Familial and Syndromic Intracranial Aneurysms

Familial clustering of saccular aneurysms of the cerebral arteries without a recognisable syndrome, and intracranial aneurysms arising in monogenic disorders with systemic vascular involvement (autosomal dominant polycystic kidney disease, vascular Ehlers–Danlos syndrome, Loeys–Dietz syndrome, microcephalic osteodysplastic primordial dwarfism type II and others).

Literature and regulatory information updated: 9 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

Saccular intracranial aneurysms (IAs) are acquired pathological dilatations that form at the bifurcations of the major cerebral arteries, particularly in the circle of Willis; when unruptured, they are termed unruptured intracranial aneurysms (UIAs) and occur in up to 3% of the adult population, with a prevalence 1.6 times higher in women and similar across Europe, North America and Japan [24]. Their clinical importance stems from rupture, which causes aneurysmal subarachnoid haemorrhage (aSAH), with a case fatality of 35–45% and severe neurological or neurocognitive impairment in around 30% of survivors [24]. Most IAs have no recognisable monogenic cause; the hereditary component manifests as familial clustering without an associated syndrome, termed familial intracranial aneurysm (FIA, from familial intracranial aneurysm), and as a group of monogenic disorders of connective tissue and the vascular wall in which IAs are part of a systemic vasculopathy [11].

Orphanet defines familial cerebral saccular aneurysm (ORPHA:231160) as a rare genetic neurovascular malformation characterised by saccular dilatations of the cerebral arteries caused by weakening of the endothelial layer, and recognises familial occurrence when there are two or more affected first- to third-degree relatives; it adds that these patients more frequently have multiple aneurysms, a higher rupture risk and poorer outcomes after rupture than patients with sporadic aneurysms [1]. In clinical cohorts and screening recommendations, the operational definition is narrower: two or more first-degree relatives with aSAH or UIA [20, 25, 33]. This difference has practical consequences, because the empirical risks and screening intervals described in the literature were obtained from families defined by the first-degree criterion. ORPHA:1057, “intracranial aneurysms–multiple congenital anomalies syndrome”, is classified as obsolete and has no definition, and acquired aSAH (ORPHA:90065) is treated by Orphanet as a particular clinical situation rather than a genetic disease [2].

The article covers three groups: non-syndromic FIA; IAs associated with monogenic disorders with systemic vascular involvement, of which ADPKD, vEDS and LDS are the most relevant because of their frequency or severity; and less frequent associations or those with more limited evidence (MOPD II, NF1, CoA, FMD, HHT, ACTA2-related multisystemic smooth muscle dysfunction syndrome and occasional occurrences in malformation syndromes). Renal management of ADPKD, aortic management of heritable aortopathies, the other forms of Ehlers–Danlos syndrome, HHT and NF1 are not developed; only aspects concerning intracranial aneurysms and the cervicocephalic arteries are addressed here.

1.2. Historical overview

Familial clustering of aSAH was demonstrated at population level by Schievink and colleagues in a community study in Rochester, Minnesota (United States), analysing patients with confirmed aSAH between 1970 and 1989: of 76 patients with a complete family history, 15 (20%) had a first- or second-degree relative with aSAH, and 11 cases were observed among first-degree relatives versus 2.66 expected, a relative risk of 4.14 (95% CI 2.06–7.40) [34]. In his 1997 review of IA genetics, the same author estimated that heritable connective tissue disorders, then represented by “type IV” Ehlers–Danlos syndrome (now vEDS), Marfan syndrome, NF1 and ADPKD, accounted for at least 5% of cases, although only the association with ADPKD was firmly established; familial aneurysms without connective tissue disease accounted for 7–20% of aSAH, with several modes of inheritance, a screening yield of around 10% in families with two or more affected members and a low likelihood of a major-effect gene [11].

In the following decade, large screening studies quantified risk in relatives. The Dutch MARS study (Magnetic Resonance Angiography in Relatives of patients with Subarachnoid hemorrhage) found aneurysms in 4.0% of 626 first-degree relatives of patients with apparently sporadic SAH [35]; the US FIA study (Familial Intracranial Aneurysm), a multicentre study funded by the National Institute of Neurological Disorders and Stroke (NINDS), screened first-degree relatives with smoking and/or hypertension in families with multiple affected members and found aneurysms in 19.1–20.6% [28, 36]; the Utrecht cohort followed serial screening of individuals with two or more affected first-degree relatives over two decades [20]. In parallel, the natural history of UIAs was described by ISUIA (International Study of Unruptured Intracranial Aneurysms) and the Japanese UCAS cohort (Unruptured Cerebral Aneurysm Study of Japan), whose pooled data gave rise to the PHASES (rupture risk) and ELAPSS (growth risk) scores [37–40].

1.3. Molecular milestones

Linkage analyses in multiple families identified a series of susceptibility loci (ANIB1 to ANIB12 in OMIM), with little replication across studies, reflecting the heterogeneity of FIA [1]. Exome sequencing in selected families identified candidate genes: SMAD3 in a family with thoracic aortic and intracranial aneurysms (2011), RNF213 in French Canadian families (2016), THSD1 in a large family with nine affected members (2016), ANGPTL6 in a large French family (2018), PCNT in autosomal dominant families (2018), PPIL4 (2021) and, more recently, CTSO in two French families (2026) [5, 41–46]. The cross-ancestry genome-wide association study (GWAS) by Bakker and colleagues (2020), with 10,754 cases and 306,882 controls, identified 17 loci and showed that polygenic architecture explains more than half of heritability, with substantial genetic overlap with smoking and blood pressure [6].

1.4. Nomenclature and reclassifications

The former “Ehlers–Danlos syndrome type IV” corresponds to vEDS in the 2017 classification, defined by the presence of a pathogenic variant in COL3A1 [47, 48]. LDS, recognised in 2005, was initially divided into clinical types (type I with craniofacial features, type II with minimal or absent craniofacial features, overlapping with vEDS, and type III with osteoarthritis, corresponding to SMAD3-related aneurysms–osteoarthritis syndrome); GeneReviews now considers LDS caused by variants in any of the seven known genes (SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1 and TGFBR2 in heterozygosity, and IPO8 in homozygosity or compound heterozygosity) to constitute a continuum of combinations of clinical features, and OMIM numbers LDS1 to LDS5 continue to correspond, in this order, to TGFBR1, TGFBR2, SMAD3, TGFB2 and TGFB3 [9, 14]. The 2022 US guideline groups five of these genes under “transforming growth factor beta (TGF-β) vasculopathies”, whereas the 2024 European guideline lists six, including SMAD2 [23, 48]. Aneurysms in MOPD II and RNF213-associated moyamoya vasculopathy belong to disorders distinct from FIA, although they share candidate genes with non-syndromic familial forms [10, 49].

2. Molecular Genetics and Pathophysiology

2.1. Genetic architecture of intracranial aneurysm

IA formation, growth and rupture result from the interaction between haemodynamic loading at arterial bifurcations, the integrity of the endothelium and extracellular matrix of the wall, and acquired factors, of which smoking and hypertension are the strongest and the only modifiable ones [21, 24]. Heritability manifests at three levels of effect. At the polygenic level, the 2020 cross-ancestry GWAS (European and East Asian populations; 10,754 cases and 306,882 controls) identified 17 risk loci, 11 of them novel, with high genetic correlation between ruptured and unruptured aneurysms, evidence implicating endothelial cells and pleiotropy with targets of antiepileptic and sex hormone drugs; genetic risk for smoking and high blood pressure contributes substantially and explains most of the genetic correlation with other cerebrovascular diseases [6]. The 9p21.3 locus, known for its association with coronary artery disease, is also associated with abdominal aortic aneurysm and IA in several populations [50]. At the oligogenic level, rare variants in candidate genes segregate in multiple families, with incomplete penetrance and frequent unaffected carriers (section 2.2). At the monogenic level, IAs are a manifestation of systemic vascular disorders of known cause (sections 2.3 to 2.6).

In July 2026, a multi-ancestry GWAS with fine mapping added three novel loci and 40 credible candidate genes, including GPX1 and NPC1; a gene expression-based classifier achieved an area under the curve (AUC) of 0.89, and a polygenic score applied to UK Biobank had an AUC of 0.83 (0.81–0.84), with a nominal interaction with smoking (p=0.011) [51]. These are research findings: the polygenic score requires independent validation before any clinical use. Another 2026 study, involving 1078 population participants and 682 patients with IA, explored the genetics of circle of Willis configuration and found four suggestive loci (DPYSL2, CSMD3, TRPC6, PKD1L2), with SNP-based heritability estimated at 0.95 (standard error 0.25) for the second principal component of morphology; anatomical variation of the circle is therefore a plausible mediator of risk [52].

2.2. Susceptibility genes in familial intracranial aneurysm

No gene explains a substantial proportion of FIA. Orphanet annotates ANGPTL6 and THSD1 as germline loss-of-function causal genes, ENG as a “major susceptibility factor” and COL3A1 and TGFBR3 as tested candidate genes [1]. The clinical sources consulted do not document the basis for the ENG annotation: the HHT GeneReviews chapter, updated in February 2026, describes cerebral arteriovenous malformations (AVMs) in around 10% of patients but does not describe saccular aneurysms, so the relationship between ENG and isolated saccular IA cannot be quantified from these sources [18].

Exome sequencing of 38 patients with UIA or aSAH (Hamburg) found 20 variants with an allele frequency ≤5% in 18 individuals, distributed across PCNT (9), RNF213 (4), THSD1 (3), ANGPTL6 (2), ADAMTS15 and TMEM132B, and proposed EDIL3 as a new candidate [56]. These data require cautious interpretation: each gene accounts for a small proportion of cases, penetrance is incomplete, and most associations derive from one or two families or from burden studies without independent replication. None of these genes has a definitive gene–disease association established by a curation panel in the sources consulted, and none by itself changes the clinical management of a carrier [3, 4].

