietz syndrome genes [1, 3, 56]

2.4. Non-syndromic HTAD: matrix and contractile apparatus

Non-syndromic HTAD has autosomal dominant inheritance with reduced penetrance and variable expressivity [1]. The ClinGen panel assessed 53 candidate genes and classified nine as definitive and two as strong, designating these 11 as “HTAAD genes” (category A), meaning clinically actionable for aortic surveillance, intervention and cascade screening [26]. Variants in LDS genes and FBN1 also cause HTAD without extra-aortic signs: FBN1 accounts for approximately 3% of non-syndromic families, TGFBR1/2 approximately 3–5% and SMAD3 approximately 2% [1, 57].

ACTA2 encodes smooth muscle alpha-2 actin and is the most frequent monogenic cause of non-syndromic HTAD, accounting for 12% to 21% of cases; variants are almost all missense with a dominant negative effect [1, 40]. The p.Arg179 variant (de novo) causes multisystemic smooth muscle dysfunction syndrome, and variants affecting p.Arg179 and p.Arg258 confer greater aortic risk, whereas p.Arg185Gln and p.Arg118Gln confer lower risk [58, 59]. MYH11 encodes the smooth muscle myosin heavy chain; most carriers have patent ductus arteriosus, and the aortic wall shows increased angiotensin-converting enzyme and insulin-like growth factor 1, with activation of angiotensin II, PI3K and canonical and non-canonical TGF-β pathways [1, 39]. MYLK encodes myosin light chain kinase; p.Arg1480Ter and p.Ser1759Pro reduce kinase activity and segregated with acute dissection with little or no previous dilatation [41]. PRKG1 encodes type I cGMP-dependent protein kinase; the recurrent variant c.530G>A (p.Arg177Gln) is gain-of-function, leaving the kinase constitutively active and reducing smooth muscle contraction [42]. This historical numbering refers to the Iα isoform transcript (NM_001098512.3); on the MANE Select transcript, the same variant is designated NM_006258.4:c.575G>A (p.Arg192Gln), classified as pathogenic in ClinVar by multiple submitters without conflict (VCV000065477, last evaluated on 25/10/2025) [60]. LOX encodes lysyl oxidase, which establishes collagen and elastin cross-links; loss-of-function alleles reduce these links in the media [2, 61]. MFAP5 (microfibril MAGP-2 protein) has only moderate validity, and in a European cohort of 368 dissections all (likely) pathogenic variants were in definitive or strong genes [26, 62, 63].

Cytoskeletal integrity is necessary for assembly of fibronectin fibrils, on which the association of fibrillins into microfibrils depends; a dysfunctional contractile apparatus compromises the matrix and triggers cellular responses including increased TGF-β signalling, bringing the two pathophysiological axes together [1].

3. Clinical Spectrum and Manifestations by System

3.1. Marfan syndrome

MFS is a systemic connective tissue disease with high penetrance and marked inter- and intrafamilial variability; it should be understood as a continuum, ranging from mild manifestations in one or two systems to severe, rapidly progressive multiorgan disease in the newborn [1, 4]. As a general rule, manifestations “run in the family”, indicating that the FBN1 variant is the main determinant of phenotype, and most manifestations have age-dependent penetrance [1, 4].

Table 4. Frequency of cardinal MFS manifestations in adults [1, 4]

Cardiovascular system

Dilatation of the sinuses of Valsalva, found in up to 80% of adults, gives the aortic root its typical “pear-shaped” appearance [1]. Onset and progression are highly variable: it rarely begins in utero, and some patients never reach critical diameters [1]. As normal dimensions depend on body surface area (BSA), sex and age, measurements — particularly in children — must be compared with nomograms and expressed as Z scores; in adults, a root ≥40 mm can generally be considered dilated [1, 64]. Dissection is exceptional in early childhood [4]. In adults, the risk of dissection or rupture becomes significant when the maximum dimension approaches 5.0 cm; risk increases with diameter, growth rate and family history of dissection, but dissection may occur with mild or absent dilatation [1, 4]. Without preventive surgery, dissections are almost always type A (Stanford), involving the root and frequently extending into the descending aorta; dissection causes sudden death in up to 50% of patients in whom it occurs [1, 7].

With improved survival after root replacement, distal disease has increased: in approximately 17% of patients the aorta distal to the root is the first complication site, 8% to 15% require initial surgery on the descending aorta, and 20% require intervention in non-aortic arterial segments (iliac, supra-aortic) after their first aortic intervention [1, 7]. Patients with previous prophylactic root surgery have a substantial risk of type B dissection, even with little descending aortic dilatation; predictors of distal growth and events are diameter, reduced distensibility, aortic tortuosity index and previous root replacement [1]. The reintervention rate is 86% after initial type B dissection versus 42% after type A dissection [1]. Vertebral artery tortuosity occurs in MFS but is much more prevalent in LDS [1].

The atrioventricular valves are most affected, with thickening, prolapse and mitral and tricuspid regurgitation [1]. Mitral prolapse with heart failure is the main cause of cardiovascular morbidity and mortality — and the main surgical indication — in children with severe forms; in most adults with prolapse, regurgitation is tolerable and progresses little [4]. Aortic regurgitation usually results from annular stretching [1]. Mild left ventricular systolic and diastolic dysfunction unexplained by valvular disease, arrhythmias and an increased frequency of sudden death have been described, so patients with palpitations should undergo Holter monitoring [1]. Fatigue is related, at least partly, to orthostatic intolerance, which can be countered by counterpressure manoeuvres (crossing the legs, contracting muscles) [1]. Intracranial aneurysms, mitral annular calcification and cardiomyopathy occasionally occur [7].

Eye

Ectopia lentis, often bilateral, symmetrical and with upward displacement (although it may occur in any direction), is a major criterion and occurs in approximately 60% of patients; it should always raise suspicion of MFS in the absence of trauma [1, 7]. It usually appears in childhood (often preschool age) and may progress slowly [1]. Myopia, often rapidly progressive in childhood, is the most frequent ocular finding and is associated with increased axial globe length, a flat cornea, hypoplasia of the iris or ciliary muscle (with reduced miosis), and increased risk of retinal detachment, glaucoma and early cataract [1, 4, 7]. Slit-lamp examination after maximal pupillary dilatation is essential [4].

Skeleton and growth

Excessive growth of long bones produces disproportionately long limbs relative to the trunk, with an increased arm span/height ratio (>1.05 in adults) and reduced upper segment/lower segment ratio (<0.85 in Caucasian adults; <0.75 in African Americans) [4, 7]. Patients are taller than expected for their family but not necessarily tall relative to the population (Figure 19.6 in CARDIO illustrates an 8-year-old child with MFS who is the same height as their sister, two years older) [1]. Smith growth data give a mean length at birth of 53 cm and final height of 191 cm in males, and 52.5 cm and 175 cm in females, with peak growth velocity 2.4 years (boys) and 2.7 years (girls) earlier and mean menarche at 11.7 years [7]. Arachnodactyly and joint hypermobility produce the wrist sign (Walker–Murdoch: complete overlap of the distal phalanx of the thumb and fifth finger around the opposite wrist) and thumb sign (Steinberg: the distal phalanx of the thumb extends beyond the ulnar border of the closed hand) [1, 3, 46]. Excessive rib growth causes pectus excavatum or carinatum; scoliosis (~60%) may be severe and progressive and cause pain and respiratory restriction; flat feet with hindfoot deformity, acetabular protrusion with accelerated erosion, reduced elbow extension (<170°) and, paradoxically, some reduction in finger mobility and pes cavus occur [1, 4, 7]. The face is long and narrow, with dolichocephaly, enophthalmos, downward-slanting palpebral fissures, malar hypoplasia and retrognathia, a high narrow palate and dental crowding [1, 7]. Skeletal abnormalities emerge and progress during periods of rapid growth [1].

Lung, dura mater, skin and other manifestations

Enlargement of distal airspaces and apical blebs may occur, with a risk of spontaneous pneumothorax; increased residual volume reduces aerobic capacity [1, 4, 7]. Almost one in three patients has at least mild obstructive sleep apnoea, associated with aortic events in one study [1]. Lumbosacral dural ectasia (approximately two thirds of patients) is often asymptomatic but may cause low back pain, proximal lower-limb pain and paraesthesiae, genital or rectal pain, bone erosion, nerve compression and cerebrospinal fluid fistulae with postural headache [1, 4, 7]. Skin texture is normal in most patients, but atrophic striae develop at sites not subject to stretching (lumbar region, anterior and posterior shoulders), as do inguinal and umbilical hernias and recurrent or incisional hernias; muscle and adipose tissue hypoplasia contribute to the asthenic appearance [1, 7]. Intelligence is normal; Smith reports learning difficulties and attention deficit in 42% of 19 children with normal IQ, and the VASCERN/AEPC statement estimates that up to 50% of paediatric patients have neuropsychological deficits, including attention deficit hyperactivity disorder (ADHD) [7, 15]. Intellectual disability should raise suspicion of a contiguous deletion involving FBN1 or another diagnosis [7, 28]. The great majority of patients over 13 years report a positive self-image [4].

Early and rapidly progressive form (“neonatal MFS”)

Severe MFS diagnosed in the first three months of life results from point variants or small deletions in the middle third of the protein (exons 25–32) [7]. Approximately 80% have severe cardiac defects (mitral prolapse, valvular regurgitation, root dilatation), often with heart failure; 64% have congenital contractures; a characteristic face, dolichocephaly, high palate, micrognathia, hyperlaxity, arachnodactyly, flat feet, chest deformity, iridodonesis, megalocornea and lens dislocation are frequent; 14% die in the first year [7]. GeneReviews and the Oxford Desk Reference consider that “neonatal” does not define a discrete category but the extreme of a continuum, and prefer the terms “early onset” and “rapidly progressive” [4, 28].

3.2. Non-Marfan FBN1-related disorders

Familial ectopia lentis (ectopia lentis syndrome) combines lens dislocation with subtle skeletal features and an FBN1 variant not associated with aortic dilatation, or without an identified variant [11, 28]. The MASS phenotype (Mitral valve, Aorta, Skeleton, Skin) comprises mitral prolapse, myopia, borderline non-progressive aortic dilatation (Z <2), skeletal features (systemic score <5 with at least one skeletal feature) and striae, without ectopia lentis; mitral valve prolapse syndrome corresponds to mitral prolapse without aortic dilatation, systemic score <5 and no ectopia lentis [11, 28]. Distinguishing the MASS phenotype from “emerging” MFS in a sporadic case, particularly in children, is difficult, and one study showed that aortic dilatation in these entities is mild and does not progress [1, 4]. There are also rare individuals with predominantly mitral or aortic disease and minimal systemic manifestations [4].

Weill–Marchesani syndrome is characterised by microspherophakia (a small spherical lens), causing lenticular myopia — usually the first finding —, ectopia lentis with downward displacement and pupillary block glaucoma, which may lead to blindness; mean age at recognition of the ocular problem is 7.5 years, and visual loss is earlier and more severe than in other lens dislocation syndromes [5]. Adult height is 142–169 cm in males and 130–157 cm in females, with brachydactyly, short metacarpals, progressive joint stiffness, thick skin and a “pseudomuscular” build; heart disease (patent ductus arteriosus, pulmonary or aortic stenosis, mitral prolapse), prolonged QT and mild intellectual disability in 11% to 17% occur [5]. Estimated prevalence is 1:100,000; dominant (FBN1) and recessive (ADAMTS10, ADAMTS17, LTBP2) forms are clinically indistinguishable [5, 65].

Acromicric dysplasia manifests in early childhood with short stature (final height 115–140 cm), a round face with narrow palpebral fissures, a short bulbous nose, prominent upper lip, short hands and feet, joint stiffness (particularly of the fingers), frequent upper respiratory infections, a hoarse voice and carpal tunnel syndrome; radiological findings include short tubular bones with medial notching of the 2nd and lateral notching of the 5th metacarpal, delayed bone age and small proximal femoral epiphyses [44, 55]. Congenital heart disease has been described but not progressive valvular thickening [55]. Geleophysic dysplasia (from the Greek “happy nature”, because of the full face) presents at birth with short stature (adult 140–150 cm), short hands and feet, contractures, thick skin, hepatomegaly and, crucially for prognosis, progressive cardiac valvular thickening and tracheal narrowing; in Smith, of approximately 25 cases, two children died of tracheal stenosis at 3 and 4 years and three of valvular heart failure at 5 months, 1 year and 5 years [52, 55]. The recessive form (ADAMTSL2) is the original; OMIM also recognises dominant forms caused by FBN1 (type 2) and LTBP3 (type 3), and lysosome-like inclusions have been described in skin, trachea, liver, cartilage and valves [52, 55]. Stiff skin syndrome is a congenital scleroderma with hardened skin, cutaneous nodules, contractures, relatively short stature and compression neuropathies [44, 53]. Marfan–lipodystrophy syndrome (marfanoid–progeroid–lipodystrophy syndrome) combines marfanoid features, congenital lipodystrophy and a progeroid face [4, 48].

3.3. Loeys–Dietz syndrome

LDS is a spectrum ranging from severe syndromic presentations in young children to isolated thoracic aortic aneurysm in adults, with marked intrafamilial variability even for the same variant [1, 3]. The initial reports of LDS types 1 and 2 indicated a mean age at death of 26 years (aortic dissection and cerebral haemorrhage), a figure probably biased by the severity of the first patients; subsequent series show mean rates of root growth similar to those in MFS, and the extent of craniofacial and skeletal features is an indicator of aortic severity, particularly in women of short stature with TGFBR2 variants [1]. In the French series of 71 patients with a TGFBR2 variant compared with 243 with FBN1, the proportion with aortic dilatation (78% vs. 79%), age at surgery and age at dissection were similar; however, dilatation, dissection or sudden death was the index event in 65% of TGFBR2 families, compared with 32% of FBN1 families, and mortality was higher before diagnosis, becoming equal after the disease was recognised [66]. The systematic review by Gouda and colleagues brought together 3,896 cases: the most frequently reported manifestations were aortic aneurysms and dissections, arterial tortuosity, a high palate, an abnormal uvula and hypertelorism; LDS2 appears to have more aggressive aortic disease, LDS3 more mitral prolapse and arthritis, and LDS4 and LDS5 less musculoskeletal and cardiovascular involvement [56].

Cardiovascular system

Root dilatation is present in more than 95% of probands, and the root is the most frequent site of dissection [3]. Around 50% of patients have aneurysms in other arteries, undetectable by echocardiography — the subclavian, renal, superior mesenteric, hepatic, coronary and iliac arteries and the neck and intracranial vessels — and type A dissection has been described from 3 months (CARDIO) or 6 months of age (GeneReviews) [1, 3]. Dissection occurs at diameters considered safe in other diseases (≤45 mm) or without previous dilatation, except in LDS5, in which early dissections or dissections at small diameters have not been described [1]. Arterial tortuosity, particularly of the vertebral and carotid arteries, is present in the majority, and its severity correlates with the degree of aortic dilatation and with younger age at dissection, surgery and death [1, 3]. Carotid or vertebral dissection, or cerebral haemorrhage, rarely occurs without aortic involvement [3]. Mitral prolapse is less frequent than in MFS; patent ductus arteriosus, atrial septal defect and bicuspid aortic valve are at least five times more frequent than in the general population [3, 67]. Atrial fibrillation (24%) and left ventricular hypertrophy (18%) have been described in LDS3, and left ventricular systolic dysfunction in LDS1 [1].