2.3. Autosomal dominant polycystic kidney disease

ADPKD results from variants in PKD1 (around 77–78% of families) or PKD2 (around 14–15%), which encode polycystins 1 and 2; GANAB and other rare genes account for mild phenotypes [7, 25]. The 5′ three-quarters of PKD1 are duplicated in six pseudogenes on chromosome 16, requiring specific methods for sequencing (long-range polymerase chain reaction (PCR)) and rearrangement detection (multiplex ligation-dependent probe amplification (MLPA) or microarray) [12]. Patients with variants in either PKD1 or PKD2 are at risk of IA [7]. PKD1 is associated with more diagnoses of IA or SAH than PKD2, but with possible confounding factors (ruptures before renal diagnosis in PKD2 families and more screening in PKD1 families) [21].

Variant position was associated with vascular risk in a 2003 study that described more vascular disease with variants in the 5′ region of PKD1 [7]. The 2025 Kidney Disease: Improving Global Outcomes (KDIGO) guideline reviews this issue and concludes that no specific PKD1 variant is associated with IA: the earlier association with the historical deletion c.5014_5015delAG, normalised as NM_001009944.3:c.5014_5015del p.(Arg1672GlyfsTer98), is explained by its being the gene's most common pathogenic variant (around 1–2%), and a larger study found no association between variant position or type and risk; the guideline states that no genetic determinants of IA formation in ADPKD have been identified [21, 58]. In the Mayo Clinic cohort (812 patients undergoing presymptomatic magnetic resonance angiography), genotype was similar in patients with and without IA [59]. Conversely, a three-generation Chinese family with a PKD1 variant described as “c.G10086T” (notation that does not follow Human Genome Variation Society (HGVS) nomenclature, with no transcript specified in the abstract) had IA in 8 of 21 carriers (38.1%), with functional studies of polycystin 1 trafficking and calcium signalling; this is evidence from a single family and does not allow generalisation of the concept of high-risk PKD1 variants [60].

An August 2026 preprint, not yet peer reviewed, analysed 2200 patients with ADPKD from the Irish Kidney Gene Project, FinnGen and Genomics England: IA or SAH in 158 (7.2%; mean age at diagnosis 51.1 years), female sex with a hazard ratio (HR) of 2.21 (1.50–3.25), smoking with an HR of 2.06 (1.43–2.96), diabetes with an HR of 0.39 (0.22–0.70), no association with the causal gene, and an IA polygenic score with an HR of 1.30 per standard deviation (1.09–1.57), retained in the multivariable model (HR 1.26; 1.03–1.55) [61]. If confirmed, this observation suggests that IA risk in ADPKD depends more on polygenic background and acquired factors than on the PKD1 or PKD2 allele. In the PCK rat model, induced aneurysms develop more rapidly, circle of Willis variations resemble those in patients, and expression of ZO-1, claudin-5 and collagen III in the wall is reduced (preclinical data) [62].

Hypomorphic non-truncating PKD1 alleles, such as p.Arg3277Cys, have reduced penetrance; digenic inheritance with COL4A1 is documented, whose dominant HANAC phenotype (hereditary angiopathy with nephropathy, aneurysms and muscle cramps) includes renal cysts, haematuria, retinal arterial tortuosity, cerebral small vessel disease and aneurysms [12]. The sources consulted do not specify the reference transcript for p.Arg3277Cys.

2.4. Vascular Ehlers–Danlos syndrome

COL3A1 encodes the pro-α1 chains of type III procollagen, a homotrimer abundant in the arterial wall, intestine and uterus [48]. Most pathogenic variants are glycine substitutions in the triple helix or splice variants causing exon skipping, with a dominant-negative effect: in a heterozygote producing normal and abnormal chains in equal amounts, only 1/8 of trimerised molecules have three normal chains [63, 64]. Null variants (around 5% of COL3A1 variants) act through haploinsufficiency and are associated with an approximately 15-year delay in the onset of complications, life expectancy close to that of the general US population and fewer obstetric and intestinal complications; survival is shorter with splice donor site variants and with glycine substitutions by bulky residues (valine, aspartic acid, glutamic acid, arginine) [8]. Penetrance approaches 100% in adults with missense or exon-skipping variants in families ascertained through complications [8]. ClinVar records 1261 pathogenic, 533 likely pathogenic and 2147 variants of uncertain significance (VUS) in COL3A1 [27]. Biallelic COL3A1 variants cause a different phenotype, with polymicrogyria, cerebellar microcysts and white matter disease [64]. Rare COL1A1 variants involving arginine-to-cysteine substitution (p.(Arg312Cys), p.(Arg574Cys), p.(Arg1093Cys)) are associated with arterial fragility overlapping with vEDS; the source does not specify the transcript [63].

2.5. Loeys–Dietz syndrome and other heritable aortopathies

LDS genes encode components of the transforming growth factor beta (TGF-β) pathway: receptors (TGFBR1, TGFBR2), ligands (TGFB2, TGFB3) and intracellular mediators (SMAD2, SMAD3) [9, 48]. In SMAD3, truncating variants are distributed across all nine exons and missense variants cluster in the MH2 domain, with a probable loss-of-function effect and no clear genotype–phenotype correlation; TGFB2 and TGFB3 variants (missense, frameshift, nonsense and splice variants) also act through loss of function [14]. There is considerable intrafamilial variability and apparent non-penetrance, and the most severe cases are predominantly de novo [14]. In the Montalcino consortium (212 carriers of SMAD3 variants), median age at the first aortic event was 42 years with MH2 missense variants and 49 years with haploinsufficiency variants [15]. The family in which SMAD3 was identified as a cause of familial thoracic aortic aneurysm also had intracranial and abdominal aortic aneurysms, with a frameshift variant (c.652delA) and a combined LOD of 5.21 with three other families; SMAD3 accounts for around 2% of familial thoracic aortic aneurysms and dissections [41].

Among the other aortopathies, multisystemic smooth muscle dysfunction syndrome, caused by de novo variants at codon R179 of ACTA2, combines cerebral small vessel disease, intracranial arterial stenoses and fusiform dilatation of the internal carotid arteries with terminal stenoses, a pattern similar but not identical to moyamoya [14].

2.6. Other monogenic disorders with intracranial aneurysms

MOPD II, the most common form of microcephalic primordial dwarfism, results from biallelic loss-of-function variants in PCNT (pericentrin, a centrosomal protein) and causes a global vasculopathy with neurovascular (moyamoya and aneurysms), coronary and renal disease [10]. Founder variants have been described in Colombia (c.1468C>T, p.(Gln490Ter)) and in the Druze population of Israel (c.3465-1G>A, p.(Ala1157ProfsTer36)); the source does not specify the transcript [10]. In NF1, vasculopathy includes stenoses and ectasia of the cerebral arteries, moyamoya and IAs more frequent than in the general population, without a numerical frequency in GeneReviews [17]. Non-syndromic fibromuscular dysplasia has no identified genetic cause, but clusters in first-degree relatives and has PHACTR1 as a susceptibility locus [9]. RNF213 encodes mysterin, an atypical E3 ubiquitin ligase of around 591 kDa with an AAA+ ATPase domain, whose East Asian founder allele p.R4810K, normalised as NM_001256071.3:c.14429G>A p.(Arg4810Lys), is the main susceptibility factor for moyamoya [49, 58].

2.7. Normalisation of the cited variants

The cited variants were normalised using VariantValidator on the MANE Select (Matched Annotation from NCBI and EMBL-EBI) transcript and the GRCh38 genome; those described by the sources without a coding position or transcript retain their original nomenclature [58].

3. Clinical Spectrum and Manifestations by Organ System

3.1. Natural history of unruptured aneurysm in the general population

Most UIAs are asymptomatic and discovered incidentally; symptoms, when they occur before rupture, result from compression (cranial nerve palsies, particularly the third nerve, mass effect) or thromboembolic events [12, 24]. A meta-analysis of 68 studies (83 populations from 21 countries; 94,912 people) estimated a prevalence of 3.2% (95% CI 1.9–5.2) in a population without comorbidity, with a mean age of 50 years, a prevalence ratio of 1.61 (1.02–2.54) in women, increasing to 2.2 (1.3–3.6) above 50 years, and an almost zero prevalence below 30 years (ratio of 0.01 relative to ages over 80 years) [19]. Prevalence does not differ significantly in Japan (ratio 0.8; 0.4–1.7) or Finland (1.0; 0.4–2.4) compared with the United States, so the higher incidence of SAH in these countries is explained by higher rupture risk rather than higher prevalence [19].

The meta-analysis of nine prospective cohorts used by the 2022 European Stroke Organisation (ESO) guideline (309 ruptures in 33,923 patient-years) estimated a 1-year rupture risk of 0.81% (95% CI 0.61–1.05), with heterogeneity of 73.3% [24]. The individual participant data analysis that generated the PHASES score (8382 participants from six prospective cohorts; 230 ruptures in 29,166 person-years) observed risks of 1.4% (1.1–1.6) at one year and 3.4% (2.9–4.0) at five years and identified population (Population), hypertension (Hypertension), age ≥70 years (Age), size (Size), previous SAH from another aneurysm (Earlier SAH) and site (Site) as predictors; 5-year risk ranges from 0.25% (under 70 years, no vascular risk factors, aneurysm <7 mm in the internal carotid artery) to over 15% (70 years or older, hypertension, previous SAH, giant posterior circulation aneurysm), and Finnish and Japanese individuals have 3.6- and 2.8-fold higher risks [39]. PHASES does not include morphology, family history, smoking or changes in hypertension over time, was developed in cohorts of patients selected for no treatment, and has a 5-year horizon, which is short for young patients [24].

Growth is a marker of instability. In the pooled ELAPSS analysis (10 cohorts; 1507 patients; 1909 aneurysms; 5782 patient-years), growth occurred in 17% of patients and 14% of aneurysms, and the risk of growth ranged from less than 5% to over 42% at three years and from less than 9% to over 60% at five years, depending on previous SAH, site, age over 60 years, population, size and shape; the score did not include family history or smoking during follow-up [24, 40]. After documented growth (≥1 mm in any direction), absolute rupture risk is 2.9% (0.9–4.9) at six months, 4.3% (1.9–6.7) at one year and 6.0% (2.9–9.1) at two years; in a multicentre study of 312 patients with 329 untreated growing aneurysms (864 aneurysm-years), 25 (7.6%) ruptured, with size ≥7 mm (HR 3.1; 1.4–7.2) and irregular shape (HR 2.9; 1.3–6.5) as predictors, and the triple-S model (size, site and shape) estimates 1-year rupture risks of 2.1–10.6% [24]. Smoking and a family history of SAH are additional rupture risk factors [24].

3.2. Familial intracranial aneurysm

Familial aneurysms differ from sporadic aneurysms in several respects. In the FIA study, 2874 participants from 542 families were assessed and 548 relatives without a known aneurysm underwent magnetic resonance angiography: 113 (20.6%) had 148 aneurysms, almost all small; two ruptures occurred (3- and 4-mm anterior communicating artery aneurysms), corresponding to 1.2 ruptures per 100 person-years (95% CI 0.14–4.3), around 17 times the rate observed in ISUIA for aneurysms of equivalent size and site (0.069%/year), and no ruptures in the 435 with negative magnetic resonance angiography [36]. This is an indirect comparison, relatives were selected for smoking and/or hypertension, and the calculation is based on only two events [25]. In the Utrecht cohort (1994–2016), 62 patients with FIA (91 UIAs) had 3 ruptures (0.77 per 100 aneurysm-years; 0.20–2.09) and 412 patients with sporadic aneurysms (542 UIAs) had 7 (0.51; 0.22–1.01), a hazard ratio of 2.9 (0.6–14) without statistical significance, despite familial aneurysms being smaller and located at lower-risk sites [33].

Familial aneurysms rupture at younger ages, but there is no intrafamilial concordance in age or size at rupture, so the size of a relative's ruptured aneurysm should not guide management of another relative's UIA [25]. In the FIA study, 10 of 58 relatives with an aneurysm (17.2%) had multiple aneurysms, and female sex (odds ratio [OR] 2.46), 20 pack-years compared with never smoking (OR 3.24), and each 10 years of hypertension (OR 1.26) predicted detection [28]. In the MARS study, siblings had four times the risk of offspring, and risk was higher when the index case had multiple aneurysms or was younger [35].

3.3. Autosomal dominant polycystic kidney disease

IAs are the most serious non-cystic manifestation of ADPKD, which also includes aneurysms of other arteries, dolichoectasia, aortic root dilatation, thoracic aortic and cervicocephalic arterial dissections, valvular disease and mitral valve prolapse [12, 21]. The KDIGO meta-analysis (six screening studies; 389 of 3031 patients) estimated a prevalence of 12.9% (10.4–15.4), with studies ranging from 9.2% (Sanchis, Mayo Clinic) to 18.5% (Yoshida, Japan), and 17.1% (13.4–21.1) with a family history; ADPKD is associated with a prevalence ratio of 6.9 relative to the general population [19, 21]. Older textbook sources give lower figures (around 6% in Oxford Desk Reference and around 10% in GeneReviews, the latter with 22% among those with a family history of intracranial haemorrhage versus 6% without), because they were based on series with less systematic screening [7, 12]. In the French Genkyst cohort, with non-systematic screening, 4.7% of participants had a diagnosed IA and 47% of these had a family history; frequency reached 8.1% by age 70, higher in women (10.8% versus 5.4%) [12]. These figures measure frequencies in clinical cohorts with different degrees of screening, not population prevalences.

Most aneurysms detected on screening are smaller than 5 mm and around 90% are in the anterior circulation; 15–25% of patients with IA have multiple aneurysms [21]. The pooled rupture incidence is 0.57 per 1000 patient-years (0.19–1.14), around seven times that of the general population (0.079 per 1000 person-years), with considerable variation between cohorts: 1.71 per 1000 in France (2008–2015), 1.00 in Japan, 0.37 at Mayo Clinic and 0.24 in a US cohort of 9110 patients [21]. Rupture occurs at a median age of around 41 years, versus 52 years in the general population; in the Finnish Kuopio cohort (database of 4436 patients with IA), the 53 patients with ADPKD had aSAH ten years earlier (42.8 years), from smaller aneurysms (median 6.00 versus 8.00 mm), with more multiple aneurysms (45% versus 28%) and de novo formation of 1.3% per patient-year versus 0.2% (HR 7.7; 2.8–20) [21, 66]. At rupture, most patients have normal renal function and up to 30% have normal blood pressure [12].

Aneurysms detected on screening show little growth. At Mayo Clinic, 45 saccular aneurysms in 38 patients (median 3.5 mm) were followed for 243 imaging-years, with one new aneurysm, two instances of growth and no rupture during 316 years of clinical follow-up; in a later series from the same centre, 75 patients followed by magnetic resonance angiography had no ruptures, 13% showed growth (a mean of 2 mm over six years), and five developed new aneurysms [21, 67]. In a Japanese cohort of 712 patients with baseline and follow-up imaging (4580 person-years), the incidence of new aneurysms was 1.2 per 100 person-years when initial screening was positive and 0.26 when it was negative (adjusted HR 3.81; 1.50–9.67) [68]. Rupture carries a combined rate of severe morbidity and mortality of 35–55% at three months; KDIGO reports mortality exceeding 30% and morbidity of 50%, and outcomes after SAH are similar with and without ADPKD (good outcome at 12 months in 75% versus 71% in Kuopio) [12, 21].

ADPKD is also associated with vasospasm and transient ischaemic complications after cerebral angiography, central retinal arterial and venous occlusions, and spinal meningeal diverticula with intracranial hypotension due to cerebrospinal fluid leakage [12]. In older series, angiography complications occurred in 25% versus 10% of patients without ADPKD, and complications of coiling and clipping in 9.4% versus 3.0% and 11.8% versus 6.4%, respectively [21].

3.4. Vascular Ehlers–Danlos syndrome

vEDS is an arteriopathy of medium-sized arteries, with dissections, aneurysms, ruptures and arteriovenous fistulae that may occur without preceding dilatation; rupture without a prior aneurysm occurred in 33% of patients with a severe haemorrhagic complication in one review [14, 48]. Vascular rupture or dissection, gastrointestinal perforation or organ rupture is the presenting feature in 70% of adults with a COL3A1 variant: arterial rupture sites are the thorax and abdomen in 66%, head and neck in 17%, and extremities in 17% [8]. Complications are rare in childhood, but occur in up to 25% before age 20 and in 80% before age 40; 70% of adults have a major complication before age 30, and the first major arterial or gastrointestinal event occurs at a mean age of 31 years [27, 63, 64]. In Pepin's 2000 series, around 80% of deaths from dissection or rupture involved thoracic or abdominal vessels, and fewer than 10% resulted from intracranial haemorrhage [63].

In the cervicocephalic territory, vEDS affects the vertebral and carotid arteries and causes IA, SAH, dissections with infarction and, characteristically, spontaneous carotid–cavernous fistula (CCF) [14, 27]. CCF presents with sudden blurred vision, diplopia due to sixth nerve palsy, ocular pain, proptosis and chemosis, almost always requires prompt intervention to preserve vision, and affects up to 10% of patients, predominantly women [8]. In the French single-centre cohort of 133 patients (2000–2017), 13 (9.8%) had spontaneous direct CCF, 92.3% were women, with a median age of 33 years; variants were glycine missense (7) and splice variants (6), none causing haploinsufficiency, and female sex was the only predictor; the authors conclude that spontaneous direct CCF in an apparently healthy young adult should raise strong suspicion of vEDS [69]. In the US collaborative natural history study (557 patients with a COL3A1 variant), women had more CCF and more spontaneous coronary artery dissections, men more aortic disease and iliac and visceral arterial disease (74.2% versus 57.9%), and overall mortality was 32.3% in men versus 20.4% in women (p=0.001) [70].

Outside the vascular system, vEDS causes intestinal perforation (around 15–25%, mainly sigmoid), uterine rupture, spontaneous pneumothorax (12%), easy bruising (the most frequent initial sign in children), thin translucent skin, acrogeria, tendon rupture and, in newborns, clubfoot (8%) and congenital hip dislocation [8, 14, 64]. The characteristic facial appearance (thin nose and lips, prominent eyes, sunken cheeks) is present in fewer than 30% of patients [14].

3.5. Loeys–Dietz syndrome

In LDS, aneurysms and dissections predominantly involve the aortic root, but around 50% of patients have aneurysms in other arteries, including cerebral arteries, and most have tortuosity of the head and neck arteries, particularly vertebral and carotid arteries, more frequent than in Marfan syndrome and associated with an adverse prognosis [9, 14]. The 2022 American College of Cardiology/American Heart Association (ACC/AHA) guideline reports cerebral aneurysms in 10–18% of patients with LDS; in a series of 90 patients with TGFBR1 or TGFBR2 variants, 10% had aneurysms of head and neck branches [23]. Initial reports of LDS1 and LDS2 indicated a mean age at death of 26 years, with aortic dissection and cerebral haemorrhage as the main causes, probably affected by ascertainment bias [14]. In aneurysms–osteoarthritis syndrome (SMAD3; 44 patients from 7 families), 9 of the 16 patients with cerebrovascular imaging (56%) had a cerebrovascular abnormality [15].