Skeleton, skull and face

Overgrowth is less pronounced than in MFS and affects the fingers more than the long bones; the wrist and thumb signs coexist in around one-third of patients, and acetabular protrusion is also present in around one-third [3]. Clubfoot, camptodactyly and other contractures are characteristic, alongside hypermobility with congenital hip dislocation and recurrent subluxations [1, 3]. Cervical spine abnormalities (malformation or instability) were found in 51% of patients with LDS1 and LDS2 in MacCarrick's series; GeneReviews estimates that at least 15% have structural abnormalities and at least 25% cervical instability [1, 3]. There is a higher incidence of osteoporosis, fractures and delayed union [3]. The distinguishing triad compared with MFS is hypertelorism, cleft palate or bifid uvula (the latter, the minimal form of cleft, may merely be broad or have a median raphe) and arterial tortuosity; craniosynostosis most frequently involves the sagittal suture (dolichocephaly), but also the coronal and metopic sutures [1, 3]. Craniofacial features may be subtle or absent; in the old terminology, subtype A had severe craniofacial features and subtype B mild or absent features, both carrying widespread vascular risk and coexisting within the same family [1, 28].

Skin, allergy, gastrointestinal tract, eye and other manifestations

The skin is velvety, thin and translucent, with visible veins on the chest, easy bruising, slow healing and dystrophic scars, as well as facial milia — findings that overlap with those of vascular Ehlers–Danlos syndrome [1, 3]. There is an allergic and inflammatory predisposition: asthma, food allergy, eczema, allergic rhinitis, eosinophilic oesophagitis and gastritis and inflammatory bowel disease, with raised IgE, eosinophils and Th2 cytokines in some patients [1, 3]. Children frequently have growth retardation and constipation [1]. Myopia is less frequent and less severe than in MFS; strabismus, blue sclerae and, rarely, retinal detachment occur; ectopia lentis does not occur, apart from very rare reports of uncertain significance [3]. Pneumothorax, dural ectasia (at a frequency similar to that in MFS), Chiari type I malformation, hydrocephalus, hernias and spontaneous rupture of the spleen, bowel and gravid uterus complete the clinical picture [1, 3]. Developmental delay, when present, is associated with craniosynostosis or hydrocephalus and is rarely a primary manifestation [3].

Gene-specific features

In LDS3 (SMAD3), early osteoarthritis — affecting the spine, hands/wrists and knees — osteochondritis dissecans, meniscal lesions and disc degeneration are characteristic and may be the presenting complaint [1, 34]. However, several carriers do not have osteoarthritis, and in the Montalcino Aortic Consortium cohort (212 individuals, 51 variants), aortic events occurred in 37% (70% dissections), cumulative risk reached 50% at 54 years, the median age at the first event was 42 years for MH2 missense variants compared with 49 years for haploinsufficient variants, and there were no childhood events [1, 68]. Cramps, paraesthesiae, hypoaesthesia and gait disturbances have also been described in LDS3 [1]. In LDS4 (TGFB2) and LDS5 (TGFB3), aortic phenotypes appear less severe and non-penetrance more frequent, and arterial tortuosity was not observed in LDS5 [1]. LDS5 was defined in 43 patients from 11 families with thoracic and abdominal aneurysms, mitral disease, cleft palate, bifid uvula, skeletal overgrowth, cervical instability and clubfoot [37]. LDS6 (SMAD2) has a variable cardiovascular phenotype, including congenital heart disease [3]. VISS syndrome (IPO8, recessive) combines early thoracic aortic aneurysm, motor delay, hyperlaxity, craniofacial dysmorphism and immune dysfunction [38].

3.4. Non-syndromic HTAD

The diagnosis of non-syndromic HTAD requires familial dilatation and/or dissection of the thoracic aorta, in the absence of MFS, LDS, vascular Ehlers–Danlos syndrome or other syndromic features and of secondary causes such as atherosclerosis [1]. In the majority, dilatation of the sinuses of Valsalva and/or ascending aorta precedes dissection, but dissection may occur well below conventional thresholds; patients with familial HTAD present younger than non-familial cases, but older than patients with MFS, and growth rates were higher in familial cases [1]. The presentation is usually acute dissection, and the family history should include intracranial arterial disease, premature coronary disease, congenital heart disease (coarctation, patent ductus arteriosus) and bicuspid aortic valve [1]. Additional risk factors include smoking, hypertension, strenuous exercise and bicuspid valve [1].

Table 5. Gene-specific phenotypes of non-syndromic HTAD [1, 2, 41, 42, 58, 59, 61, 62, 69]

4. Clinical Recognition and Warning Signs

Early recognition is decisive, because prophylactic surgery prevents dissection and rupture [1, 7]. Clinicians should consider a heritable aortopathy in the following situations:

• Root or ascending aortic aneurysm, or type A dissection, at a young age — atherosclerosis is an infrequent cause of ascending aneurysm; CARDIO defines the group at high risk of genetic predisposition as thoracic aneurysm ≥45 mm or dissection diagnosed before 50 years, or between 50 and 60 years without hypertension, or with a positive family history, or with syndromic features, and bases the indication for genetic testing on a flowchart (adapted from the VASCERN network) combining age, root Z-score and hypertension; GeneReviews emphasises disease before 60 years [1, 2].
• Type B dissection in a young person, particularly with a family history — suggests ACTA2 or PRKG1 [1, 69].
• Non-traumatic ectopia lentis — requires exclusion of MFS (and homocystinuria), lens dislocation being exclusive to FBN1 variants among aortopathies [1].
• Triad of hypertelorism + bifid uvula/cleft palate + arterial tortuosity, craniosynostosis, clubfoot, translucent skin, allergies and eosinophilic oesophagitis — LDS [1, 3].
• Early osteoarthritis or osteochondritis dissecans with aneurysm — LDS3; 20% of patients who presented with joint complaints died suddenly from dissection [1, 70].
• Fixed congenital mydriasis with patent ductus arteriosus in the neonate — ACTA2 p.Arg179 [1, 59].
• Patent ductus arteriosus with familial aneurysm — MYH11 [1].
• Livedo reticularis, iris flocculi, early stroke or coronary disease with aneurysm — ACTA2 [1].
• Family history of aneurysm, dissection, unexplained sudden death before 60 years, aneurysms in other arteries or early valve surgery [2, 28].
• Spontaneous pneumothorax, atypical striae, recurrent hernias, scoliosis and pectus in a tall adolescent — calculate the systemic score [11, 28].
• A “long and floppy” infant with contractures, arachnodactyly and rapidly progressive valve disease — early-onset MFS [7, 28].
• Short stature with short hands, joint stiffness and thick skin, particularly with microspherophakia, valve thickening or tracheal stenosis — “short” fibrillinopathies [44, 55].

The 2025 French PNDS (National Diagnosis and Care Protocol) organises suspicion around three entry situations: in the child, ectopia lentis, particularly from stage 2 onwards, or high and progressive myopia, which point first to FBN1; in the adolescent, the body habitus (tall stature, arachnodactyly, pectus, rapidly progressive scoliosis, flat or cavus feet, increased arm span, facial dysmorphism); and, usually in the adult, aortic dilatation or dissection before 60 years without another cause (hypertension, bicuspid valve), particularly with a family history of aortic disease or sudden death at a young age [6]. Faced with any of these, the protocol requires a search for the signs of the other two and the construction of a pedigree before requesting genetic testing [6]. The classification of ectopia lentis reproduced in the PNDS has six stages: 0, normal; 1, anteroposterior displacement; 2, anteroposterior and superior displacement; 3, anteroposterior subluxation; 4, subluxation with stretching; 5, luxation with rupture [6]. Suspicion also arises from other specialties: dermatology (striae in atypical locations, such as the shoulders), respiratory medicine (recurrent pneumothorax with skeletal signs), vascular medicine and radiology (peripheral arterial aneurysm, dissection or tortuosity) [6]. Regarding skeletal signs, isolated scoliosis above 20° or isolated pectus do not justify referral to a reference centre; referral is justified when at least three of the following are combined: wrist sign, thumb sign, hindfoot deformity, flat foot, upper/lower segment ratio <0.86, arm span/height ratio >1.05, elbow extension <170°, scoliosis or kyphosis, and pectus excavatum or carinatum [6]. Some signs point immediately to a gene: bifid uvula, hypertelorism, tortuosity of the supra-aortic trunks and early osteoarthritis to the TGF-β pathway; livedo reticularis and iris flocculi to ACTA2 [6].

4.1. Alarm signs requiring urgent action

Aortic dissection manifests as sudden, severe chest pain migrating to the neck, back, abdomen or limbs, which may be accompanied by nausea, vomiting, dyspnoea and collapse; it requires activation of the emergency service and transport to a hospital with computed tomography angiography (CT angiography), magnetic resonance angiography (MR angiography) or transoesophageal echocardiography [28]. For mortality from untreated type A dissection, the historical risk was 1% to 2% per hour in the first 48 hours, and most deaths outside hospital result from retrograde rupture into the pericardium with tamponade [2]. Sudden loss of the visual field suggests retinal detachment, and chest, neck or back pain aggravated by inspiration suggests pneumothorax; both require urgent assessment [28]. In vascular Ehlers–Danlos syndrome, which forms part of the differential diagnosis, any unusual sudden pain requires immediate imaging investigation [1]. In its summary for the attending physician, the French PNDS orders the reasoning for chest pain in a patient with MFS or a related syndrome: think first of aortic dissection and then of pneumothorax; the sudden perception of a veil in the visual field or eye pain requires urgent ophthalmological consultation, and reduced visual acuity or ocular discomfort in a child requires a search for ectopia lentis or high myopia [6]. In France there is a dedicated care and emergency card, produced by the Ministry of Health with the reference centre, Orphanet and the MARFANS association, available at the centres, and an Orphanet emergency sheet for MFS and related syndromes [6].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Initial clinical assessment

History-taking should include a three-generation pedigree with targeted questions about parental height, chest deformities, scoliosis, eye problems (lens dislocation, myopia, cataract, glaucoma, retinal detachment), aneurysm or dissection and its location, valve surgery, sudden death at a young age, hypermobility and dislocations, dental crowding and orthodontic treatment, hernias, bruising and abnormal scars, striae and pneumothorax [28]. Physical examination records height, weight, arm span, lower segment and body surface area; scleral colour; intercanthal and interpupillary distances; shape of the head and face, palate and uvula; arachnodactyly, wrist and thumb signs, contractures; Beighton score; chest, spine, skin and feet [28]. Baseline investigations are echocardiography with age and body surface area nomograms, ophthalmological examination with a slit lamp, molecular testing and, when appropriate, plasma homocysteine; thoracic MR angiography or CT angiography is indicated in adults with MFS, in young people with an ambiguous diagnosis and when diffuse vascular disease is suspected [28].

Aortic diameters are measured perpendicular to the flow axis, at reproducible anatomical points; echocardiographic measurements tend to be smaller than CT or MRI measurements [2]. The VASCERN/AEPC paediatric statement recommends measuring the aorta at seven levels (annulus, sinuses, sinotubular junction, ascending, arch, descending and abdominal), using the “inner edge to inner edge” method in systole with Lopez Z-scores, or, alternatively, “leading edge to leading edge” in diastole with the Campens nomograms, always maintaining the same method during follow-up [15]. The Oxford Desk Reference appendix reproduces Roman's two-dimensional nomograms (1989), which warn of overdiagnosis of dilatation when two-dimensional data are applied to M-mode nomograms [64]. In patients whose height differs greatly from the average, indexing to body surface area (aortic size index) or height is more appropriate [2].

The French PNDS makes echocardiography, electrocardiography, ophthalmological examination and spinal radiography systematic in the initial assessment [6]. On echocardiography, diameters are measured at the sinuses of Valsalva, the sinotubular junction, the ascending aorta, the arch, the descending aorta and the abdominal aorta, preferably in a short-axis view; the annulus is measured from trailing edge to leading edge (internal diameter) and the sinuses, the junction and the ascending aorta from leading edge to leading edge, including the anterior wall [6]. Interpretation is by Z-score according to sex, age, height and weight, which must appear in the report: the Campens nomogram is the reference; the Devereux nomogram, based on height alone, is used in obesity or a very slender habitus; under 18 years the Gautier nomogram is used, with measurement in diastole; and the result is more reliable the more concordant the nomograms are [6]. The protocol considers dilatation to be present above Z 2.5 in the adult and Z 3 in the child, reporting thresholds distinct from the Ghent thresholds (Z ≥2 at 20 years or older and Z ≥3 under 20 years), which the same PNDS reproduces in the diagnostic criteria [6] [11]. Echocardiography also looks for bicuspid aortic valve, mitral prolapse, patent ductus arteriosus and atrial septal defect, and assesses left ventricular function [6]. In the adult, ECG-gated thoracoabdominal CT angiography or MR angiography is performed in the initial work-up, extended from head to pelvis if the cause is not FBN1; it validates the echocardiographic diameters, serves as the reference examination and looks for extra-aortic aneurysms [6]. The ECG looks for repolarisation abnormalities (long QT); the ophthalmological examination includes refraction, slit lamp and fundoscopy with the peripheral retina, possibly with ocular ultrasound and axial length measurement; and anteroposterior and lateral radiography of the whole spine, preferably with the EOS system, includes the femoral heads, to measure the Cobb angle, the sagittal profile and acetabular protrusion [6]. Optional investigations are plasma homocysteine (skeletal signs, developmental delay or ectopia lentis), bone age in tall stature, to predict final height, and, in adulthood, cerebral vascular imaging in familial forms of aneurysm and in non-FBN1 syndromic forms, which looks for tortuosity, of prognostic value, and aneurysms [6].

5.2. Marfan syndrome: revised Ghent nosology (2010)

The 2010 nosology rests on two cardinal manifestations — aortic root dilatation/dissection and ectopia lentis — and the FBN1 molecular result; the remaining manifestations form a systemic score [1, 11].

Table 6. Revised Ghent criteria for the diagnosis of MFS [11, 28, 46]

Alternative entities defined by the same nosology: ectopia lentis syndrome (ectopia lentis with or without systemic features and an FBN1 variant not associated with aortic dilatation, or without a variant); MASS phenotype (Z <2 and systemic score <5 with at least one skeletal feature, without ectopia lentis); mitral valve prolapse syndrome (mitral prolapse, Z <2, score <5, without ectopia lentis) [11, 28].