Cohorts with systematic imaging provide a more precise picture. In a multicentre Mayo Clinic study, 18 of 60 patients with LDS and cerebrovascular imaging (30%) had IA, 4 with multiple aneurysms, 23 of the 24 aneurysms in the anterior circulation and none ruptured; after matching, only smoking remained associated (p=0.009) [71]. At Washington University (St. Louis), 19 of 83 patients (22.9%) had at least one aneurysm, with a mean size of 3.2 ± 1.8 mm, predominantly in the cavernous carotid, ophthalmic and anterior cerebral arteries; growth was 0.43 ± 0.53 mm/year, similar to the general population, and three patients were treated, one with transient hemiparesis [72]. At the same centre in 2026, 16 of 63 patients (25%) had IA; carotid and vertebral tortuosity was much greater than in 50 controls (highest with TGFBR2), but was not associated with aneurysm presence [73]. A systematic review of 25 studies (through March 2025) estimated prevalences of 19.4–30%, a mean size of 3.6 mm and arterial dissections in 22.2% [22]. Among 47 children and young adults at Texas Children's Hospital, 39 with neuroimaging, intracranial tortuosity was present in 79.5% and cervical tortuosity in 64.1%, with progression in 3 of the 21 followed [74].

3.6. Microcephalic osteodysplastic primordial dwarfism type II

MOPD II combines extreme intrauterine and postnatal growth restriction (birth weight −4 standard deviations, subsequently head circumference and height between −8 and −10 standard deviations; adult height below 110 cm), relatively preserved development, brachydactyly, coxa vara, small secondary dentition, insulin resistance and early dyslipidaemia [75–77]. In a cohort of 47 individuals, 25 had IA (several with multiple aneurysms), 22 moyamoya vasculopathy, 17 both and 17 neither; around half of patients with moyamoya or aneurysms had ischaemic or haemorrhagic stroke, respectively [10]. Aneurysm risk remains relatively constant throughout childhood and appears to persist throughout life, whereas moyamoya risk is higher before age 5 and may begin in utero; hypertension affects almost 50% of adolescents and young adults, one-third develop chronic kidney disease (stage III at a mean age of 22 years), and patients with stroke have more cognitive impairment [10].

3.7. Other associations

In CoA, IA prevalence is around 10% versus 2% in the adult population, higher in older and hypertensive patients, and many aneurysms are small [23]. In NF1, IAs are more frequent than in the general population and predominantly affect the internal carotid, middle cerebral and anterior cerebral arteries; stroke is more frequent and occurs earlier than in the general population, and moyamoya is around three times more frequent than expected in children irradiated for a brain tumour [17]. Alagille syndrome (JAG1, NOTCH2) is associated with neurovascular events in 15%, aneurysms of the basilar, carotid and middle cerebral arteries, and moyamoya syndrome in up to one-third [78]. In fibromuscular dysplasia, macroaneurysms and dissections are complications of the “string-of-beads” lesions of the renal and internal carotid arteries [9]. In multisystemic smooth muscle dysfunction syndrome (ACTA2), intracranial stenoses are present in 77%, ischaemic stroke in 27% and periventricular hyperintensities in 95%, without moyamoya-type collaterals [14].

ADPKD, vEDS and LDS also involve dissections of the cervical and vertebral arteries; isolated carotid dissection without aortic root involvement has been described in LDS, but isolated cervical dissections generally have no identified genetic cause [8, 9]. IAs are mentioned as occasional abnormalities in Marfan syndrome, 3M syndrome, Floating-Harbor syndrome (SRCAP; a case of a ruptured aneurysm), Aarskog syndrome (FGD1; ruptured posterior communicating artery aneurysm), frontometaphyseal dysplasia (unruptured cerebral aneurysm with sinus of Valsalva aneurysm), adult Pompe disease (arteriopathy due to glycogen accumulation in vascular smooth muscle), SAMHD1-related Aicardi–Goutières syndrome (stenoses, aneurysms and intracerebral haemorrhage) and recessive THSD1 deficiency (fetal hydrops, sometimes with haemangiomas and IA) [55, 79–85]. In Marfan syndrome, the 2024 European guideline indicates intracerebral vessel imaging only when symptoms or clinical manifestations of aneurysm or rupture are present [48].

3.8. Aneurysmal subarachnoid haemorrhage

aSAH occurs at a mean age of 50–55 years and is more frequent in women; around one-third of patients die within the first few weeks and only 5% return to their premorbid life without restrictions [25, 26]. In-hospital mortality in the United States fell from 13.7% in 2006 to 13.1% in 2018, but 22–26% of patients die before reaching hospital, and population case fatality decreased by 1.5% per year between 1980 and 2020 [26]. The 2026 European guideline estimates aSAH case fatality at around 40% [86]. Global SAH incidence fell from 10.2 per 100,000 person-years in 1980 to 6.1 in 2010, alongside the reduction in smoking [21].

4. Clinical Recognition and Red Flags

4.1. When to suspect a familial or syndromic form

Recognition begins with the family history. In a patient with IA or aSAH, history-taking should include a three-generation pedigree with specific questions about SAH, unexplained sudden death and relatives' causes of death [7, 21]. FIA is suspected when two or more first-degree relatives have aSAH or UIA; a single affected first-degree relative modestly increases risk and does not by itself constitute an FIA family [25]. Suspicion of a syndromic cause should be greater when the aneurysm or SAH occurs at a young age, when there are multiple aneurysms, when arterial dissections, extracranial aneurysms or aortic disease coexist, or when the patient has extravascular features of a connective tissue disorder [14, 65].

The converse also applies: in families with aortopathy, asking only about aortic disease is insufficient. The 2022 ACC/AHA guideline recommends (class 1, level B-NR) obtaining a multigenerational family history of thoracic aortic disease, unexplained sudden deaths, and peripheral and intracranial aneurysms in patients with an aortic root or ascending aortic aneurysm or aortic dissection, and the 2020 cardiogenetics chapter advises also asking about intracerebral arterial disease, premature coronary artery disease, CoA, patent ductus arteriosus and bicuspid aortic valve [14, 23].

4.2. Warning signs and emergencies

Thunderclap headache, reaching maximal intensity in less than one minute, sometimes accompanied by nausea, vomiting, seizures or altered consciousness, requires immediate assessment in an emergency department with computed tomography (CT); KDIGO recommends educating all patients with ADPKD and their carers to recognise this symptom [21]. A survey of 420 nephrologists in France, Belgium and Switzerland showed that when screening was not indicated, only 35% systematically informed patients about the risk [21]. A cranial nerve palsy, particularly of the third nerve, or another new focal deficit suggests compression by a growing aneurysm and indicates treatment [12, 24].

In vEDS, sudden unexplained pain at any site should prompt immediate medical attention and urgent non-invasive imaging; sudden-onset diplopia, proptosis and chemosis suggest CCF and require prompt intervention to preserve vision [8, 48]. Patients should carry an alert document (emergency card or “vEDS passport”) indicating the diagnosis and precautions [8, 47].

4.3. Newborn screening and ages of suspicion

There is no newborn screening for any of the entities in this article. In MOPD II, cerebral magnetic resonance imaging (MRI) and magnetic resonance angiography are recommended at diagnosis, including at birth, because in utero stroke and neonatal moyamoya have been described [10]. In vEDS, bruising is the most common sign and initial complaint in children, and half of children diagnosed without a family history had a complication before age 11 [64]. In ADPKD, IA rupture in childhood is very rare and KDIGO advises against screening before adulthood [21]. In the general population and FIA families, aneurysms are rare before age 30, but serial screening in Utrecht found aneurysms in 6 of 129 people younger than 30 (5%; 2–10) [19, 20].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

FIA has no formal diagnostic criteria published by a scientific society. The operational definition used in screening and natural history studies is two or more first-degree relatives with confirmed aSAH or UIA, after exclusion of syndromic disorders through clinical assessment and, when indicated, genetic testing [20, 33]. Orphanet adopts a broader definition involving first- to third-degree relatives [1].

In syndromic forms, diagnosis rests on specific criteria. In ADPKD, age-specific ultrasound or MRI criteria and an autosomal dominant family history establish the diagnosis, and IA is one of the suggestive findings, alongside bilateral renal cysts, hepatic, pancreatic, seminal vesicle or arachnoid cysts, and hypertension before age 35 [12]. In vEDS, the 2024 European guideline and 2017 international consensus require identification of a causal variant in COL3A1 for diagnosis [47, 48]; clinical criteria guide the decision to test and include, as major criteria, arterial dissection, aneurysm or rupture at a young age, intestinal rupture, uterine rupture during pregnancy and a family history of vEDS, and, as minor criteria, thin translucent skin, characteristic facial appearance, acrogeria, CCF, small joint hypermobility, tendon or muscle rupture, early varicose veins, pneumothorax or haemopneumothorax, easy bruising, chronic dislocations, congenital hip dislocation and clubfoot [63, 64]. Two or more major criteria are highly suggestive [64]. In LDS, diagnosis is established in a proband with characteristic features or by identifying a heterozygous pathogenic variant in SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1 or TGFBR2, or biallelic variants in IPO8 [9].

5.2. Imaging: modalities, performance and limitations

Time-of-flight magnetic resonance angiography without gadolinium is the preferred modality for presymptomatic screening because it requires neither contrast nor ionising radiation [21, 25]. Its sensitivity ranges from 74% to 98% and, on a 3.0-T scanner, exceeds 95% for aneurysms of 3 mm or less [21]. High-resolution CT angiography (CTA) is the alternative when MRI is contraindicated (claustrophobia, some devices), with sensitivity of 95–97% and specificity of 100% for 3–5-mm aneurysms, but only 84–86% for aneurysms smaller than 3 mm; it involves iodinated contrast (caution if estimated glomerular filtration rate is below 30 ml/min/1.73 m²), radiation and artefacts from clips or coils [21]. Digital subtraction angiography (DSA) remains the reference standard but should not be used for presymptomatic screening [21]. In ADPKD, angiography is associated with more vasospasm and transient ischaemic complications [12]. In vEDS, conventional arteriography is discouraged because of the risk of dissection at the puncture site and arterial injury from injection pressure, and is reserved for planned therapeutic procedures [8, 64].