Table 7. Systemic score (maximum 20 points; ≥7 contributes to the diagnosis) [1, 4, 11, 46]

In practice, dural ectasia is assessed by lumbosacral MRI or CT (SGRT suggests MRI of the entire spine), acetabular protrusion and flat foot by radiography, and pneumothorax by chest radiography [1, 46]. In children and adolescents (<20 years) who do not yet fulfil the criteria, provisional designations are suggested: “non-specific connective tissue disorder” if the systemic score is <7 and/or the root Z-score borderline (<3) without an FBN1 variant, until echocardiographic follow-up demonstrates Z ≥3; and “potential MFS” if an FBN1 variant never associated with aortic dilatation is identified in a sporadic case with Z <3 [4, 7]. CARDIO notes that diagnosis remains essentially clinical and that some patients need follow-up before a definitive judgement, and Smith emphasises that the 2010 revision gave more weight to cardiovascular and ocular manifestations and molecular studies than the 1996 Ghent criteria [1, 7].

5.3. Loeys–Dietz syndrome

There are no consensus clinical criteria [1, 3]. Molecular diagnosis is established in a proband with a heterozygous pathogenic or likely pathogenic variant in SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1 or TGFBR2, or biallelic variants in IPO8, and any one of: root dilatation (Z ≥2) or type A dissection; other characteristic features (craniofacial, skeletal, cutaneous or vascular — particularly tortuosity of the head and neck vessels and aneurysms of medium- and large-calibre muscular arteries); or an established family history of LDS [3]. A variant of uncertain significance (VUS) neither confirms nor excludes the diagnosis [3]. Assessment of disease extent requires MR angiography or CT angiography with three-dimensional reconstruction from head to pelvis [3].

5.4. Non-syndromic HTAD

A diagnosis of HTAD may be established in the presence of: (1) a highly penetrant pathogenic variant in an HTAD gene; (2) thoracic aortic disease with one or more affected relatives; or (3) thoracic aortic disease with specific features of an associated syndrome [2]. Assessment of the proband incorporates clinical history (poorly controlled hypertension, dyslipidaemia, sleep apnoea, excessive isometric exercise, smoking), physical examination directed at syndromic features, a three-generation family history with review of records (including aortic histopathology at autopsy), and aortic and arterial imaging [2]. The 2024 European guidelines recommend that patients with suspected genetic aortopathy be assessed in specialised centres, that the entire aorta and other vascular territories be investigated, and that, when suspicion of a genetic cause is strong but testing is negative, genetic reassessment after 3 to 5 years be considered [13, 45].

5.5. Molecular strategy

Table 8. Yield and strategy of molecular testing [1–4, 63]

A larger panel increases the probability of diagnosis, but also of VUS, which occur in around 20% of patients tested; patients with sporadic early thoracic dissection have pathogenic variants in 9% and VUS in HTAD genes in up to 28% [1]. In the 2026 European cohort, carriers of (likely) pathogenic variants had dissection at a younger age and around twice the risk at any age (HR 1.98), COL3A1 carriers had a median age at dissection of 22 years, and patients with more than one VUS dissected earlier [63]. The lists of “core” and “additional” HTAD genes and ClinGen curation guide panel composition [1, 26].

In France, the 2025 PNDS provides for panel testing of approximately forty genes, by next-generation sequencing, in an expert laboratory, possibly complemented by genome sequencing within the France Genomic Medicine Plan when the panel is negative in familial forms or in syndromic sporadic forms; the diagnostic yield is higher in young patients, in the complete syndromic form and when the signs are not explained by another disease [6]. Prescription follows article L. 1131-2 of the French Public Health Code: a geneticist, a genetic counsellor under the geneticist's responsibility, or a non-geneticist physician who knows the disease, its familial consequences and the interpretation of the result and who works with a clinical genetics team [6]. Table 8a summarises the indications of the protocol.

Table 8a. Indications for genetic testing according to the French PNDS (2025) [6]

5.6. Practical algorithm

1. In the presence of root/ascending aneurysm or dissection: measure and convert to a Z-score; assess family history, physical and ocular examination; image the entire aorta [1, 2].
2. If ectopia lentis and aortic dilatation are present: clinical diagnosis of MFS; confirm with FBN1 [11].
3. If LDS features are present (hypertelorism, bifid uvula, tortuosity, craniosynostosis, clubfoot): HTAD panel and MR/CT angiography from head to pelvis [3].
4. If syndromic features are absent: HTAD panel with definitive/strong genes; imaging screening of first-degree relatives, regardless of the result [2, 12].
5. After identification of the variant: gene-specific management and cascade testing; relatives without the variant may be discharged from surveillance [2].

The French PNDS referral algorithm for thoracic aortic disease separates patients at 60 years: up to that age, aortic dissection and dilatation without hypertension lead directly to an experienced centre, and dilatation with hypertension only justifies this if the Z-score at the sinuses or the tubular aorta is ≥3 or there is another risk factor; above 60 years, the patient with Z ≥3 or dissection is referred if there is no hypertension and, if there is, only in the presence of another risk factor; in the remaining cases investigation for heritable aortic disease is not pursued [6].

5.7. Limitations of genetic testing and report content

Coverage depends on the method and not only on the gene. FBN1 sequencing detects missense, nonsense and canonical splice variants and small insertions/deletions but, depending on the method, may not detect deletions or duplications of one or more exons or of the entire gene, which require targeted analysis (MLPA, quantitative PCR or targeted microarray) when sequencing is negative [4]. Panels differ between laboratories in their gene lists and sensitivity for each gene, and their composition should follow ClinGen gene–disease validity curation [4, 26]. Deep intronic variants and complex structural alterations escape panels and exome sequencing and may require genome sequencing and, potentially, RNA studies [1, 2]. Parental leucocyte DNA does not detect all cases of somatic mosaicism and never detects exclusively germline mosaicism, which justifies a recurrence risk slightly higher than that of the population when parents are clinically normal [4]. A negative test does not exclude MFS when the clinical Ghent criteria are fulfilled, nor does it exclude HTAD in a family with aggregation of aortic disease, because the yield in non-syndromic families is only 20% to 30%; in these cases, imaging screening of first-degree relatives is maintained and genetic reassessment after 3 to 5 years is considered [2, 13].

The report should state the gene, reference transcript with version, HGVS nomenclature at cDNA and protein level, zygosity (heterozygosity in dominant genes; biallelic, in homozygosity or compound heterozygosity confirmed by phasing, in IPO8), classification according to ACMG/AMP criteria and the limitations of the method [71]. ClinGen specifications for ACMG/AMP criteria exist for FBN1 (FBN1 Variant Curation Expert Panel, version 1.0, CSpec record GN022, published and updated on 5/1/2022) [72]. The MANE Select transcripts (version 1.5) of the main genes are: FBN1 NM_000138.5; TGFBR1 NM_004612.4; TGFBR2 NM_003242.6; SMAD2 NM_005901.6; SMAD3 NM_005902.4; TGFB2 NM_003238.6; TGFB3 NM_003239.5; IPO8 NM_006390.4; ACTA2 NM_001613.4; MYH11 NM_002474.3 (and NM_001040113.2 as MANE Plus Clinical); MYLK NM_053025.4; PRKG1 NM_006258.4; LOX NM_002317.7; MFAP5 NM_003480.4; and COL3A1 NM_000090.4 [73]. When the literature uses different numbering, both should be stated: the PRKG1 variant “c.530G>A (p.Arg177Gln)” corresponds to NM_006258.4:c.575G>A (p.Arg192Gln) in the MANE transcript [60]; ACTA2 p.Arg179His (NM_001613.4:c.536G>A) and MYLK p.Ser1759Pro and p.Arg1480Ter (NM_053025.4:c.5275T>C and c.4438C>T) already use MANE numbering in ClinVar [60]. Transcript errors also occur in publications: in the real case in section 10.2, the article gives NM_006412.4, which is an AGPAT2 transcript; in the TGFBR1 MANE transcript (NM_004612.4), codon 351 is GAC (aspartate), consistent with the notation c.1051G>T p.(Asp351Tyr) [60, 74].

A variant of uncertain significance is not reclassified as pathogenic on the basis of response to medical treatment or partial segregation: in non-syndromic HTAD, reduced penetrance dependent on age and sex makes unaffected relatives poorly informative, and segregation is described as research until it reaches the weight required by the criteria [2, 71]. A VUS should not be used for predictive testing or to discharge relatives who have not inherited it from surveillance; in these families, surveillance is based on imaging [2, 3]. In the European dissection cohort, patients with more than one VUS dissected earlier, which is a research finding and not a criterion for individual classification [63].

6. Differential Diagnosis

The entities described overlap clinically and genetically and should be included reciprocally in the differential diagnosis; correct diagnosis has prognostic value and changes management and lifestyle [1].

Table 9. Differential diagnosis of heritable aortopathies and marfanoid habitus [1, 2, 4, 28, 46, 75]

The French PNDS organises the differential diagnosis by entry sign (aortic dilatation, ectopia lentis, recurrent pneumothorax, severe scoliosis in the child, marfanoid habitus) and defines marfanoid habitus as the set of isolated Marfan-type skeletal, muscular and cutaneous signs: stature above 2 SD, dolichostenomelia, pectus carinatum or excavatum, wrist and thumb signs, arachnodactyly, high-arched palate, dolichocephaly, scoliosis with or without spondylolisthesis, acetabular protrusion, ligamentous laxity, flat or valgus feet and striae [6]. The final rows of Table 9 add the entities that the protocol includes in the differential diagnosis by entry sign [6].

The distinction between MFS and LDS rests on the triad of hypertelorism, cleft palate/bifid uvula and arterial tortuosity, the absence of ectopia lentis and less marked long-bone overgrowth in LDS [1]. The term “Marfan type 2”, used in 2004 for patients with a TGFBR2 variant, should not be used; no patient with a TGFBR1/2 variant fulfilled Marfan criteria when the absence of discriminating LDS features was required [3, 4]. Nevertheless, in the French series, 10% of TGFBR2 patients fulfilled international MFS criteria, three of them with LDS features [66]. Shprintzen–Goldberg syndrome has highly penetrant intellectual disability and developmental delay, with cardiovascular manifestations that are less frequent and milder than in MFS or LDS; its cause is SKI (missense variants clustered in the R-SMAD-binding domain of exon 1), and ClinGen classifies the association with FBN1 as disputed [4, 75, 79, 80].

Table 10. Comparison of clinical features between MFS, LDS (by gene) and Shprintzen–Goldberg syndrome (− absent; + present; ++ more often present; +++ most frequent) [4]; SGS column according to Table 3 of the SGS GeneReviews [76]

7. Treatments and Risk Management Strategies

7.1. General principles

Many aspects of treatment for heritable aortopathies derive from the experience accumulated in MFS [1]. Management rests on four pillars: regular imaging surveillance of the aorta (and, depending on the gene, of the entire arterial tree); reduction of haemodynamic stress with beta-blockers and/or ARBs; modification of risk factors and lifestyle; and prophylactic surgery at the threshold appropriate to the entity and gene [2, 12, 13]. Prophylactic surgery is the intervention with the greatest impact on survival [1]. The multidisciplinary team includes a clinical geneticist, cardiologist, cardiothoracic surgeon, ophthalmologist and orthopaedic specialist, and follow-up should take place in an experienced tertiary centre [1, 4, 13]. No drug has an indication approved by regulatory agencies for MFS, LDS or HTAD; beta-blockers and ARBs are approved for arterial hypertension, and their use in these diseases is off-label, based on randomised clinical trials (MFS) and expert consensus (the remaining entities) [2, 18–20].

In France, the 2025 PNDS entrusts the initial assessment to a multidisciplinary consultation at a reference or competence centre and requires the beta-blocker or ARB to be initiated by a cardiologist or paediatric cardiologist; the attending physician provides follow-up, screening and management of intercurrent illness, with at least an annual review [6]. Systematic involvement includes the attending physician or paediatrician, cardiologist, ophthalmologist (in FBN1 variants), rheumatologist or orthopaedic surgeon and geneticist; optional involvement extends to respiratory medicine, cardiac and vascular surgery, vascular medicine, physical and rehabilitation medicine, endocrinology, neurology, dermatology, obstetrics and gynaecology, radiology, pain clinic and dentistry and orthodontics; non-medical professionals include physiotherapist, adapted physical activity teacher, psychomotor therapist, occupational therapist, podiatrist, orthotist-prosthetist, speech and language therapist, genetic counsellor, nurse and dietitian [6]. The protocol provides for day hospital admission for a standardised work-up bringing together the various professionals and access to a clinical psychologist from the time the diagnosis is disclosed, with twelve sessions reimbursable by health insurance (“Mon soutien psy” scheme) [6]. Therapeutic education takes place in the centres, often in groups and by teleconference, with patient partners and the MARFANS association, and is recommended in particular during the transition from adolescence to adulthood [6].

7.2. Medical therapy in Marfan syndrome

Rationale and evidence

Beta-blockers reduce the rate of aortic dilatation by lowering blood pressure and ventricular ejection force, and have been standard treatment for decades [1]. The TGF-β hypothesis led to the study of ARBs: following the effect of losartan in the murine model [31], a series of 18 children with severe dilatation refractory to other therapy showed a reduction in root growth from 3.54 ± 2.87 mm/year to 0.46 ± 0.62 mm/year on ARBs (17 with losartan, 1 with irbesartan) [81]. The randomised trials summarised in Table 11 followed.

Table 11. Main randomised trials of ARBs and beta-blockers in MFS [1, 22, 50, 82–86]

Limitations of comparisons between trials. The trials are not directly comparable: primary outcomes differ (Z-score indexed to body surface area, absolute diameter at the sinuses of Valsalva or dilatation in any segment), as do imaging methods (echocardiography or MRI), populations (children and young people in PHN; adults, including those with previous surgery, in COMPARE; 86% on a beta-blocker in Marfan Sartan) and comparators (placebo, open-label control or active drug) [22, 82–86]. The results are mean slopes by group and do not describe the course of each patient; a reduction of 0.07 Z units per year corresponds, in absolute terms, to around 0.2 Z units after three years, and no trial had the power to demonstrate a reduction in dissection, surgery or death [15, 22]. The negative trials (Marfan Sartan, Forteza and the absence of superiority in PHN) form part of the evidence and should not be omitted; the beta-blocker estimate relative to control in the meta-analysis is indirect, and the trials do not allow drugs to be ranked against each other beyond the direct ARB vs. beta-blocker comparison, which showed no difference [22].

COMPARE and Marfan Sartan diverged despite testing the same drug, which is attributed to differences in design, population and beta-blocker dose [1]. The 2022 meta-analysis concluded that, assuming additivity, the combination of an ARB and a beta-blocker from diagnosis would produce greater reductions in aortic growth than either drug alone [22]. There is no demonstration of benefit in hard clinical outcomes (dissection, death) with either class [15]. Smith retains beta-blockers as first-line therapy and losartan for intolerance or progression, reflecting the literature up to 2019 [7], whereas current guidelines treat the two classes as alternatives.