For follow-up of untreated UIAs, ESO recommends, by consensus, magnetic resonance angiography or CTA, which are sensitive and obviate serial DSA; following endovascular treatment, magnetic resonance angiography is the primary tool, following clipping CTA is preferred, and DSA is used only when these are inconclusive [24]. Aneurysm wall enhancement on high-resolution vessel wall MRI is more frequent in unstable aneurysms but remains an investigational biomarker [24].

A negative screen excludes neither future aneurysms nor very small aneurysms below the technique's resolution. In the Utrecht cohort, 3% of people with two negative screens had a de novo aneurysm, and a new aneurysm ruptured three years after the last negative screen; in ADPKD, aneurysms may develop and rupture within a 5-year interval [20, 21]. Screening also detects incidental findings (silent infarcts, meningiomas, arachnoid cysts, cavernomas, pituitary adenomas) [21, 25].

5.3. Indications for intracranial aneurysm screening

Screening indications depend on the risk group and are summarised in section 11.2. In FIA families with two or more affected first-degree relatives, initial screening yield is around 11% (9–14) and lifetime aSAH risk may exceed 20%, higher in siblings than in parents and offspring and in smokers and hypertensive individuals [20, 25]. The 2023 American Heart Association/American Stroke Association (AHA/ASA) aSAH guideline reports an aneurysm prevalence of 12% in people with two or more first-degree relatives with known cerebral aneurysms and considers radiological screening cost-effective every 5–7 years between ages 20 and 80, based on modelling studies [26]. The 2015 AHA/ASA UIA guideline also addresses screening; its full text was not accessible for this article and its recommendations are not reproduced here [87]. The 2022 ESO guideline recognises the increased risk in people with two or more first-degree relatives with aSAH and in polycystic kidney disease, but focuses on management of already detected UIAs and makes no screening recommendations [24].

Source: Rinkel and Ruigrok 2022, based on MARS and the Utrecht cohort; lifetime risks were calculated from incidence and life expectancy, without confidence intervals [25].

With a single affected first-degree relative, the MARS study found aneurysms in 4.0% (2.6–5.8), and modelling showed increased life expectancy but reduced quality-adjusted life-years (QALYs); a more recent model, with a lifetime risk of 3–4% and fewer treatment complications, considered screening twice, at ages 40 and 55, cost-effective at a threshold of €20,000 per QALY, but with a probability of cost-effectiveness of only around 50%; the authors advise informing and offering counselling rather than routine screening [25, 35]. When affected relatives have only UIAs without SAH, there are no data, and the same authors tend to discourage screening; with one first-degree relative with SAH and at least one other with UIA, they advise screening every five years, without specific evidence [25].

In ADPKD, KDIGO recommends informing all adults about the increased risk of IA and SAH (recommendation 1C) and screening patients with a personal history of SAH or a family history of IA, SAH or unexplained sudden death who are eligible for treatment and have a reasonable life expectancy (recommendation 1D) [21]. Yield with a family history is around 17%, about four times that in ADPKD overall, and is highest when there is SAH in a first-degree relative or IA or SAH in two or more relatives; however, 50–60% of patients with IA and around 40% of patients with rupture have no family history [21]. KDIGO therefore proposes also discussing screening in de novo ADPKD, with an unknown family history or few affected relatives, with a personal or family extracerebral vascular phenotype, before kidney or liver transplantation or major elective surgery, at the request of informed individuals, before pregnancy in women with these factors, and in occupations where occupational health requires it (bus drivers, pilots) [21]. This selective position differs from the proposal for universal screening: in the French cohort of 495 patients, four of five ruptures occurred in patients without a family history, and systematic screening was cost-effective (+0.68 QALYs versus targeted screening), but with a rupture rate five times that of other cohorts [21, 88]. At Mayo Clinic, a family history of SAH was present in 29% of patients with IA and 11% without IA, and the authors advocate highly selective screening [59, 67].

In LDS, the 2022 ACC/AHA guideline recommends baseline MRI or CT from head to pelvis to assess the entire aorta and its branches, including aneurysms, dissections and tortuosity (class 1, level C-LD), and considers surveillance for cerebral aneurysms by MRI or CT every 2–3 years reasonable when initial screening is normal (class 2a, level C-EO) [23]. In vEDS, typical protocols include baseline head-to-pelvis imaging and periodic surveillance (section 11.2) [23, 47]. In adults with CoA, IA screening by MRI or CT “may be reasonable” (class 2b, level B-NR), through shared decision-making that considers age, risk factors and anticoagulation [23]. In heritable thoracic aortic disease of unknown genetic cause, head and neck imaging may be indicated in first-degree relatives when there is also a family history of intracranial and cervical aneurysms or dissections [16]. In MOPD II, MRI and magnetic resonance angiography are performed at diagnosis and periodically thereafter [10]. For vEDS, LDS and fibromuscular dysplasia, international consensuses (Byers 2017 for vEDS, MacCarrick 2014 for LDS and Gornik 2019 for fibromuscular dysplasia) acknowledge that IA screening may be considered, according to the review by Rinkel and Ruigrok, but series are small and reliable yield estimates are lacking [25, 47, 89].

Counselling before any imaging should address the purpose of screening, the probability of finding an aneurysm at the initial and subsequent screens, aSAH risk, possible treatments and their risks, hypertension and smoking control, starting and stopping ages, the possibility of finding small aneurysms requiring prolonged follow-up, residual risk between screens, consequences for children who become eligible for screening, implications for driving and pilot licences, life insurance and loans, and incidental findings, allowing time for the decision [21, 25]. Everyone, whether screened or not, should stop smoking and control blood pressure [25].

5.4. Genetic testing

Genetic testing has different roles in the two groups. In FIA, no gene has sufficient clinical validity for predictive testing: a positive result in ANGPTL6, THSD1 or RNF213 does not define individual risk, given incomplete penetrance and unaffected carriers, and a negative result does not reduce relatives' empirical risk, which remains determined by the family history [3, 4, 43]. Testing of these genes belongs in research. The clinical role of testing in FIA is to exclude a syndromic disorder when clinical clues are present (multiple aneurysms or aneurysms at a young age, dissections, extracranial aneurysms, aortic disease, signs of connective tissue disease), using a heritable vascular disease panel including at least COL3A1, LDS genes, ACTA2 and other aortopathy genes; in the case in section 10, the panel included 17 genes [9, 65].

In vEDS, COL3A1 sequencing detects missense, nonsense and splice variants and small deletions and insertions, and next-generation sequencing may detect exon deletions and duplications; if no variant is found, RNA analysis in cultured fibroblasts may identify intronic variants that insert new sequence, and MLPA detects intragenic deletions and duplications [8]. Biochemical studies of procollagen III in fibroblasts identify more than 95% of affected individuals, but availability is limited and they have become second-line tests [63, 64]. In ADPKD, testing identifies a pathogenic variant in around 90% of cases, and PKD1 analysis requires methods that circumvent pseudogenes [7, 12]. In LDS, the panel should include IPO8, SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1 and TGFBR2 [9].

Testing limitations are shared by all genes: exome or panel sequencing may miss deep intronic variants, structural rearrangements and duplicated regions; low-level mosaicism may escape blood sequencing; and the proportion of variants detectable by a method is not equivalent to the clinical sensitivity of the test for the disease. A report should specify the gene, versioned reference transcript, HGVS nomenclature, zygosity and classification according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria. VUS, frequent in COL3A1 (more than 2000 in ClinVar), should not guide clinical decisions or predictive testing; familial segregation and, in vEDS, RNA or protein studies may contribute to reclassification [8, 27]. The DiSCOVER trial excluded patients with VUS and haploinsufficiency variants, illustrating the importance of variant classification and type in therapeutic selection [90].

5.5. Prenatal and preimplantation diagnosis

When the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible in vEDS and may be offered in heritable thoracic aortopathies, including LDS [8, 14]. The sources consulted for this article do not address their application to ADPKD or MOPD II; in the latter, which is recessively inherited, sibling recurrence risk is 25% [10]. The Oxford Desk Reference considers prenatal diagnosis rarely indicated in forms of Ehlers–Danlos syndrome, with the possible exception of vEDS, and GeneReviews recommends molecular testing as the prenatal approach in vEDS, noting that experience with assisted reproduction in women with vEDS is limited [8, 63]. In FIA without an identified causal variant, there is no basis for prenatal diagnosis.

5.6. Practical algorithm

6. Differential Diagnosis

6.1. Comparative table

6.2. Main differential diagnoses

The first distinction is morphological. Collagen and TGF-β pathway disorders frequently cause fusiform aneurysms, pseudoaneurysms and dissections, rather than only saccular aneurysms at bifurcations: in the case described in section 10, middle cerebral artery dilatation with distal stenosis represented a dissection with a flap on vessel wall MRI [65]. Detection of an intracranial dissection, spontaneous CCF or marked tortuosity in a young patient should prompt investigation for vEDS or LDS before any invasive procedure [14, 69].

When distinguishing ADPKD from FIA, a family history of renal disease may be absent with de novo variants (around 10%) and in late-presenting PKD2 families, making renal imaging useful in a patient with IA and a family history of SAH without a renal diagnosis [7, 93]. In distinguishing LDS from Marfan syndrome, absence of ectopia lentis, a bifid uvula and arterial tortuosity point towards LDS; in Marfan syndrome, IAs are occasional and cerebral imaging is not systematic [14, 48]. In vEDS, complications may arise without typical skin or facial features: the patient in section 10 fulfilled only three minor criteria at the time of dissection [65].