Guideline recommendations

The 2022 ACC/AHA guidelines recommend a beta-blocker or an ARB, at maximally tolerated doses, or both, to reduce the rate of aortic dilatation in MFS [2, 12]. The 2024 ESC guidelines likewise recommend beta-blockers or ARBs at maximally tolerated doses [13, 45]. The 2024 European VASCERN/AEPC paediatric statement recommends starting treatment when the root Z-score reaches 2; considering it in children with a confirmed diagnosis and a normal aorta but indicators of an aggressive vascular phenotype (arterial tortuosity, a truncating variant or a variant causing loss of cysteine in a cbEGF domain, family history of early dissection); using combined therapy when the root is ≥40 mm, Z ≥5 or growth >5 mm/year with an increase in Z of +1 SD/year; titrating to the maximally tolerated dose (potentially guided by reduction in baseline heart rate); considering angiotensin-converting enzyme inhibitors (ACE inhibitors) only when beta-blockers and ARBs are contraindicated; and avoiding calcium channel blockers, which may increase the risk of acute aortic events [15]. The authors note that treating all children regardless of dilatation would mean unnecessary lifelong treatment in around 20%, given the incomplete penetrance of dilatation [15]. GeneReviews, in turn, starts treatment at diagnosis at any age (including children without dilatation if there is a family history of aortic involvement or a variant previously associated with aortic disease), aims for high doses regardless of blood pressure, optimises one drug before adding another and avoids ACE inhibitors and calcium channel blockers owing to a lack of direct evidence [4]. CARDIO recommends systolic pressure below 120 mmHg in all patients with MFS and below 110 mmHg after dissection [1].

Table 12. Recommended oral doses in children with MFS (VASCERN/AEPC 2024 statement) and reference doses in adults [15, 18–20, 83–85]

In MFS, all these drugs are used off-label; paediatric doses come from the VASCERN/AEPC consensus and adult doses from the hypertension label or the cited trials.

The 2025 French PNDS proposes treatment from confirmation of the diagnosis of MFS or a related syndrome in two situations: when there is aortic dilatation and, without dilatation, from 4 years of age in carriers of a pathogenic or likely pathogenic variant [6]. Treatment is continued after aortic surgery, because only part of the aorta has been replaced, and during pregnancy (except ARBs), and is not stopped after delivery [6]. The protocol recalls that the initial randomised trial used propranolol, with beta-blockade defined by heart rate limited to 110/min at peak exercise, and that bisoprolol is now the most widely used beta-blocker in France, although there is no specific study at full dose; beta-blockers may cause orthostatic hypotension or fatigue, which resolve with dose reduction, and are used with caution in severe asthma, in liaison with the respiratory physician [6]. ARBs are an alternative or complement to beta-blockers outside pregnancy, with efficacy suggested by meta-analysis [6] [22]. Calcium channel blockers and ACE inhibitors are no longer considered appropriate treatments to limit aortic dilatation [6].

Table 12a. French PNDS regimens (2025) compared with the European paediatric consensus and with the labels [6, 15, 20, 87]

Divergences between the PNDS and other sources. (1) Initiation without dilatation: the PNDS treats all carriers of a pathogenic or likely pathogenic variant from 4 years of age; the VASCERN/AEPC statement starts at Z ≥2 and only considers treating a normal aorta in the presence of indicators of an aggressive phenotype, and GeneReviews treats at diagnosis at any age [6] [4, 15]. (2) Bisoprolol: the adult full dose in the PNDS (10–20 mg/day) matches the range of the US label for hypertension, whereas the European paediatric consensus sets the maximum at 10 mg; the PNDS gives the paediatric starting dose, but not a maximum [6] [15, 87]. (3) ACE inhibitors: the PNDS excludes them; the paediatric consensus accepts them when beta-blockers and ARBs are contraindicated (Table 12) [6] [15].

Adverse effects and precautions

Beta-blockers are relatively contraindicated in asthma and, according to the paediatric statement, in hyperinsulinism or with difficult glycaemic control [15, 28]. The atenolol label contraindicates it in sinus bradycardia, atrioventricular block greater than first degree, cardiogenic shock and overt heart failure; advises against beta-blockers in bronchospastic disease (atenolol, relatively β1-selective, may be used cautiously at the minimum dose); warns against abrupt withdrawal; and lists bradycardia, cold extremities, postural hypotension, dizziness, fatigue, depression and dyspnoea as the most frequent effects [19]. Atenolol crosses the placenta, and exposure from the second trimester is associated with newborns who are small for gestational age [19]. ARBs carry a boxed warning of fetal toxicity: they should be discontinued as soon as pregnancy is detected, because drugs acting on the renin–angiotensin system in the second and third trimesters reduce fetal renal function and cause oligohydramnios, pulmonary hypoplasia, skeletal deformities, hypotension and fetal or neonatal death [18, 20]. The most frequent adverse effects of losartan (≥2% and above placebo) are dizziness, upper respiratory infection, nasal congestion and low back pain; those of irbesartan in hypertension include diarrhoea, dyspepsia and fatigue, and in diabetic nephropathy hyperkalaemia and orthostatic dizziness [18, 20]. The paediatric statement considers adolescents without contraception and infants under 1 year to have a relative contraindication to ARBs [15]. In practice, the choice of drug in a woman of childbearing age should be discussed before conception.

Drugs and circumstances to avoid

The following should be avoided: contact and competitive sports and isometric exercise; activities causing joint pain or injury; cardiovascular stimulants, including regularly used decongestants and excessive caffeine (which may exacerbate arrhythmias); vasoconstrictors such as triptans; LASIK refractive surgery; breathing against resistance (wind instruments) or positive-pressure ventilation (scuba diving) when there is a predisposition to pneumothorax; fluoroquinolone antibiotics, owing to evidence of worsening predisposition to aneurysm and dissection; and antihypertensive classes without direct evidence in MFS (calcium channel blockers, ACE inhibitors) [4]. In ADHD, non-stimulant drugs are considered safer; if stimulants are necessary, heart rate and blood pressure should be monitored and they should be discontinued if hypertension develops [15].

Investigational therapies

Resveratrol, which reduced aortic growth in a murine model, was tested in a single-arm trial in 57 adults with MFS: after 1.2 years, root diameters remained stable, with a non-significant trend towards less growth (p = 0.072), and a randomised trial is needed [88]. Doxycycline, a metalloproteinase inhibitor, showed benefit only in animal models [89]. Allopurinol, proposed for its antioxidant effect on the basis of several murine models of MFS, received orphan medicinal product designation from the European Commission on 25/03/2025 for the treatment of MFS (EU/3/25/3041; applicant Consorcio Centro de Investigación Biomédica en Red) [23]. The 2026 review advocating its addition to standard treatment describes that designation as “approval”, which is imprecise: orphan designation recognises rarity and plausibility criteria and does not constitute marketing authorisation or proof of efficacy [23, 24]. A letter from October 2026 recommends that future trials include HLA-B*58:01 and renal function screening and stratification by sex, given the dimorphic effects observed in animal models [90]. The ClinicalTrials.gov search on 6/10/2026 did not identify a registered allopurinol trial in MFS, nor new or updated pharmacological trials in the preceding 12 months for MFS or LDS; interventional studies updated during that period were non-pharmacological, such as an adapted physical activity programme in children and adolescents (NCT05838235, recruiting) and a nutritional ketosis study (NCT07495267, not yet recruiting) [91]. The absence of records does not prove that there are no trials in other registries.

7.3. Surgery in Marfan syndrome

Table 13. Thresholds for prophylactic root/ascending aortic surgery in MFS [1, 2, 4, 12, 15, 28, 89]

Women have aortas that are, on average, 5 mm smaller, a difference only partially explained by body surface area, which supports indexed thresholds in patients of short stature [1]. In children, every effort is made to allow the aortic annulus to reach ≥2.0–2.2 cm, permitting a graft suitable for adulthood; many centres use the adult threshold of 5.0 cm given the rarity of dissection in young children [4, 15]. Data from large databases indicate that around 0.5% of dissections in MFS occur before adulthood, particularly in adolescence [15].

Composite replacement of the valve and ascending aorta (Bentall operation) was a low-risk, durable operation for 30 years; in a series of 675 patients with MFS, operative mortality was 1.5% for elective surgery and 11.7% for emergency surgery [1]. In patients with a normal aortic valve, valve-sparing root replacement with coronary reimplantation (David operation, reimplantation technique) is now preferred, with 94.8% freedom from valve reoperation and slow deterioration of valve function in the long term; the remodelling technique (Yacoub) has a higher rate of reintervention for aortic regurgitation [1, 15]. In-hospital mortality from elective surgery in experienced centres is below 1% [15]. Personalised external aortic root support (PEARS) stabilises the root and appears to prevent dilatation, with mortality below 1% in adults, but long-term data are lacking [1, 15]. Endovascular treatment in MFS with dissection should be restricted to emergencies, as a bridge to definitive surgery, owing to progressive dilatation, a high rate of endoleaks, mortality of 12% and the need for further surgery in 14% to 18% [1]. In a contemporary series of 96 thoracoabdominal repairs in MFS, survival was 97% [1]. Mitral surgery (usually repair) should be considered for significant mitral regurgitation with emerging ventricular dysfunction; in children, severe and progressive mitral regurgitation is the principal indication for cardiovascular surgery, and concomitant root surgery should be considered cautiously [4, 28].

The French PNDS considers aortic valve preservation the rule in MFS and related syndromes, with established durability provided that the annulus is contained, to avoid the progressive dilatation sometimes observed with the Yacoub technique (Tirone David or Lansac techniques) [6]. When the valve cannot be preserved, the Bentall operation generally uses a mechanical prosthesis, with lifelong anticoagulation with a vitamin K antagonist and a target INR of 2.5, preferably with self-monitoring (CoaguChek®); a bioprosthesis is an option mainly in women who wish to become pregnant, and direct oral anticoagulants are not used with a mechanical prosthesis [6]. PEARS remains under evaluation [6]. After surgery, protective medical treatment is maintained, because the whole aorta is fragile, as are the rules on physical activity [6]. For the mitral valve, the indications are those of prolapse from other causes, but repair is often difficult because of bivalvular commissural prolapse and, as regurgitation remains moderate for a long time, surgery is rare [6]. An abdominal aortic aneurysm may also justify intervention [6]. Divergences: the growth that brings surgery forward is >3 mm/year in the PNDS, >2 mm/year in CARDIO (ESC 2014) and >5 mm/year with a Z increase of +1 SD in the child (VASCERN/AEPC); for the descending aorta, the PNDS cites 60 mm and CARDIO >5.5 cm in the thoracoabdominal aorta [6] [1, 15].

7.4. Surveillance in Marfan syndrome

Table 14. Recommended surveillance in MFS [1, 4, 15, 28, 46]

MRI allows assessment of descending aortic elasticity, which proved to be an independent predictor of progressive descending dilatation [1]. MRI of the cerebral arteries is not necessary in children with MFS [15].

Table 14a. Follow-up according to the French PNDS (2025) [6]

The PNDS spaces out the ophthalmological examination to every 3 years when the first shows no subluxation, whereas Table 14 (GeneReviews, Oxford Desk Reference) proposes an examination at least annually; in the child, visual acuity is assessed at the protocol's six-monthly paediatric consultation [6] [4, 28]. CT or MRI every 5 years with a stable aorta matches the CARDIO interval for a normal aorta [6] [1].

7.5. Extracardiac manifestations of Marfan syndrome

Refractive errors are usually corrected with spectacles; early and aggressive correction is mandatory in children to prevent amblyopia [4, 28]. Lens removal (surgical aphakia) may be necessary if the lens is freely mobile or its edge obstructs the visual axis, with an intraocular lens to be implanted after growth is complete; retinal detachment is a described, although relatively rare, complication of this surgery [4, 28]. Severe or progressive scoliosis may require bracing or arthrodesis, and tends to stabilise at the end of growth [4, 28]. Pectus correction is primarily cosmetic and rarely medically indicated [4]. Acetabular protrusion is treated with physiotherapy, analgesics and anti-inflammatory drugs; flat foot with insoles or orthoses [4]. Hernias recur and benefit from supporting mesh; recurrent pneumothorax may require chemical or surgical pleurodesis or resection of bullae [4, 28]. There is no effective treatment for symptomatic dural ectasia [4]. Hormonal therapy to limit stature, considered only when extreme height is anticipated, has fallen out of use because of the psychosocial effects of accelerated puberty, the acceleration of growth before growth plate closure and the possible effect of the pubertal rise in blood pressure on the aorta [1, 4, 28]. Some adolescents with severe MFS may have malnutrition requiring nutritional intervention [4]. Endocarditis prophylaxis is recommended only in patients with a prosthetic valve, previous endocarditis or repair with prosthetic material in the first six months (or with a residual defect) [1]; Smith, referring to earlier recommendations, advises it before dental procedures when mitral or aortic regurgitation is present [7]. The French PNDS, following the European endocarditis recommendations, indicates antibiotic prophylaxis with a prosthetic valve, previous valvular or aortic surgery (including repair) and previous endocarditis, excludes isolated mitral prolapse and, after ascending aortic surgery, limits it, in another passage, to cases with a valvular procedure (repair or replacement); it adds education of the high-risk patient, with careful dental care and avoidance of piercings and tattoos [6].

The French PNDS adds detailed guidance for the musculoskeletal system [6]. In children and adolescents it recommends vitamin D supplementation during growth, as in the general population, and an adequate calcium intake, preferably dietary, because of the risk of lower bone mass; in adults, a balanced diet, limitation of bone toxins (alcohol, tobacco, corticosteroids), physical activity and maintenance of 25-hydroxyvitamin D at 30 ng/ml when reduced bone mass is demonstrated or there are fragility fractures; at menopause, densitometry and an individual decision on bone-active treatment; and, at any age, aetiological investigation of fragility fractures, with densitometry and a calcium-phosphate work-up [6]. During growth, bracing is indicated for progressive scoliosis, sagittal plane disorders (kyphosis) and pectus carinatum, combined with physiotherapy; spinal or low back pain prompts a search for growth-related vertebral dystrophy and spondylolysis, and school and home furniture should be adapted to stature; in adults, a cervical collar, lumbar support or rigid brace may be prescribed for pain with functional impact [6]. Dural ectasia may cause low back pain and orthostatic headache, treated in a specialised centre, possibly with an epidural blood patch, a position that diverges from the GeneReviews statement that there is no effective treatment for symptomatic dural ectasia [6] [4]. Growth restriction is only discussed when the predicted final height is very high, in a specialised paediatric centre; the indications, preferably surgical, are exceptional, individual and off-label [6]. In the presence of pulmonary bullae, smoking is discouraged and cessation is encouraged [6].

Rehabilitation aims at exercise reconditioning: muscle assessment in physical and rehabilitation medicine looks for deconditioning, a source of fatigue and pain, and muscle strengthening avoids isometric efforts; physiotherapy treats joint pain and instability and prevents or monitors spinal deformities; psychomotor therapy addresses gross and fine motor disorders in the child; and occupational therapy intervenes as soon as difficulties arise in daily, school or working life and in the trial of furniture and technical aids [6]. Medical devices include custom-made orthopaedic insoles and therapeutic footwear, joint orthoses, braces, collars and lumbar supports, orthodontic appliances, sleep apnoea devices and optical correction (spectacles or contact lenses) in aphakia, anisometropia, high myopia, marked astigmatism or keratoconus [6].

Table 14b. Extracardiac surgical indications according to the French PNDS (2025) [6]

7.6. Physical exercise and sport

The general recommendation is to avoid activities that abruptly increase blood pressure and heart rate: maximal exertion, competitive sport, contact sports (owing to the risk of retinal detachment and aortic injury through deceleration) and isometric exercise (weightlifting, rowing, press-ups, sit-ups), while maintaining regular moderate aerobic activity, such as walking, swimming and non-competitive cycling [1, 4, 28, 46]. The VASCERN/AEPC statement, based on the 2020 ESC sports cardiology guidelines adapted for children, classifies sports as skill, power, mixed and endurance sports, and recommends: competitive sport limited to low-intensity skill sports (bowling, golf, curling); up to 10 years, any recreational sport without restriction, discussing future restrictions; after 10 years, avoiding power sports; above 10 years with root Z <3, skill, mixed or endurance sports at a recreational level and any intensity; with Z ≥3 or ≥40 mm, the same sports at moderate intensity (able to maintain a conversation during exercise) [15]. A prospective study suggested that a personalised home-based endurance and strength training programme may be safe in adults with MFS and an aorta up to 45 mm, and in murine models light aerobic exercise reduced elastic fragmentation [15]. The 2024 ESC guidelines included specific exercise prescription recommendations in MFS [45]. Vocational guidance should take account of the physical demands of the future profession [15].

The French PNDS recommends physical activity as in the general population — at least one hour daily of moderate intensity before 18 years and 150 minutes weekly between 18 and 65 years — for its benefits on quality of life, cardiovascular risk factors and the aortic wall [6]. Before 10 years of age there is no systematic restriction and school sport and active play are encouraged; after 10 years, high-intensity intermittent exertion is avoided [6]. In the adult, competitive sport is contraindicated and aerobic activity at 55–65% of maximal oxygen consumption is advised, without competition or testing limits, with strength exercises limited to 70% of the one-repetition maximum, in short sets of 10 to 12 repetitions with 2-minute recoveries; in team sports, a position with little contact and few abrupt stops is chosen [6]. Jumps and impacts favour ocular complications (lens luxation, retinal detachment) [6]. Table 14c reproduces the protocol's classification of sports, to be discussed with the team and with the adapted physical activity teacher.

Table 14c. Sports in MFS according to the French PNDS (2025) [6]

Tennis appears both among the sports permitted in children and among those strongly discouraged, an internal contradiction of the protocol that may reflect the 10-year limit; scuba diving, permitted as leisure by the PNDS unless there is a history of pneumothorax, is discouraged by GeneReviews when there is a predisposition to pneumothorax; and the PNDS intensity limits (55–65% of maximal oxygen consumption, 70% of the one-repetition maximum) do not appear in the VASCERN/AEPC statement, which uses the ability to converse during exercise as a marker of moderate intensity [6] [4, 15].

7.7. Loeys–Dietz syndrome

Management should take place in a centre familiar with LDS and follows the 2014 primer, updated in 2026 [3, 16, 17]. Many measures applied in MFS also apply to LDS: avoiding isometric exercise, contact and competitive sports and exercise to exhaustion; reducing haemodynamic stress with beta-blockers or ARBs (some centres use ACE inhibitors); and avoiding cardiovascular stimulants, decongestants and triptans [1, 3]. No trial comparing beta-blockers and ARBs in LDS has been completed; ACC/AHA guidelines consider a beta-blocker, an ARB or both at maximally tolerated doses reasonable, extrapolating from MFS and animal models [2, 3, 12]. Reviews from 2026 confirm that LDS recommendations rest on expert consensus and experience with other connective tissue diseases, and that evidence for HTAD subtypes beyond MFS is only emerging [92, 93]. The real clinical case described in section 10 illustrates that medical treatment should begin after genetic confirmation, regardless of blood pressure [74].

Surveillance. Echocardiography of the root and ascending aorta at least annually and MR angiography or CT angiography with three-dimensional reconstruction from head to pelvis at least every two years, more frequently according to genotype, family history, absolute diameter, growth rate or vascular pathology [3]. The ACC/AHA guidelines specify: baseline echocardiography repeated at 6 months and then annually if stable; baseline MRI or CT from head to pelvis; surveillance from chest to pelvis every 2 years in the absence of distal disease; annual MRI or CT of dilated or dissected segments; and cerebral imaging every 2 to 3 years if the initial study is normal [12, 94]. Flexion–extension cervical radiographs should be obtained at diagnosis, repeated every 3–5 years during growth and obligatorily before intubation or cervical manipulation [1, 3].

Table 15. Thresholds for prophylactic root/ascending aortic surgery in LDS by gene [1–3, 12, 89]

CARDIO, reflecting the 2014 primer, indicated surgery for LDS1–3 when the ascending aorta approaches 4.5 cm or grows more than 0.5 cm/year, and in children when it exceeds the 99th percentile (severe craniofacial features) or 4.0 cm (mild features), preferably when the annulus allows a graft adequate for growth [1]. The 2024 ESC and EACTS/STS guidelines also allow the threshold to be lowered to 4.0 cm in LDS, depending on the variant, growth and individual profile, a decision to be made by a multidisciplinary aortic team [89]. Replacement of the root and ascending aorta should be performed together, because aneurysms due to FBN1, SMAD3, TGFBR1, TGFBR2 and TGFB2 almost always involve the root; valve preservation is the intervention of choice [1, 2]. For intact segments of the arch, descending or abdominal aorta, replacement may be considered from 4.5 cm in disease due to TGFBR1, TGFBR2 or SMAD3 (ACC/AHA, class 2b) [12]. For aneurysms in other arteries, elective intervention should be considered when the diameter exceeds two to three times that expected or there is rapid growth [1]. The risk of aortic surgery in LDS is around 1.7% and may be higher in patients with overlap with vascular Ehlers–Danlos syndrome [1]. Surgery does not eliminate the risk of dissection and death, because disease extends beyond the root [3].

The French PNDS applies to TGF-β pathway variants, whose spectrum ranges from syndromic LDS to limited familial aneurysms or dissections and asymptomatic carriers, the same medical therapy as in MFS, with imaging of all vessels, including the cerebral vessels, and the same operative technique; it indicates surgery at a smaller diameter, 45 mm for TGFBR1, TGFBR2 and TGFB2, a value it considers debatable and to be reassessed case by case in an expert centre, and makes no specific obstetric provision for the related syndromes [6]. The 45 mm threshold for TGFBR1 and TGFBR2 is higher than that of GeneReviews (approaching 4.0 cm) and than the lower limit of the ACC/AHA range (≥4.0 to ≥4.5 cm), and coincides with these sources for TGFB2 (Table 15) [6] [3, 12]. The absence of obstetric specificity in the PNDS contrasts with the 4.0 cm pre-pregnancy threshold for TGFBR1, TGFBR2 and SMAD3 (Table 19) [6].

Other manifestations. Cervical instability may require surgical fixation; cleft palate and craniosynostosis are treated by a craniofacial team; clubfoot by orthopaedic correction; severe osteoporosis with fractures under endocrinology guidance; allergies and eosinophilic disease in the standard manner, with referral to allergy/immunology and gastroenterology in severe cases; refractive errors should be corrected aggressively in children [3]. Subacute bacterial endocarditis prophylaxis should be considered for mitral or aortic regurgitation before dental procedures [3]. Patients should be informed about the risk of splenic, bowel and uterine rupture [3].

7.8. Non-syndromic HTAD

Imaging. Baseline echocardiography (CT or MRI if the ascending aorta is not visualised); repeat in 6–12 months to determine the growth rate; thereafter every 6 to 24 months according to diameter and risk factors, more frequently if growth exceeds 0.5 cm/year [2]. Screening for coronary and cerebrovascular disease is recommended in carriers of ACTA2 variants predisposing to occlusive disease, and in ACTA2 carriers disease frequently extends to the distal thoracic aorta, justifying more extensive CT or MRI and simultaneous repair of the root, ascending aorta and arch when surgery is planned [1, 12]. In ACTA2 p.Arg179 syndrome, recommendations are to close the ductus arteriosus early (delay aggravates pulmonary hypertension), assess the entire aorta at diagnosis, begin surveillance of the descending and abdominal aorta at 10 years (or earlier if abnormal), defer root surgery until the annulus can accommodate an adult graft, discuss valve-sparing surgery at 45 mm and monitor peripheral aneurysms annually by ultrasound, repairing those that are symptomatic, thrombosed or >20 mm [1, 59].

Medical therapy and risk factors. Hypertension should be treated aggressively in all patients and relatives at risk, even without aneurysm, with a beta-blocker as first-line therapy and an ARB if necessary; the efficacy of these drugs has not been investigated in molecular causes of HTAD beyond MFS, and their use rests on consensus [2, 12]. Intense isometric exercise, Valsalva manoeuvres, contact sports, smoking and untreated dyslipidaemia should be discouraged [2].

For the contractile apparatus genes (ACTA2, MYLK, PRKG1, MYH11), the French PNDS maintains the cardiological and vascular management of MFS, without skeletal, pulmonary or ophthalmological involvement except in particular forms (such as ACTA2 p.Arg179 syndrome), and leaves operative indications to the reference centre, case by case, according to family history and variant type, recalling that these genes can cause dissection without prior dilatation and with variable penetrance [6].

Table 16. Surgical thresholds in non-syndromic HTAD [1, 2, 12, 95]

The ACC/AHA guidelines adopted gene-specific thresholds, whereas the 2014 ESC guidelines did not; more recent studies indicate that TGFBR-related disease may be less aggressive in at least one subgroup [1]. In the PRKG1 series, most acute type B dissections were treated medically, with repair for aneurysmal degeneration in the chronic phase in 58% (median 2 years) [69]. A recent paediatric review reports that, in PRKG1-related disease, the 2024 AHA statement recommends intervention from 17 years even with mild dilatation [95].

7.9. Non-Marfan FBN1 disorders

In Weill–Marchesani syndrome, early removal of the ectopic lens reduces the risk of pupillary block and glaucoma; glaucoma may require peripheral iridectomy or trabeculectomy, medical treatment being difficult owing to the paradoxical response to miotics and mydriatics, which should be avoided; surveillance includes annual ophthalmological examination, annual assessment of height and joint mobility, regular echocardiography and electrocardiography and careful pre-anaesthetic assessment (joint stiffness, dental malocclusion, maxillary hypoplasia) [5]. Treatment in acromicric and geleophysic dysplasias is symptomatic; in geleophysic dysplasia, valve replacement and airway surveillance may be necessary [52, 55]. Intermittent cardiovascular imaging is recommended in the MASS phenotype and familial ectopia lentis to exclude emerging MFS, particularly in sporadic cases and children [4, 28].

7.10. Regulatory status, evidence hierarchy and off-label use

No medicinal product has FDA or European Union authorisation for MFS, LDS or non-syndromic HTAD; the drugs used are authorised for hypertension and other cardiovascular indications, and their use in these diseases is off-label in both jurisdictions [18–21, 96, 97]. Table 17 summarises the status of the main drugs.

Table 17. Regulatory status of drugs used in heritable aortopathies [18–21, 23, 96, 97]

The hierarchy of evidence should be explicit. In MFS, the recommendation for a beta-blocker or ARB rests on peer-reviewed randomised trials and an individual participant data meta-analysis, but with a surrogate outcome (root growth) rather than dissection or death [12, 15, 22]. In LDS and non-syndromic HTAD, the same recommendation results from extrapolation from MFS and animal models, that is, expert consensus [2, 3, 12]. An orphan designation, such as that for allopurinol, is a regulatory decision about rarity and plausibility, distinct from a favourable CHMP opinion and an authorisation decision; and an authorisation, when it exists, does not guarantee marketing, reimbursement or access in each country, which depend on INFARMED in Portugal and ANVISA and CONITEC in Brazil [23, 97].

Extrapolation of evidence and off-label use are distinct concepts. Off-label use is defined by the wording of the label, age and jurisdiction: ARBs and atenolol are used off-label in MFS at any age; in children, losartan has a US paediatric label only for hypertension from 6 years, irbesartan has no authorised paediatric posology in the US or EU, and atenolol has no established paediatric safety [18–21]. Extrapolation refers to the evidence: applying results obtained in other populations to LDS, non-syndromic HTAD or young children, which adds uncertainty even when the drug is the same [2, 3, 15]. In pregnancy, the issue is not merely the absence of an indication: ARBs carry a boxed warning of fetal toxicity in the US and are contraindicated in the 2nd and 3rd trimesters in the EU, and the European SmPC recommends replacing them before conception with an antihypertensive with an established safety profile in pregnancy unless they are considered essential [18, 20, 21].

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risk

Table 18. Genetic counselling by entity [2–5, 28, 46]

In MFS, in an apparently isolated case, both parents should be examined clinically, with echocardiography and a slit lamp, and tested for the proband's variant; if the parents are unavailable, siblings are assessed [4, 28]. A “negative” family history can only be stated after this assessment, given missed recognition in relatives or the early death of a parent [4]. A parent with somatic and germline mosaicism may be minimally affected [4]. Ectopia lentis may be discordant between affected relatives [28].

8.2. Predictive testing and cascade screening

When the familial variant is known, cascade testing should be offered to parents, siblings, children and other relatives at risk; carriers enter gene-specific management and confirmed non-carriers may be discharged from surveillance [2]. In MFS and LDS, relatives' genetic status should be clarified at any age, because severe cardiovascular manifestations occur in childhood and early treatment is beneficial, justifying predictive testing in asymptomatic children [1, 3, 4]. Without a known variant, a clinical diagnosis of MFS in a first-degree relative is established with ectopia lentis, systemic score ≥7 or Z ≥2 (≥20 years) or ≥3 (<20 years); echocardiography may be deferred in infants until they cooperate without sedation, unless there are signs of valve dysfunction or heart failure [4]. In non-syndromic HTAD, the medical benefit of testing in children is less evident, and testing is usually deferred until adulthood to preserve autonomy; testing of minors should always include psychosocial support [1]. The 2024 ESC guidelines assign class I to screening all first-degree relatives of patients with risk factors for heritable disease, and ACC/AHA class 1 to imaging first-degree relatives of patients with aneurysm or dissection [12, 13, 98]. In France, the PNDS proposes targeted testing of first-degree relatives as soon as a (likely) pathogenic variant is identified in the proband, but does not usually perform presymptomatic diagnosis before 4 years of age, the age from which the result changes management, which diverges from the GeneReviews recommendation to clarify genetic status at any age [6] [4]. Informing at-risk relatives has been a legal obligation since decree no. 2013-527 of 20 June 2013: it is the patient's responsibility, or the parents' if the patient is a minor, to pass on the information, but the physician or genetic counsellor may, at the patient's request, inform relatives directly, respecting medical confidentiality; the result is communicated in a dedicated consultation, with referral to a reference or competence centre and psychological support systematically offered [6].