HHT merits separate mention because Orphanet annotates ENG as a major susceptibility factor for familial saccular aneurysm, but the typical cerebral lesions in HHT are AVMs, present in around 10% of patients and more frequent with ENG; multiple cerebral AVMs are highly suggestive of HHT and indicate MRI screening with and without contrast, ideally in the first year of life [1, 18]. The sources consulted do not quantify saccular aneurysms independent of AVMs in HHT. Moyamoya, in turn, is predominantly a stenosing vasculopathy, but in MOPD II coexists with aneurysms in 36% of patients, and ACTA2-related multisystemic smooth muscle dysfunction syndrome produces a similar pattern without moyamoya collaterals [10, 14].

7. Treatment and Risk Management Strategies

7.1. General principles

There is no treatment directed at the genetic cause of any form of IA described in this article. Management of a UIA in a patient with FIA or ADPKD follows general UIA guidelines, adjusted for the additional risk factors conferred by the family history or underlying disease; in connective tissue disorders, arterial fragility substantially alters procedural risk [8, 21, 24]. The reference European UIA guideline is the 2022 ESO guideline, developed using GRADE (Grading of Recommendations Assessment, Development and Evaluation), in which all recommendations rest on very low-quality evidence because no completed randomised trials compare preventive treatment with observation: the TEAM trial, which intended to randomise 2002 patients between endovascular treatment and conservative management, stopped after 80 patients because of insufficient recruitment [24, 94]. The 2015 AHA/ASA guideline covers the same field; its full text was not accessible for this article [87].

7.2. Decision to treat an unruptured aneurysm

ESO suggests preventive repair, using the most effective and safest modality for that aneurysm, in adults whose estimated 5-year rupture risk exceeds treatment risk, and when follow-up imaging shows growth (weak recommendations in favour) [24]. When complication risk exceeds 5-year rupture risk, it recommends radiological monitoring (strong recommendation), with individualised frequency and duration, while treatment remains an option [24]. By consensus, the decision should be made by a multidisciplinary team (neurosurgery, interventional neuroradiology and neurology) at a high-volume centre (at least 100 patients with UIA assessed annually), based on aneurysm size, site and lobulation, rupture risk factors (previous SAH from another aneurysm, family history of UIA or SAH, smoking, hypertension), growth of 1 mm in any diameter or de novo formation, life expectancy and complication risk factors (age, comorbidity, morphology, estimated treatment risk); the final decision is shared with the patient [24]. Symptomatic UIAs (cranial nerve deficits, mass effect, thromboembolic events) should be repaired, whereas asymptomatic UIAs in patients with significant comorbidity or life expectancy below five years should not [24].

Scores help structure the decision, but none has been validated in familial or syndromic forms. PHASES does not include family history and has not been validated in ADPKD [21, 24]. ELAPSS also does not include family history [40]. UIATS (Unruptured Intracranial Aneurysm Treatment Score), developed through a Delphi consensus of 69 experts, weighs 29 factors, including family history, and compares a score favouring treatment with one favouring conservative management [95]. For most UIAs, the risk of a poor outcome from a treatment complication is around 2–4%, and 5-year rupture risk is no greater than 1–2%; a meta-analysis of 114 studies (106,433 patients) estimated 30-day clinical complications at 4.96% and case fatality at 0.3% for endovascular treatment, and 8.3% and 0.1%, respectively, for surgery [21, 24].

In FIA families, the potentially increased rupture risk (section 3.2) favours treatment, and the Utrecht cohort authors recommend treating familial UIAs more actively [33]; ESO includes family history among factors to consider without setting a different threshold [24]. Older textbook sources proposed fixed size thresholds (conservative management below 10 mm and surgery above 10 mm in the 2017 Oxford Desk Reference; observation up to 5 mm, controversial management between 6 and 9 mm, and intervention above 10 mm in the ADPKD GeneReviews chapter, based on retrospective ISUIA data from 1998) [7, 12]. These thresholds are historical: current guidelines replace them with individual estimation of rupture and complication risk, and subsequent prospective data show non-negligible rupture risks in 7–9-mm aneurysms and at high-risk sites [24, 37, 38].

7.3. Choice of repair modality

ESO cannot globally recommend either the endovascular or microsurgical approach; by consensus, the choice should consider age (which increases surgical risk), female sex (a slight increase in endovascular risk and a strong increase in surgical risk, in the guideline's wording), anticoagulation (strong increase in surgical risk), a wide neck (increased endovascular risk), calcification (increased surgical risk) and the posterior circulation, where the endovascular approach is the first option [24]. Repair should be performed in centres treating more than 100 aneurysms annually and by operators treating more than 30 patients annually with the proposed modality [24]. Flow-diverters should be used only when there is no other option with a risk lower than the 5-year rupture risk (weak recommendation against), because a trial comparing flow-diversion with the best standard option was stopped for safety, with 12 of 75 patients (16%) dead or dependent at three months [24].

The CURES trial (Canada and France, 2010–2020; 291 patients with 3–25-mm UIAs suitable for both approaches), published in 2023, showed treatment failure at one year (failure of occlusion, intracranial haemorrhage or residual aneurysm, assessed by a core laboratory) in 9% with clipping versus 19% with endovascular treatment (relative risk 2.07; 1.12–3.83), with mRS (modified Rankin Scale) above 2 at one year in 2% in both arms, but more new neurological deficits after clipping (22% versus 12%) and hospital stays longer than five days in 48% versus 8% [96]. The result was determined mainly by 1-year angiography, and the trial was unblinded.

7.4. Medical treatment and lifestyle measures

For ADPKD, KDIGO adds avoiding all tobacco products, limiting alcohol to one drink daily for women and two for men (consumption above 150 g/week is a risk factor for SAH), limiting caffeine to less than 400 mg/day, and avoiding cocaine and methamphetamines, which cause hypertensive crises and vasospasm [21]. In ADPKD, early hypertension control and smoking cessation are the two most influential modifiable measures, and in the Genkyst cohort smoking above 20 pack-years and hypertension were independently associated with an approximately twofold higher risk of IA or SAH [21]. In FIA families, smoking cessation and blood pressure control apply to all relatives, whether screened or not [25].

7.5. Follow-up after repair

ESO suggests initial radiological follow-up 3–12 months after UIA repair, while retreatment remains an option, and recommends shared decision-making between retreatment and surveillance when recurrence occurs; a meta-analysis of 24 studies (4842 patients treated endovascularly, mean follow-up 3.2 years) reported 12 ruptures (0.25%) [24]. After aSAH, the 2026 ESO/EANS/ESMINT guideline indicates imaging follow-up while retreatment remains an option: at least once at 12 months or later after coiling; usually no prolonged follow-up after clipping with complete occlusion documented by six months; and prolonged follow-up after partial occlusion or new devices [86]. The same guideline recommends, by consensus, imaging every five years in patients at high risk of new aneurysms (young age, a family history of aSAH or ADPKD) [86]. Risk factors for de novo aneurysms after aSAH are age below 60 years (relative risk 1.41; 1.25–1.58), female sex (1.63; 1.27–2.08), smoking (1.37; 1.07–1.80), a family history of IA (2.30; 1.32–4.00) and multiple aneurysms (1.69; 1.11–2.58), according to a meta-analysis of 19 cohorts (9351 patients) in which 3.25% developed new aneurysms [86]. The 2023 AHA/ASA guideline also considers monitoring for de novo aneurysms important in younger patients with multiple aneurysms or with two or more first-degree relatives with aSAH, and reports recurrence of 2.1% annually in clipped aneurysms with a remnant versus 0.26% without a remnant [26].

7.6. Aneurysmal subarachnoid haemorrhage

Treatment of aSAH does not differ in familial forms, except for the precautions specific to connective tissue disorders. The 2026 ESO/EANS/ESMINT guideline (15 evidence-based recommendations and 37 consensus statements) recommends, with high-quality evidence, oral nimodipine for all patients and coiling rather than clipping when both are equally suitable in patients in good clinical condition; it recommends against routine antifibrinolytics before aneurysm treatment, tirilazad, statins, magnesium sulphate and endothelin receptor antagonists; and, by consensus, treatment in a dedicated unit at a centre with at least 70 aSAH cases annually (35 in remote areas), treatment of the ruptured aneurysm within the first 24 hours, operators treating at least 30 aneurysms annually, and decision-making by at least one neurosurgeon and one neurointerventionalist [86]. The 2023 AHA/ASA guideline also considers early enteral nimodipine beneficial and does not recommend routine statins or intravenous magnesium [26]. In the International Subarachnoid Aneurysm Trial (ISAT), recurrent SAH from the treated aneurysm occurred in 1.9% after endovascular treatment and 0.6% after surgery within the first 30 days; during 18-year follow-up of the UK cohort, in 1.6% versus 0.5% [26, 86]. The ADPKD GeneReviews statement that neck clipping is the main treatment for a ruptured aneurysm reflects literature predating these data [12].

7.7. Autosomal dominant polycystic kidney disease

KDIGO refers decisions about a detected IA to a multidisciplinary team at a high-volume centre, following the 2022 ESO guideline, with the endovascular approach as the first option in the posterior circulation [21]. Untreated IAs should undergo imaging surveillance, initially at six months and then every one to two years [21]. Mayo Clinic data support conservative management of most small aneurysms detected on screening: 38 patients with saccular aneurysms had no ruptures over a median of 7.9 years, nor did 75 patients followed by magnetic resonance angiography [21]. KDIGO does not recommend routine screening of other arteries without a family history of aneurysms or dissections, but recommends screening for aortic aneurysm in patients with ADPKD and their first-degree relatives when there is a family history of aortic root or thoracic aortic aneurysm, using echocardiography, CTA or magnetic resonance angiography; if dilatation is present, it proposes smoking cessation, a statin and antihypertensives including a beta-blocker and an angiotensin-converting enzyme inhibitor (ACE inhibitor) or an ARB, and highlights the association, of uncertain magnitude, between fluoroquinolones and dissection [21]. Renal management includes tolvaptan.