Imaging screening of relatives without an identified variant (CARDIO, Fig. 19.18). In familial HTAD, begin at 25 years or 10 years before the youngest case in the family (if that case is younger than 25 years); if normal, repeat every 5 years (10-year intervals if diameters are very small or stable); stop at 65 years, and if the first screening is after 60 years, perform at least one follow-up [1]. In sporadic thoracic aortic disease (aneurysm ≥45 mm or dissection before 50 years, or between 50 and 60 years without hypertension or syndromic features), a single screening is sufficient, considering a second after 50 years if the first was performed before 40 [1]. Transthoracic echocardiography is the primary examination, with CT or MRI at the initial assessment; abdominal aortic screening is recommended and, if there are extrathoracic aneurysms, dissections or tortuosity in the family, more extensive screening; screening for intracranial aneurysms is recommended in families with at least two affected individuals [1]. Recommendations co-produced with patients and relatives and published in 2026, based on a synthesis of observational studies, indicate a diagnostic yield above 25% for aneurysm in first-degree relatives of patients with non-syndromic thoracic aortic disease, compared with around 2% incidental findings in the general population, and recommend non-selective imaging screening of these relatives [98].

8.3. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing (PGT-M) are possible [4, 28, 46]. Ultrasound in the first two trimesters has low sensitivity for LDS, although prenatal aortic dilatation has been described [3]. In a French study, 74% of patients with MFS favoured prenatal diagnosis; discussion should take place within a multidisciplinary team, respecting the couple's autonomy [1, 4]. The ideal time for reproductive counselling is before pregnancy, and it should be offered to young adults who are affected or at risk [3, 4]. Consideration of DNA banking from probands without a molecular diagnosis is recommended [3]. In the French PNDS, prenatal diagnosis, invasive or non-invasive, and preimplantation diagnosis may be offered when the familial variant is pathogenic or likely pathogenic, after multidisciplinary assessment of the request (geneticist, obstetrician of the multidisciplinary prenatal diagnosis centre, psychologist) explaining the variability of expression, the psychological risk of a termination of pregnancy and its modalities, with acceptance by the centre and the laboratory and after a period of reflection by the couple [6]. Chorionic villus sampling is performed from 11 weeks of gestation; when the variant is paternally transmitted, non-invasive prenatal diagnosis in maternal blood is possible from 10 weeks; and preimplantation diagnosis requires in vitro fertilisation with selection of an embryo without the variant [6]. The protocol emphasises the rarity of these requests [6].

8.4. Pregnancy

For women with MFS, pregnancy presents a dual problem: a 50% probability of transmission and an increased risk of dissection during and, particularly, shortly after pregnancy, since the third trimester, delivery and the first postpartum month are the period of greatest vulnerability [1, 7]. Most peripartum dissections occur in the third trimester and up to 12 weeks after delivery [2]. With an aorta <40 mm and mild cardiovascular involvement, pregnancy is generally well tolerated, without long-term worsening of dilatation; with an aorta >40 mm, moderate or severe aortic regurgitation, or a family history of early dissection, risk increases [28, 99]. In a study of 55 pregnancies in 35 women with MFS, aortic growth during pregnancy was 0.3 mm/month, decreasing after delivery but remaining above the pre-pregnancy value; in women with root >40 mm, pregnancy influenced long-term growth (0.36 vs. 0.14 mm/year) [1, 99]. More preterm deliveries, premature rupture of membranes and higher offspring mortality are also observed in MFS [1].

Table 19. Thresholds for aortic surgery before pregnancy and guidance on delivery [1, 2, 12, 14, 94, 100]

The 2025 ESC guidelines on cardiovascular disease and pregnancy introduced the mWHO 2.0 risk classification with modifiers derived from CARPREG II, propose an individualised approach to heritable aortopathies (aortic morphology, underlying pathology, family history and genetics) to decide on prior prophylactic surgery and mode of delivery, and recommend care by a cardio-obstetrics team; commentators note that guidance remains limited for LDS and non-syndromic HTAD [14, 100]. Prophylactic root replacement reduces but does not eliminate risk, because it does not protect against descending aortic dissection [4, 28]. Beta-blockers should be continued during pregnancy, acknowledging that they are associated with fetal growth restriction; Oxford Desk Reference reports a slightly more favourable effect of metoprolol than atenolol on birth weight, and the atenolol label confirms the association with newborns small for gestational age, neonatal bradycardia and hypoglycaemia [1, 19, 28]. ARBs and ACE inhibitors should be discontinued before pregnancy or as soon as it is detected [4, 18, 28]. Rapid dilatation during pregnancy may require hospitalisation, intensive care and intravenous therapy [28].

The French PNDS informs women of a risk of dissection in pregnancy approximately eight times higher than in the general population (data from Roman and colleagues, 2016, cited in the protocol) and recalls that dissection can occur without dilatation and even after replacement of the ascending aorta, in the descending aorta [6]. Before pregnancy it requires a work-up in a reference centre, with genetic counselling, information on the follow-up of the pregnancy and of the child, echocardiography and CT or MRI of the whole aorta [6]. During pregnancy it recommends a maternity unit with an experienced obstetric and anaesthetic team (the protocol publishes the list of reference maternity units and obstetricians): level 2 is necessary and sufficient, and a cardiac surgery service must be accessible, preferably on site if the maximum diameter at the start of pregnancy exceeds 40 mm [6]. Echocardiography is performed at least at the end of the second and third trimesters, the beta-blocker is not modified during pregnancy or afterwards, and fetal ultrasound is monthly from the sixth month, because of the risk of fetal growth restriction, which may justify delivery before 37 weeks [6]. The anaesthetic consultation takes place early, to assess epidural analgesia or spinal anaesthesia in the presence of lumbar osteosynthesis material and dural ectasia, possibly with spinal MRI during pregnancy [6]. With a stable cardiac situation, the ideal term is around 37 weeks, with induction between 37 and 38 weeks, preceded if necessary by cervical ripening (prostaglandins are not contraindicated); instrumental delivery is not systematic but shortens expulsive efforts, and pain control limits blood pressure variations [6]. Paediatricians should know that the mother is taking a beta-blocker, to monitor the newborn's heart rate and blood glucose in the first days [6]. After delivery the beta-blocker is continued, because the risk appears highest in the postpartum period; breastfeeding is rather discouraged, particularly if the drug passes into the milk, lactation suppression with cabergoline (Dostinex®) is not contraindicated, and echocardiography is performed in the first month, possibly before discharge [6]. Divergences: the PNDS recommends caesarean section with any history of aortic surgery and not only after dissection (ACC/AHA), does not define the 4.0–4.5 cm zone in which the ACC/AHA consider caesarean section and prefers delivery at 37 weeks; the minimum echocardiography schedule is twice in pregnancy (second and third trimesters) in the PNDS, once per trimester in the ACC/AHA and the Oxford Desk Reference and every 2–3 months in GeneReviews [6] [4, 12, 28].

In LDS, pregnancy and the puerperium carry a risk of aortic dissection or rupture and uterine rupture; with close surveillance and high-risk obstetric care, pregnancy may be tolerated [3]. In Gouda's systematic review, among 222 women with 522 pregnancies, 4% had aortic dissection and peripartum mortality was 1% [56]. In the French series, most pregnancies were uneventful in both TGFBR2 (38 of 39) and FBN1 (213 of 217) families [66].

9. Special Considerations: Population Diversity and Epidemiology

MFS affects men and women equally and all ethnic groups, without known enrichment in any population [1, 4, 46]. Prevalence estimates diverge primarily because of differences in ascertainment: 1:3,000–5,000 in CARDIO, 1:5,000 in Smith, 1:5,000–1:10,000 in GeneReviews, and 6.5/100,000 (around 1:15,000) in the Danish national registry, which applied the 2010 nosology and showed increasing prevalence over time, attributed to the progressive construction of the registry, without differences between sexes [1, 4, 7, 8]. Orphanet classifies MFS in the prevalence class of 1–5/10,000 and records as validated values a point prevalence of 20/100,000 in Europe (expert estimate), 10/100,000 in the US and 7/100,000 in the UK, where the validated birth prevalence is 10.2/100,000; these values measure different quantities (point and birth prevalence) with distinct ascertainment methods and should not be added or compared directly [10]. The 2025 French PNDS adopts the estimate of 1:5,000, which corresponds to approximately 12,000 patients in France; this is an extrapolation from prevalence and not a registry count [6]. The anthropometric ratios used in diagnosis depend on ancestry: the upper/lower segment ratio threshold is <0.85 in Caucasian adults and <0.75 in African Americans [7].

For LDS, prevalence is unknown (estimate of 1:50,000); Orphanet records only a prevalence class of <1/1,000,000 for aneurysm–osteoarthritis syndrome (SMAD3) [3, 10]. For non-syndromic HTAD, there are no population figures by gene; it is known that around 20% of thoracic aneurysms are heritable and that genetic yield is 20% to 30% in non-syndromic families [1, 2]. HTAD penetrance is reduced, particularly in women, and in LDS short stature in women with TGFBR2 variants is associated with more severe disease [1, 2]. Weill–Marchesani syndrome has an estimated prevalence of 1:100,000, and a complete ADAMTS10 deletion is a founder variant in the Amish population [5].

The population data available in the main sources come primarily from Denmark, the UK and the US [8, 10]. No population epidemiological data for MFS, LDS or HTAD in Portugal or Brazil were identified in the sources consulted; the Brazilian reference chapter (SGRT) reproduces the Danish data [46]. This gap in the sources consulted does not demonstrate that no published studies exist, and hospital series, when available, measure the caseload of a centre rather than prevalence. In Europe, patients are guided by the European Reference Network for Multisystemic Vascular Diseases (VASCERN), whose HTAD working group (HTAD-WG) produced the flowchart for indications for genetic testing and the paediatric statement on MFS [1, 15, 25].

10. Illustrative Clinical Case

10.1. Illustrative case: adolescent with Marfan syndrome (case constructed for teaching purposes)

A 14-year-old boy referred to the genetics clinic for myopia of −6 dioptres and “tall stature”. He is 182 cm tall, while his father is 172 cm and his mother 160 cm. He has positive wrist and thumb signs (3 points), pectus carinatum (2), flat foot without hindfoot deformity (1), thoracolumbar scoliosis of 18° (1), lumbar striae (1) and myopia >3 dioptres (1): a systemic score of 9. Slit-lamp examination after mydriasis shows bilateral superior lens subluxation. Echocardiography reveals an aortic root of 36 mm at the sinuses of Valsalva (Z = +3.4 by the Lopez method) and mitral prolapse without significant regurgitation. There is no known family history; the father and mother have normal echocardiography and ophthalmological examinations.

The patient fulfils the Ghent criterion “root Z ≥2 and ectopia lentis” regardless of molecular testing [11]. FBN1 sequencing identifies a de novo missense variant eliminating a cysteine in a cbEGF domain, a class of variants associated with frequent ectopia lentis [1, 49]. Medical treatment is started at Z ≥2, according to the VASCERN/AEPC statement: an ARB or a beta-blocker titrated to the maximally tolerated dose, according to Table 12 (for example, losartan 0.7–1.4 mg/kg/day, maximum 100 mg above 50 kg, off-label use) [15]. Plans are made for annual echocardiography, aortic MRI when tolerated without sedation, annual ophthalmological examination, scoliosis surveillance until skeletal maturity and counselling on moderate-intensity recreational physical activity, avoiding power, contact and competitive sports [4, 15]. Recurrence risk for siblings is low, but higher than in the population because of the possibility of germline mosaicism; for the patient's future offspring it is 50% [4]. If the root reaches 50 mm, or 45 mm with growth >5 mm/year, valve-sparing surgery is discussed [15].

10.2. Real case: TGFBR1-related Loeys–Dietz syndrome with multiterritorial arterial disease (Zhang et al., 2026)

A 44-year-old Chinese woman, with marfanoid habitus (arachnodactyly, thumb sign, severe lumbar scoliosis, flat foot, hypermobility), thin, velvety, translucent skin with easy bruising, myopia and palpitations, and no family history of aneurysm, dissection or sudden death, had right scapular pain in 2018; imaging revealed an abdominal aortic aneurysm of 33.5 mm, with normal iliac and renal arteries [74]. A commercial genetic test identified a variant in the TGF-β pathway, and testing of her parents, sister and daughter was negative. Because blood pressure (105/67 mmHg) and heart rate were normal, neither a beta-blocker nor an ARB was started [74]. The aneurysm grew to 38 mm in 2021 and 39 mm in 2023; in October 2024, with recurrent pain, CT angiography showed 44.8 mm (around 7 mm in 15 months), dilatation of the common iliac arteries and multiple renal aneurysms. Exome sequencing confirmed the de novo heterozygous TGFBR1 c.1051G>T (p.Asp351Tyr) variant, in the kinase domain, classified as (likely) pathogenic [74]. The article's abstract classifies it as likely pathogenic and the text as pathogenic (criteria PS2, PP3 moderate, PM2 and PM5 supporting); the transcript cited in the article (NM_006412.4) belongs to AGPAT2, and in the TGFBR1 MANE transcript the equivalent notation is NM_004612.4:c.1051G>T p.(Asp351Tyr) (section 5.7); the variant was not listed in ClinVar at consultation on 6/10/2026 [60, 74]. The CT angiography images (before and after surgery, with the type B dissection), trio Sanger chromatograms, in silico predictions and structural modelling with immunohistochemistry for phosphorylated SMAD2/SMAD3 are in Figures 1 and 2 of the original open-access article (Europe PMC, PMC13184162), which are not reproduced here [74].

Because of pain, rapid growth and the diagnosis of LDS, she underwent open aneurysm resection with a prosthesis and aortorenal bypass in January 2025, despite the diameter being below the conventional threshold of 50–55 mm [74]. In February 2025, after an episode of emotional stress, acute type B dissection developed without malperfusion; treated medically in intensive care for 3 weeks, she underwent surgery in March 2025 (partial replacement of the thoracic aorta), during which a patent ductus arteriosus undetected on echocardiography was discovered and ligated; she was discharged in April 2025, maintained on oral bisoprolol 5 mg/day and lifelong imaging surveillance (management in the report, not a dose recommendation) [74]. Histology showed fragmentation of elastic fibres and increased SMAD2/SMAD3 phosphorylation, confirming paradoxical TGF-β activation [74]. The authors draw three lessons: the need for periodic imaging of the entire arterial tree from head to pelvis, as recommended by the 2022 ACC/AHA and 2024 ESC guidelines; the requirement to start medical treatment after genetic confirmation, regardless of blood pressure; and the fragility of the residual aorta after major surgery [74]. The case also illustrates the increased frequency of congenital heart disease in LDS (patent ductus arteriosus) and the de novo origin characteristic of many cases [3].