7.8. Vascular Ehlers–Danlos syndrome

Management of vEDS rests on a set of consensus measures: molecular confirmation, lifestyle modification, an organised care team (family medicine, vascular surgery, general surgery, cardiology, respiratory medicine and genetics), an individual emergency plan and alert document, centralisation at a referral centre, blood pressure within the normal range and aggressive treatment of hypertension [8, 47, 48]. Collision sports and extreme weightlifting, scuba diving and activities causing sudden blood pressure increases are discouraged; there is no evidence of harm from moderate recreational exercise [8, 63, 64]. Conventional arteriography, routine colonoscopy and elective surgery are discouraged; aspirin, clopidogrel, anticoagulants and non-steroidal anti-inflammatory drugs should be used only after weighing risks and benefits [8, 14, 64].

For an arterial complication, the approach is conservative whenever possible and procedures are reserved for life-threatening situations; there are no diameter thresholds for intervention, and decisions rest with a multidisciplinary team [23, 48]. Retrospective surgical series, subject to selection bias, show complications in 46% (31 patients, Mayo Clinic) and 33% (9 patients, Johns Hopkins) and mortality of 30% with open surgery, 24% with endovascular surgery and 39% overall; endovascular experience is growing and, in splenic aneurysms and dissections, was associated with fewer complications and deaths [8, 14]. CCF almost always requires prompt intervention to preserve vision [8]. There are no guidelines for elective IA repair in vEDS, and decisions are individual [8].

The 2022 ACC/AHA guideline notes that other beta-blockers are used when celiprolol is unavailable and that, at the time, there were no studies demonstrating ARB benefit [23]; ARCADE, published in 2025, is the first positive double-blind randomised trial in vEDS and adds irbesartan to celiprolol rather than replacing it [30, 102]. The 2024 ESC guideline predates ARCADE [48]. A 2026 review discusses treatment of asymptomatic patients; its content was not consulted for this article [103].

7.9. Loeys–Dietz syndrome

In LDS, ACC/AHA considers a beta-blocker and/or ARB at the maximum tolerated dose reasonable (class 2a, level C-EO), as off-label use, with a warning about losartan fetal toxicity; there are no completed comparative trials in LDS [9, 15]. Elective vascular intervention is considered when an arterial diameter exceeds two to three times the expected value or expansion is rapid, and isometric exercise and contact or competitive sports should be avoided [14]. For IAs, available data do not justify more aggressive management than in the general population: in the St. Louis series, aneurysms were small and grew at a rate similar to the general population, and one of the three treated patients had transient hemiparesis [72]. The authors of the multicentre Mayo Clinic series propose cerebrovascular imaging at diagnosis and discouraging smoking, the only factor that remained associated with IAs [71]. Aortic surgical thresholds are 45 mm, or ≥40 mm with high-risk features, in the 2024 ESC guideline and, according to GeneReviews, around 40 mm in adults with TGFBR1 or TGFBR2 variants, around 45 mm with SMAD2, SMAD3 or TGFB2 and around 50 mm with TGFB3 [9, 48].

7.10. MOPD II and moyamoya

In MOPD II, moyamoya is treated by encephaloduroarteriosynangiosis or pial synangiosis, particularly in childhood, and aneurysms by clipping, coiling or stenting, procedures that may be required in childhood and adulthood; aneurysm development is probably aggravated by hypertension, which should be measured with an appropriately sized cuff and considered from 110/70 mmHg in adults [10]. In moyamoya disease, the 2023 ESO guideline, endorsed by VASCERN, recommends direct bypass in adults with a haemorrhagic presentation (low-quality evidence, one randomised trial), direct or combined revascularisation in adults with an ischaemic presentation and children with haemodynamic impairment, 6–12 weeks after the last event, and long-term antiplatelet treatment in the non-haemorrhagic form by expert consensus; no drug is approved [49].

7.11. Perioperative care, anaesthesia and agents to avoid

In vEDS, anaesthesia requires available blood products, atraumatic intubation, preference for ventilation without positive pressure when possible, and avoidance of neuraxial techniques, central venous access and arterial punctures (or ultrasound guidance for these), tourniquets, intramuscular premedication and rectal temperature measurement [14, 27]. Surgery should be targeted and minimal, with judicious fluid restriction [8]. In ADPKD, KDIGO proposes considering IA screening before kidney or liver transplantation and major elective surgery with potential haemodynamic instability [12, 21].

7.12. Pregnancy and lactation

In ADPKD, pregnancy is generally well tolerated but requires specialist surveillance of hypertension and the increased risk of pre-eclampsia [7]. KDIGO states that no evidence indicates an increased risk of IA rupture during pregnancy or vaginal delivery, proposes considering screening before pregnancy in women with a family history of IA, de novo ADPKD, an unknown family history or an extracerebral vascular phenotype, assigns decisions on treatment of a detected IA to specialist neurosurgeons and neuroradiologists, does not alter blood pressure targets in the presence of a known IA, and recommends discontinuing tolvaptan and ACE inhibitors or ARBs before pregnancy [21].

In vEDS, pregnancy carries a risk of arterial and uterine rupture. In Pepin's 2000 series (81 women, 183 pregnancies), 12 women died in the peripartum period or within the following two weeks (5 from uterine rupture during labour, 2 from vascular rupture at delivery and 5 from postpartum vascular rupture) [63]. In Murray's 2014 series (more than 500 pregnancies in 253 women), mortality was around 5% per pregnancy (5.3%), around half of pregnancies were uncomplicated, and third- or fourth-degree tears occurred in 20%, arterial dissection or rupture in 9.2%, uterine rupture in 2.6% and preterm delivery in up to 19%; age was the main risk factor, with no survival difference between multiparous and nulliparous women [8, 14]. The 2024 ESC guideline states that pregnancy does not increase overall mortality compared with nulliparous women and recommends shared decision-making according to vascular status and variant type [48]. Increasingly, practice is planned caesarean delivery at 36–38 weeks, with preconception planning, high-risk obstetric care and a vascular surgeon available at delivery; complications are rare with null variants and glycine-to-alanine substitutions [8, 64]. In a US series of 38 women and 82 deliveries, only 13% knew their diagnosis before pregnancy [23].

In LDS, a systematic review of 222 women and 522 pregnancies recorded aortic dissection in 4% and peripartum mortality of 1%, and ACC/AHA allows consideration of aortic surgery before pregnancy from 4.0 cm for TGFBR1, TGFBR2 and SMAD3 variants (class 2b) [15]. Losartan carries a fetal toxicity warning [15]. The sources consulted provide no data on lactation during celiprolol or irbesartan treatment.

7.13. Transition to adulthood

In MOPD II, emergencies in young adulthood (intracranial haemorrhage, myocardial infarction) pose specific problems: adult hospitals are poorly equipped for patients with an infant-sized head and a young child's body, and stents, intubation equipment and drug doses should be scaled to weight, with support from paediatric specialists [10]. In vEDS and ADPKD, transition should ensure continuity of the emergency document, surveillance and information about IA risk in adulthood [21, 47].

7.14. Regulatory status

The 2019 news reports describing the FDA complete response letter refer, in one source, to BBEST as a placebo-controlled trial; BBEST was open-label, with no treatment in the control arm [29, 104]. The official FDA letter was not consulted.

7.15. Clinical trials

These trials do not permit indirect comparisons with one another: they differ in population, control, design (open-label or blinded) and outcome definition. BBEST included patients with a clinical diagnosis alone and was open-label, and its 64% relative reduction corresponds in absolute terms to a 30-percentage-point difference over around four years in a very high-risk group; in ARCADE, the absolute difference was 26 percentage points over two years, with an outcome including lesions detected by systematic imaging and a confidence interval whose upper bound approaches no effect [29, 30]. Both trials are small and French, and generalisability to other populations and patients with null variants is uncertain. In UIAs, negative or discontinued trials (atorvastatin, flow-diversion, TEAM) carry as much weight as CURES in guideline formulation, and the absence of published results from PROTECT-U, ChATIA-1 and the dimethyl fumarate trial is not equivalent to negative results.

7.16. Developments in the past twelve months

ARCADE was published in February 2025, outside the 12-month window, but is the most recent therapeutic evidence in vEDS [30].

7.17. Divergences between guidelines

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

In monogenic forms, risk follows the inheritance pattern. ADPKD, vEDS, LDS caused by heterozygous genes and NF1 are autosomal dominant, with a 50% risk for each child of a carrier [7, 9]. Around 10% of ADPKD cases result from de novo variants, and the most severe LDS cases are predominantly de novo [7, 14]. In MOPD II and IPO8-related LDS, inheritance is autosomal recessive: siblings of a patient have a 25% probability of being affected and a 50% probability of being asymptomatic carriers [9, 10]. IA risk within a family with a monogenic disorder is not uniform: in ADPKD, IA probability rises from around 12.9% to 17.1% when there is a family history of IA or SAH, and in vEDS and LDS, IAs are one of many manifestations, with variable expressivity within the family [14, 21].

In FIA, counselling is based on empirical risks. First-degree relatives of patients with aSAH have a three- to sevenfold higher SAH risk than the population, and the Rochester community study estimated a relative risk of 4.14 [34, 35]. Risk increases with the number of affected relatives: aneurysm probability on screening of 4% and lifetime aSAH risk of 3–4% with one affected first-degree relative, and 11% and up to 20%, respectively, with two or more [25]. Within the family, siblings of an affected person have higher risk than offspring, women with an affected female relative have a slightly higher probability, too small to alter counselling, and smoking and hypertension increase individual risk [25, 35]. With current data, identification of a variant in a susceptibility gene (ANGPTL6, THSD1) does not allow calculation of individual risks different from empirical risks, because unaffected carriers and affected non-carriers exist within the same family [43].