11. Prognosis and Long-Term Follow-Up

The prognosis of MFS is determined primarily by progressive aortic dilatation and dissection [1]. The mean age at death of 32 years in the untreated 1972 series has shifted to a life expectancy close to that of the general population with early diagnosis, prophylactic surgery and medical therapy, although a recent population study indicates a median age at death of 50 years, 8 to 13 years below the population [1, 4, 7, 27]. Mortality from elective root surgery is 1.5% compared with 11.7% in an emergency, justifying prophylactic surgery [1]. After root replacement, disease shifts to the distal aorta and branches: type B dissection and distal and non-aortic arterial interventions require lifelong imaging of the entire aorta [1, 7, 89]. FBN1 variants with a premature termination codon are associated with shorter life expectancy and higher lifetime risk of an aortic event [49]. Causes of premature death also include heart failure from valvular regurgitation [46]. In the neonatal-onset form, 14% die in the first year [7].

In LDS, aortic and arterial disease is the main cause of death; after recognition and treatment of the disease, outcomes approach those of MFS, and craniofacial severity predicts cardiovascular severity [1, 3, 66]. In LDS3, age at onset is later (50% cumulative risk at 54 years, without childhood events) [68]. In non-syndromic HTAD, risk depends on the gene: the earliest onset occurs with PRKG1 and the latest with SMAD3; ACTA2 has a lifetime risk of an aortic event of 76%, and ACTA2 p.Arg179 syndrome has a guarded prognosis, with frequent death before the third decade [1, 58, 59]. In geleophysic dysplasia, tracheal stenosis and valve disease determine early mortality [52].

Long-term follow-up requires organised transition from paediatrics to adult care, a reference centre with a multidisciplinary team and documentation of the course of aortic dimensions using the same method. Use of a medical alert bracelet or card and patient education about the symptoms of dissection, retinal detachment and pneumothorax are recommended [1, 28]. Psychological and social support, patient organisations (Marfan Foundation, Marfan Association UK, Marfan Trust, Loeys-Dietz Syndrome Foundation, GADA Canada) and educational and vocational guidance form part of management [3, 4, 28, 46, 101]. In Europe, the VASCERN HTAD working group brings together reference centres and includes patient representatives [25]. In France, follow-up is organised from the coordinating national reference centre (Hôpital Bichat, Paris), three constituent reference centres (Marseille, Toulouse and Lyon) and competence centres in Bordeaux, Caen, Dijon, Réunion, Lille, Nancy, Nantes, Rennes and Strasbourg, within the FAVA-Multi rare vascular diseases filière, with the MARFANS patient association [6]. The care protocol established by the referring physician, who may be the attending physician, opens entitlement to ALD 31 (“off-list” long-term condition) [6]. The PNDS sets at least an annual clinical review, a six-monthly paediatric consultation in the child (Table 14a) and psychological support accessible from the disclosure of the diagnosis to the end of life [6]. At school, an individualised reception plan may be established in case of fatigability or functional limitation, with educational adjustments (priority access to examination rooms, one-third extra time, exemption from sport), and adjustments are possible without such a plan (a locker to avoid carrying books, furniture adapted to stature, sports exemptions), keeping the child normally integrated; at work, the PNDS provides for workstation adaptation or occupational redeployment when the job requires heavy lifting [6].

12. Summary and Final Considerations

Heritable aortopathies form a genetic and clinical continuum ranging from multisystemic syndromes — MFS, LDS, vascular Ehlers–Danlos syndrome, ACTA2 p.Arg179 syndrome — to non-syndromic HTAD, united by defects in the extracellular matrix, TGF-β signalling and the smooth muscle contractile apparatus [1]. In MFS, diagnosis rests on the revised Ghent nosology, which prioritises root dilatation and ectopia lentis, combined with each other, with the FBN1 result or with a systemic score ≥7 [11]. The same FBN1 gene causes opposite phenotypes — familial ectopia lentis, MASS, Weill–Marchesani syndrome, acromicric and geleophysic dysplasias, stiff skin — which should not be managed as MFS, although they warrant targeted cardiovascular surveillance [4, 44]. LDS, without consensus clinical criteria, is distinguished by the triad of hypertelorism, bifid uvula/cleft palate and arterial tortuosity, the absence of ectopia lentis and diffuse arterial disease requiring head-to-pelvis imaging and lower surgical thresholds, ordered by gene (TGFBR1/2 < SMAD3/TGFB2/SMAD2 < TGFB3) [3, 12]. In non-syndromic HTAD, the gene guides management: ACTA2 (occlusive disease and dissection below 4.5 cm), MYLK and PRKG1 (dissection with little or no dilatation), MYH11 (patent ductus arteriosus) [2, 41, 58, 69].

Beta-blockers and ARBs reduce aortic root growth in MFS to a similar extent, with probably additive effects, but are used off-label, and ARBs carry a fetal toxicity warning that requires pregnancy planning [18, 22]. No drug is authorised for these diseases in the US or EU, and the European orphan designation of allopurinol for MFS (2025) corresponds to a research stage, not an authorisation [23]. Prophylactic valve-sparing surgery, at the threshold appropriate to the entity and gene, is the intervention that changes prognosis [1]. Genetic panel testing with genes of definitive or strong validity, cascade testing and imaging screening of first-degree relatives when no variant is identified are the tools that allow prevention to be extended to the family [2, 13, 26]. Gaps remain: the absence of medical treatment trials in LDS and non-syndromic HTAD, of well-founded thresholds for MYH11, MYLK and LOX, of specific pregnancy guidance in rare forms and, in the sources consulted, of population epidemiological data from Portugal and Brazil [2, 3, 100].

13. References

1. Mulder BJM, van de Laar IMBH, De Backer J. Heritable thoracic aortic diseases: syndromal and isolated (F)TAAD. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 309–336. https://doi.org/10.1007/978-3-030-45457-9_19
2. Cecchi AC, Milewicz DM. Heritable Thoracic Aortic Disease Overview. In: Adam MP, et al., editors. GeneReviews®. Seattle (WA): University of Washington; 2003 [updated 2023 May 4]. https://www.ncbi.nlm.nih.gov/books/NBK1120/
3. Loeys BL, Dietz HC. Loeys-Dietz Syndrome. In: Adam MP, et al., editors. GeneReviews®. Seattle (WA): University of Washington; 2008 [updated 2024 Sep 12]. https://www.ncbi.nlm.nih.gov/books/NBK1133/
4. Dietz H. FBN1-Related Marfan Syndrome. In: Adam MP, et al., editors. GeneReviews®. Seattle (WA): University of Washington; 2001 [updated 2022 Feb 17]. https://www.ncbi.nlm.nih.gov/books/NBK1335/
5. Weill-Marchesani Syndrome. In: Adam MP, et al., editors. GeneReviews®. Seattle (WA): University of Washington. https://www.ncbi.nlm.nih.gov/books/NBK1114/
6. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Syndrome de Marfan et apparentés. Centre de référence national Marfan et apparentés; filière FAVA-Multi. Saint-Denis La Plaine: HAS; text of October 2025 (published on 5 Dec 2025). Available at: https://www.has-sante.fr/jcms/c_676981
7. Jones KL, Jones MC, del Campo M. Marfan syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 658–665.
8. Groth KA, Hove H, Kyhl K, Folkestad L, Gaustadnes M, Vejlstrup N, et al. Prevalence, incidence, and age at diagnosis in Marfan Syndrome. Orphanet J Rare Dis. 2015;10:153. https://doi.org/10.1186/s13023-015-0369-8
9. Online Mendelian Inheritance in Man, OMIM®. Baltimore (MD): Johns Hopkins University. Entries 154700, 134797, 609192, 610168, 613795, 614816, 615582, 619656, 619472, 611788, 132900, 613780, 615436, 616166, 617168, 613834. https://omim.org
10. Orphanet. Marfan syndrome (ORPHA:558); Loeys-Dietz syndrome (ORPHA:60030); Aneurysm-osteoarthritis syndrome (ORPHA:284984); Familial thoracic aortic aneurysm and aortic dissection (ORPHA:91387); Isolated ectopia lentis (ORPHA:1885); Weill-Marchesani syndrome (ORPHA:3449); Acromicric dysplasia (ORPHA:969); Geleophysic dysplasia (ORPHA:2623). Paris: INSERM. https://www.orpha.net
11. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47(7):476-85. https://doi.org/10.1136/jmg.2009.072785
12. Isselbacher EM, Preventza O, Hamilton Black J 3rd, Augoustides JG, Beck AW, Bolen MA, et al. 2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2022;146(24):e334-e482. https://doi.org/10.1161/CIR.0000000000001106
13. Mazzolai L, Teixido-Tura G, Lanzi S, Boc V, Bossone E, Brodmann M, et al. 2024 ESC Guidelines for the management of peripheral arterial and aortic diseases. Eur Heart J. 2024;45(36):3538-3700. https://doi.org/10.1093/eurheartj/ehae179
14. De Backer J, Haugaa KH, Hasselberg NE, de Hosson M, Brida M, Castelletti S, et al. 2025 ESC Guidelines for the management of cardiovascular disease and pregnancy. Eur Heart J. 2025;46(43):4462-4568. https://doi.org/10.1093/eurheartj/ehaf193
15. Muiño-Mosquera L, Cervi E, De Groote K, Dewals W, Fejzic Z, Kazamia K, et al. Management of aortic disease in children with FBN1-related Marfan syndrome. Eur Heart J. 2024;45(39):4156-4169. https://doi.org/10.1093/eurheartj/ehae526
16. MacCarrick G, Black JH 3rd, Bowdin S, El-Hamamsy I, Frischmeyer-Guerrerio PA, Guerrerio AL, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014;16(8):576-87. https://doi.org/10.1038/gim.2014.11
17. MacCarrick G, Afifi RO, Allen R, Almpani K, Black JH 3rd, Boyce AM, et al. Loeys-Dietz syndrome: 2026 updated care management primer. Genet Med. 2026;28(7):102577. https://doi.org/10.1016/j.gim.2026.102577
18. Organon LLC. COZAAR (losartan potassium) tablets — prescribing information (label effective 2026-01-20). U.S. Food and Drug Administration / DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9949448f-c3b9-44ee-94ed-c1aca8c90f39
19. Upsher-Smith Laboratories, LLC. TENORMIN (atenolol) tablets — prescribing information (label effective 2025-09-18). U.S. Food and Drug Administration / DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6e850b1e-28a4-4ff8-8ed7-bb0b29faa28a
20. Sanofi-Aventis U.S. LLC. AVAPRO (irbesartan) tablets — prescribing information (label effective 2026-08-24). U.S. Food and Drug Administration / DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7885b2a8-be4e-48ab-8113-4e6ab791eb98
21. European Medicines Agency. Aprovel (irbesartan) — European Public Assessment Report, EMEA/H/C/000141. Amsterdam: EMA. https://www.ema.europa.eu/en/medicines/human/EPAR/aprovel
22. Pitcher A, Spata E, Emberson J, Davies K, Halls H, Holland L, et al. Angiotensin receptor blockers and β blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials. Lancet. 2022;400(10355):822-831. https://doi.org/10.1016/S0140-6736(22)01534-3
23. European Commission. Union Register of orphan medicinal products: EU/3/25/3041 — Allopurinol, Treatment of Marfan syndrome; Consorcio Centro de Investigación Biomédica en Red; designation dated 25/03/2025. Accessed on 6 October 2026. https://ec.europa.eu/health/documents/community-register/html/orphreg.htm
24. Egea G, de Souza RB, Teixidó-Turà G, Mas-Stachurska A, Evangelista A, Loeys B. Introducing Allopurinol to the Medical Treatment of Marfan Syndrome: Advantages, Limitations, and Potential Extension to other Aortopathies. Cardiovasc Drugs Ther. 2026 (advance online publication). https://doi.org/10.1007/s10557-026-07954-8. PMID: 42752801.
25. VASCERN — European Reference Network on Rare Multisystemic Vascular Diseases. Heritable Thoracic Aortic Diseases Working Group (HTAD-WG). Accessed on 6 October 2026. https://vascern.eu/
26. Renard M, Francis C, Ghosh R, Scott AF, Witmer PD, Adès LC, et al. Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection. J Am Coll Cardiol. 2018;72(6):605-615. https://doi.org/10.1016/j.jacc.2018.04.089
27. Murdoch JL, Walker BA, Halpern BL, Kuzma JW, McKusick VA. Life expectancy and causes of death in the Marfan syndrome. N Engl J Med. 1972;286(15):804-8. https://doi.org/10.1056/NEJM197204132861502
28. Firth HV, Hurst JA. Marfan's syndrome. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 484–488.
29. Lee B, Godfrey M, Vitale E, Hori H, Mattei MG, Sarfarazi M, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature. 1991;352(6333):330-4. https://doi.org/10.1038/352330a0
30. Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352(6333):337-9. https://doi.org/10.1038/352337a0
31. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312(5770):117-21. https://doi.org/10.1126/science.1124287
32. Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37(3):275-81. https://doi.org/10.1038/ng1511
33. Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355(8):788-98. https://doi.org/10.1056/NEJMoa055695
34. van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011;43(2):121-6. https://doi.org/10.1038/ng.744
35. Boileau C, Guo DC, Hanna N, Regalado ES, Detaint D, Gong L, et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet. 2012;44(8):916-21. https://doi.org/10.1038/ng.2348
36. Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012;44(8):922-7. https://doi.org/10.1038/ng.2349
37. Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JMA, de Graaf BM, van de Beek G, et al. Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J Am Coll Cardiol. 2015;65(13):1324-1336. https://doi.org/10.1016/j.jacc.2015.01.040
38. Van Gucht I, Meester JAN, Bento JR, Bastiaansen M, Bastianen J, Luyckx I, et al. A human importin-β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8. Am J Hum Genet. 2021;108(6):1115-1125. https://doi.org/10.1016/j.ajhg.2021.04.019
39. Zhu L, Vranckx R, Khau Van Kien P, Lalande A, Boisset N, Mathieu F, et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006;38(3):343-9. https://doi.org/10.1038/ng1721
40. Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007;39(12):1488-93. https://doi.org/10.1038/ng.2007.6
41. Wang L, Guo DC, Cao J, Gong L, Kamm KE, Regalado E, et al. Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet. 2010;87(5):701-7. https://doi.org/10.1016/j.ajhg.2010.10.006
42. Guo DC, Regalado E, Casteel DE, Santos-Cortez RL, Gong L, Kim JJ, et al. Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet. 2013;93(2):398-404. https://doi.org/10.1016/j.ajhg.2013.06.019
43. Le Goff C, Mahaut C, Wang LW, Allali S, Abhyankar A, Jensen S, et al. Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am J Hum Genet. 2011;89(1):7-14. https://doi.org/10.1016/j.ajhg.2011.05.012
44. Peeters S, De Kinderen P, Meester JAN, Verstraeten A, Loeys BL. The fibrillinopathies: New insights with focus on the paradigm of opposing phenotypes for both FBN1 and FBN2. Hum Mutat. 2022;43(7):815-831. https://doi.org/10.1002/humu.24383
45. SEC Working Group for the 2024 ESC guidelines for the management of peripheral arterial and aortic diseases and SEC Guidelines Committee. Comments on the 2024 ESC guidelines for the management of peripheral arterial and aortic diseases. Rev Esp Cardiol (Engl Ed). 2025;78(3):164-169. https://doi.org/10.1016/j.rec.2024.10.002
46. Oliveira LA, Ribeiro LO, Arrais VH, Ribeiro EM, Carvalho EDF. Síndrome de Marfan. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 265–268.
47. National Center for Biotechnology Information (NCBI). Homo sapiens fibrillin 1 (FBN1), transcript variant 1, mRNA. NCBI Reference Sequence NM_000138.5 (MANE Select; record of 05-FEB-2026) [Internet]. Bethesda: National Library of Medicine. Available at: https://www.ncbi.nlm.nih.gov/nuccore/NM_000138.5 [accessed 2026-10-29]
48. Romere C, Duerrschmid C, Bournat J, Constable P, Jain M, Xia F, et al. Asprosin, a Fasting-Induced Glucogenic Protein Hormone. Cell. 2016;165(3):566-79. https://doi.org/10.1016/j.cell.2016.02.063
49. Arnaud P, Milleron O, Hanna N, Ropers J, Ould Ouali N, Affoune A, et al. Clinical relevance of genotype-phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants. Genet Med. 2021;23(7):1296-1304. https://doi.org/10.1038/s41436-021-01132-x
50. Franken R, den Hartog AW, Radonic T, Micha D, Maugeri A, van Dijk FS, et al. Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome. Circ Cardiovasc Genet. 2015;8(2):383-8. https://doi.org/10.1161/CIRCGENETICS.114.000950
51. Korukonda S, Byers PH, Kovuri P, Dhanekula AS, Wilcox KT, DeRoo S. Genotype-aortic phenotype correlations in Marfan syndrome: a systematic review and meta-analysis of Fibrillin-1 variants. Heart. 2025 (advance online publication). https://doi.org/10.1136/heartjnl-2025-326810. PMID: 41309212.
52. Jones KL, Jones MC, del Campo M. Geleophysic dysplasia. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 516–517.
53. Loeys BL, Gerber EE, Riegert-Johnson D, Iqbal S, Whiteman P, McConnell V, et al. Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci Transl Med. 2010;2(23):23ra20. https://doi.org/10.1126/scitranslmed.3000488
54. Arnaud P, Mougin Z, Baujat G, Drouin-Garraud V, El Chehadeh S, Gouya L, et al. Pathogenic variants affecting the TB5 domain of the fibrillin-1 protein: not only in geleophysic/acromicric dysplasias but also in Marfan syndrome. J Med Genet. 2024;61(5):469-476. https://doi.org/10.1136/jmg-2023-109646
55. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Geleophysic dysplasia; Acromicric dysplasia. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 484–489.
56. Gouda P, Kay R, Habib M, Aziz A, Aziza E, Welsh R. Clinical features and complications of Loeys-Dietz syndrome: A systematic review. Int J Cardiol. 2022;362:158-167. https://doi.org/10.1016/j.ijcard.2022.05.065
57. Regalado ES, Guo DC, Villamizar C, Avidan N, Gilchrist D, McGillivray B, et al. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ Res. 2011;109(6):680-6. https://doi.org/10.1161/CIRCRESAHA.111.248161
58. Regalado ES, Guo DC, Prakash S, Bensend TA, Flynn K, Estrera A, et al. Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations. Circ Cardiovasc Genet. 2015;8(3):457-64. https://doi.org/10.1161/CIRCGENETICS.114.000943
59. Regalado ES, Mellor-Crummey L, De Backer J, Braverman AC, Ades L, Benedict S, et al. Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations. Genet Med. 2018;20(10):1206-1215. https://doi.org/10.1038/gim.2017.245
60. National Center for Biotechnology Information. ClinVar: VCV000065477 (PRKG1 NM_006258.4:c.575G>A, p.Arg192Gln; NM_001098512.3:c.530G>A, p.Arg177Gln), VCV000029598 (ACTA2 NM_001613.4:c.536G>A, p.Arg179His), VCV000030133 and VCV000030134 (MYLK NM_053025.4:c.5275T>C and c.4438C>T); RefSeq NM_004612.4 (TGFBR1) and NM_006412.4 (AGPAT2). Accessed on 6 October 2026. https://www.ncbi.nlm.nih.gov/clinvar/
61. Guo DC, Regalado ES, Gong L, Duan X, Santos-Cortez RL, Arnaud P, et al. LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections. Circ Res. 2016;118(6):928-34. https://doi.org/10.1161/CIRCRESAHA.115.307130
62. Barbier M, Gross MS, Aubart M, Hanna N, Kessler K, Guo DC, et al. MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections. Am J Hum Genet. 2014;95(6):736-43. https://doi.org/10.1016/j.ajhg.2014.10.018
63. Velchev JD, Krebsová A, Votýpka P, Zoubková V, Amsel BJ, Wildiers A, et al. Genetic yield of targeted diagnostic screening in a large European cohort of 368 thoracic aortic dissection patients. Eur J Hum Genet. 2026. https://doi.org/10.1038/s41431-026-02145-3
64. Firth HV, Hurst JA. Normal range of aortic root dimensions. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 841–843.
65. Faivre L, Gorlin RJ, Wirtz MK, Godfrey M, Dagoneau N, Samples JR, et al. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet. 2003;40(1):34-6. https://doi.org/10.1136/jmg.40.1.34
66. Attias D, Stheneur C, Roy C, Collod-Béroud G, Detaint D, Faivre L, et al. Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. Circulation. 2009;120(25):2541-9. https://doi.org/10.1161/CIRCULATIONAHA.109.887042
67. Verstraeten A, et al. Bicuspid aortic valve. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 346–353.
68. Hostetler EM, Regalado ES, Guo DC, Hanna N, Arnaud P, Muiño-Mosquera L, et al. SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium. J Med Genet. 2019;56(4):252-260. https://doi.org/10.1136/jmedgenet-2018-105583
69. Shalhub S, Regalado ES, Guo DC, Milewicz DM. The natural history of type B aortic dissection in patients with PRKG1 mutation c.530G>A (p.Arg177Gln). J Vasc Surg. 2019;70(3):718-723. https://doi.org/10.1016/j.jvs.2018.12.032
70. van der Linde D, van de Laar IM, Bertoli-Avella AM, Oldenburg RA, Bekkers JA, Mattace-Raso FU, et al. Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants. J Am Coll Cardiol. 2012;60(5):397-403. https://doi.org/10.1016/j.jacc.2011.12.052
71. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. https://doi.org/10.1038/gim.2015.30. PMID: 25741868.
72. ClinGen FBN1 Variant Curation Expert Panel. ClinGen FBN1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines, Version 1.0 (Criteria Specification Registry GN022; status: published; updated on 05/01/2022). Accessed on 6 October 2026. https://cspec.genome.network/cspec/ui/svi/doc/GN022
73. Morales J, Pujar S, Loveland JE, Astashyn A, Bennett R, Berry A, et al. A joint NCBI and EMBL-EBI transcript set for clinical genomics and research. Nature. 2022;604(7905):310-5. https://doi.org/10.1038/s41586-022-04558-8. PMID: 35388217. (MANE GRCh38 v1.5 summary file.)
74. Zhang Y, Qiu S, Hu C, Zhang L, Guo W, Fu W, et al. Type B Aortic Dissection Following Abdominal Aortic Aneurysm Repair in Loeys-Dietz Syndrome: A Novel TGFBR1 Variant. Hum Mutat. 2026;2026:2951304. https://doi.org/10.1155/humu/2951304
75. Jones KL, Jones MC, del Campo M. Shprintzen-Goldberg syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 670–672.
76. Greally MT. Shprintzen-Goldberg Syndrome. 2006 Jan 13 [updated 2020 Apr 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. https://www.ncbi.nlm.nih.gov/books/NBK1277/ PMID: 20301454.
77. Bouhatous YM, Arnaud P, Jondeau G, Bonneau D, Rouleau F, Plessis G, et al. Shprintzen-Goldberg syndrome: follow-up of the cardiovascular features in an international cohort of 29 patients with SGS. J Med Genet. 2025;62(9):600-6. https://doi.org/10.1136/jmg-2024-110341
78. Jones KL, Jones MC, del Campo M. Beals syndrome (congenital contractural arachnodactyly syndrome). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 666–669.
79. Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D, et al. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet. 2012;44(11):1249-54. https://doi.org/10.1038/ng.2421
80. Clinical Genome Resource (ClinGen). Gene-disease validity curations: FBN1 and Shprintzen-Goldberg syndrome; Heritable Thoracic Aortic Aneurysm and Dissection Gene Curation Expert Panel. https://search.clinicalgenome.org
81. Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC 3rd. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med. 2008;358(26):2787-95. https://doi.org/10.1056/NEJMoa0706585
82. Lacro RV, Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, et al. Atenolol versus losartan in children and young adults with Marfan's syndrome. N Engl J Med. 2014;371(22):2061-71. https://doi.org/10.1056/NEJMoa1404731
83. Milleron O, Arnoult F, Ropers J, Aegerter P, Detaint D, Delorme G, et al. Marfan Sartan: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2015;36(32):2160-6. https://doi.org/10.1093/eurheartj/ehv151
84. Forteza A, Evangelista A, Sánchez V, Teixidó-Turà G, Sanz P, Gutiérrez L, et al. Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: a randomized clinical trial. Eur Heart J. 2016;37(12):978-85. https://doi.org/10.1093/eurheartj/ehv575
85. Mullen M, Jin XY, Child A, Stuart AG, Dodd M, Aragon-Martin JA, et al. Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial. Lancet. 2019;394(10216):2263-2270. https://doi.org/10.1016/S0140-6736(19)32518-8
86. Groenink M, den Hartog AW, Franken R, Radonic T, de Waard V, Timmermans J, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J. 2013;34(45):3491-500. https://doi.org/10.1093/eurheartj/eht334. PMID: 23999449.
87. Solco Healthcare US, LLC. Bisoprolol fumarate tablets — prescribing information (label effective 2023-06-26). U.S. Food and Drug Administration / DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=084308e4-3b8b-40d6-acbf-d775772a8a73
88. van Andel MM, Bosshardt D, Schrauben EM, Merton R, van Kimmenade RRL, Scholte A, et al. Effects of resveratrol on aortic growth in patients with Marfan syndrome: a single-arm open-label multicentre trial. Heart. 2024;111(1):11-17. https://doi.org/10.1136/heartjnl-2024-324343
89. Oweini W, Jolou J, Sologashvili T, Murith N, Huber C, Cikirikcioglu M. Ascending Aortic Aneurysms: From Pathophysiology to Surgical Repair. J Clin Med. 2025;14(19):6993. https://doi.org/10.3390/jcm14196993
90. Ullah T, Shah MT. Allopurinol for Marfan Aortopathy: Pharmacogenomic Safety and Sex-Stratified Trial Design Warrant Consideration. Cardiovasc Drugs Ther. 2026 (advance online publication). https://doi.org/10.1007/s10557-026-07971-7. PMID: 42825862.
91. ClinicalTrials.gov. Searches for “Marfan”, “Loeys-Dietz” and “thoracic aortic aneurysm hereditary” with last update since April 2025, and for interventional studies with an assigned phase; records NCT05838235 and NCT07495267. National Library of Medicine. Accessed on 6 October 2026. https://clinicaltrials.gov/
92. Abdalla HM, Abdelnabi M, Khedr A, Jamal F, Nwaezeapu KI, Raslan MA, et al. Diagnosis and Management of Loeys-Dietz Syndrome: Evidence Gaps and Future Directions. Curr Cardiol Rep. 2026;28(1):61. https://doi.org/10.1007/s11886-026-02383-3. PMID: 42334665.
93. De Backer JFA, Muiño Mosquera L, Rodriguez-Palomares JF, Teixido-Tura G. Diagnosis and management of heritable thoracic aortic diseases. Heart. 2026 (advance online publication). https://doi.org/10.1136/heartjnl-2025-326230. PMID: 41638893.
94. Fatehi Hassanabad A, McKenzie MP, Keir M, Fedak PWM. Thoracic aortic disease in young patients: from genetics to management. Front Cardiovasc Med. 2026;13:1864645. https://doi.org/10.3389/fcvm.2026.1864645
95. Felici A, Angellotto C, Ruta A, Rongioletti MCA, Versacci P, Mastromoro G. Heritable Thoracic Aortic Diseases in Pediatric Practice: From Molecular Mechanisms to Genotype-Informed Management, a Comprehensive Narrative Review. J Clin Med. 2026;15(14):5342. https://doi.org/10.3390/jcm15145342
96. U.S. Food and Drug Administration. Drugs@FDA: NDA 020386 (Cozaar, approval 14/04/1995), NDA 020757 (Avapro, 30/09/1997) and NDA 018240 (Tenormin, 19/08/1981). Accessed on 6 October 2026. https://www.accessdata.fda.gov/scripts/cder/daf/
97. European Medicines Agency. Medicines output — medicines (EPAR) data report [database]: Aprovel (irbesartan), authorisation dated 26/08/1997; absence of centralised authorisations for losartan and atenolol. Accessed on 6 October 2026. https://www.ema.europa.eu/en/medicines/download-medicine-data
98. Abbasciano RG, Dionne JC, Miksza J, Oczkowski S, Barwell J, Shannon N, et al. Co-produced evidence-based recommendations for cascade screening and secondary prevention in the relatives of people diagnosed with non-syndromic thoracic aortic disease. Front Cardiovasc Med. 2026;13:1724843. https://doi.org/10.3389/fcvm.2026.1724843
99. Meijboom LJ, Vos FE, Timmermans J, Boers GH, Zwinderman AH, Mulder BJ. Pregnancy and aortic root growth in the Marfan syndrome: a prospective study. Eur Heart J. 2005;26(9):914-20. https://doi.org/10.1093/eurheartj/ehi103
100. SEC Working Group for the 2025 ESC guidelines for the management of cardiovascular disease and pregnancy and SEC Guidelines Committee. Insights into the 2025 ESC guidelines for the management of cardiovascular disease and pregnancy. Rev Esp Cardiol (Engl Ed). 2026;79(4):300-304. https://doi.org/10.1016/j.rec.2025.11.004
101. Patient associations: The Marfan Foundation (https://www.marfan.org/); Marfan Trust (https://www.marfantrust.org/); Loeys-Dietz Syndrome Foundation (https://www.loeysdietz.org/); GADA Canada (https://gadacanada.ca/). Pages accessed on 6 October 2026.