8.2. Cascade screening and testing

In vEDS, evaluation of all first-degree relatives is recommended, with clinical assessment and testing for the familial variant even without clinical signs [8, 64]. In ADPKD, the status of at-risk adult relatives (18 years or older) is clarified by abdominal imaging (ultrasound, CT or MRI) and molecular testing when the familial variant is known, including both variants in biallelic or digenic families; when an IA is detected in a patient, their relatives with ADPKD, particularly first-degree relatives older than 18, may become eligible for IA screening [12, 21]. In heritable thoracic aortic disease with an unknown variant, the 2020 cardiogenetics chapter proposes aortic imaging in first-degree relatives from age 25 or ten years before the age of the youngest case, repeated every five years (ten if stable) until age 65, and GeneReviews adds head and neck imaging when there is a family history of intracranial and cervical aneurysms or dissections [14, 16].

In FIA families, screening targets first-degree relatives. The Utrecht cohort screened people with two or more affected first-degree relatives between ages 16–18 and 65–70, and cost-effectiveness models suggest screening every 5–7 years between ages 20 and 70–80 [20, 25]. Yield is independent of age from the third decade onwards, so the upper age limit is determined by life expectancy and treatment risk [25]. When screening detects an aneurysm in a relative, that relative's children also become eligible [25].

8.3. Germline mosaicism

The sources consulted do not quantify germline mosaicism in vEDS, LDS or ADPKD. In an apparently de novo case, sibling recurrence risk is low but cannot be considered zero, and testing parents for the variant confirms whether the case is de novo [8, 14].

8.4. Testing in minors

Predictive testing in minors is considered justified for Marfan syndrome, LDS and other heritable aortopathies because surveillance and treatment begin in childhood [14]. In vEDS, the decision is more controversial and individual: 12–24% of carriers have a major complication by age 20, celiprolol may be considered before age 18, and testing allows reassurance of non-carriers, preparation of the family for complications and restriction of high-impact sports; it should always be accompanied by psychosocial support [14]. IA screening, in contrast, is not routinely performed in childhood: KDIGO advises against it in children and adolescents with ADPKD, with individual exceptions in families with early ruptures and marked anxiety, and FIA families start screening in late adolescence or at age 20 [20, 21, 25]. MOPD II is the exception, with cerebral imaging from diagnosis [10].

8.5. Reproductive options

In forms with an identified variant, options include prenatal diagnosis and preimplantation genetic testing (section 5.5); experience with assisted reproduction in women with vEDS is limited [8]. In vEDS and LDS, reproductive decisions by an affected woman should also consider the maternal risk of pregnancy (section 7.12). In FIA without a causal variant, reproductive counselling is limited to empirical risks and information about screening in adulthood.

8.6. Content of counselling

Counselling before screening and genetic testing should include the elements described in section 5.3: purpose, detection probabilities, residual risk between screens, small aneurysms requiring follow-up, treatment risks, consequences for children and for insurance, loans, driving and pilot licences and employment, incidental findings, and time to decide [21, 25]. It should also reinforce smoking cessation and blood pressure control in all relatives, whether screened or not, and recognition of thunderclap headache [21, 25].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

None of these figures is a prevalence of FIA as a disease. IA percentages in screening cohorts measure frequency in groups selected by family history or underlying disease, with very different degrees of screening, and should not be interpreted as population prevalences [21].

9.2. Geography, ancestry and founder effects

UIA prevalence is similar in Europe, North America and Japan, but rupture risk is higher in Finnish (3.6-fold) and Japanese (2.8-fold) individuals, explaining the higher incidence of SAH in these countries [19, 39]. KDIGO includes Japanese or Finnish ancestry among IA risk factors in the population without ADPKD [21]. In Finland, SAH incidence decreased by 24% between 1998–2000 and 2010–2012 (from 11.7 to 8.9 per 100,000), alongside a 30% reduction in daily smoking [21]. In two Japanese ADPKD centres, IA prevalence was 17.6% and 20.1% [21].

The French Canadian population of Quebec, a founder population with a high IA prevalence, showed increased rare variant burden in RNF213, possibly due to genetic drift [5]. In East Asia, the founder allele p.R4810K in the same gene is present in 95% of Japanese familial moyamoya cases, 73–79% of sporadic cases and 1.4–1.8% of controls, with a carrier frequency of 0.5–2% in Japan, Korea and China; it is also present in around 22% of Japanese individuals with intracranial stenosis or occlusion without moyamoya [49]. In MOPD II, founder variants exist in Colombia and the Druze population of Israel [10]. The reference GWAS combined European and East Asian populations, and transferability of polygenic scores to other ancestries is unestablished [6, 51].

In Europe, the reference cohorts come from the Netherlands (MARS, Utrecht), Finland (Kuopio, Juvela), France (Genkyst, Flahault, vEDS cohorts from the national referral centre, ARCADE, BBEST) and the United Kingdom (ANGPTL6, ISAT) [20, 35, 53, 66, 88, 99]. According to KDIGO, the difference in standardised smoking prevalence in 2012 (31.0% in France versus 15.8% in the United States) may contribute to differences in IA prevalence and SAH incidence between countries [21]. The sources consulted do not include data from Portugal or Brazil on familial or syndromic IAs; the Brazilian genetic syndromes handbook describes vEDS and the major criterion of arterial rupture in a young individual, without national epidemiological data [115]. This absence from the sources consulted does not demonstrate an absence of published data.

9.3. Special populations

Women have more UIAs (prevalence ratio 1.61, and 2.2 above age 50), more aneurysms detected on screening of FIA families (24% versus 11.7%; OR 2.46) and, in ADPKD, more IAs by age 70 (10.8% versus 5.4%) and an HR of 2.21 in the 2026 preprint [12, 19, 28, 61]. In vEDS, women have more spontaneous CCFs and coronary dissections, and men more aortic disease and higher mortality [69, 70]. Older people have higher rupture risk (age ≥70 in PHASES) and higher surgical risk, altering the balance of repair [24, 39]. People aged 35 or older who are current or former smokers and hypertensive have a lifetime aSAH risk up to 7% and, together with those with a positive family history, account for around 30% of aSAH, but UIA prevalence and screening cost-effectiveness in this group are unknown [25]. Some occupations (pilots, bus drivers) may require screening for occupational health reasons, and a UIA diagnosis may have implications for driving and pilot licences [21, 25]. Pregnancy and childhood are addressed in sections 7.12 and 8.4.

9.4. Reference networks and patient organisations

There is no ERN dedicated to familial IAs; ESO recommends high-volume neurovascular centres [24]. VASCERN (European Reference Network on Rare Multisystemic Vascular Diseases) incorporates the heritable thoracic aortic disease and medium-sized artery working groups, the latter including vEDS and having published a survey on surveillance in this disease [31, 113]. ERKNet is the ERN for rare kidney diseases, including ADPKD [32]. Patient organisations include PKD International, The VEDS Movement, The Ehlers-Danlos Society, Ehlers-Danlos Support UK, the Loeys-Dietz Syndrome Foundation and the Brain Aneurysm Foundation [63, 116–120].

10. Illustrative Clinical Case

In 2026, Yamaguchi and colleagues described a 46-year-old man who, while performing electrical work involving strong head vibration, developed a sudden severe headache followed by left hemiplegia [65]. His history included a spontaneous parietal subcutaneous haematoma at age 10, left biceps tendon rupture at age 28 and retroperitoneal haemorrhage at age 45, attributed to seat belt pressure; he smoked 15 cigarettes daily. The family history was suggestive: his father had died suddenly from SAH at age 40 and a cousin, the son of a paternal aunt, had died from aortic dissection in his third decade; the pedigree (figure 1 of the article, PMC13222694, figure 1) shows an autosomal dominant pattern, with the father, aunt and cousin considered carriers, without genetic confirmation [65].

On admission, blood pressure was 161/109 mmHg. The patient had large eyes, a thin nose, thin lips and a small chin, but the skin was neither hyperextensible nor translucent and there was no joint hypermobility. MRI showed an acute right frontoparietal infarct on diffusion imaging and right frontal SAH on the T2* sequence; magnetic resonance angiography showed fusiform dilatation with distal stenosis, with a “pearl-and-string” appearance, in the M2 segment of the right middle cerebral artery, and CT confirmed SAH (figure 3A–E of the article, PMC13222694, figure 3). On day 9, vessel wall MRI (black-blood) showed an intimal flap in the dilated artery, confirming middle cerebral artery dissection as the simultaneous cause of infarction and SAH (figure 3F) [65].

Treatment included nicardipine, intravenous edaravone and rehabilitation, and clopidogrel 75 mg/day from day 9. Catheter angiography was avoided because of the iatrogenic risk in connective tissue disorders. A 17-gene panel (COL3A1, FBN1, EFEMP2, SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2, ACTA2, MYH11, MYLK, PRKG1, SLC2A10, COL1A1, FBN2, FLNA) identified the heterozygous variant NM_000090.4(COL3A1):c.2438G>A, p.(Gly813Asp), a glycine substitution in the triple helix recorded as pathogenic in the Human Gene Mutation Database (HGMD), establishing the vEDS diagnosis [58, 65]. The patient fulfilled only three minor criteria (facial appearance, easy bruising, tendon rupture) in addition to arterial dissection. He was discharged to rehabilitation on day 39 with residual hemiplegia [65].

The authors reviewed published vEDS cases with stroke (SAH from an anterior communicating artery aneurysm in a 34-year-old woman, internal carotid dissection in a 16-year-old woman, left internal carotid aneurysm in a 46-year-old woman, internal carotid dissection with infarction and haemorrhage in a 30-year-old man) and noted that almost none had a previous diagnosis and that iatrogenic events had occurred, such as aortic dissection during arteriography and haemorrhage during antithrombotic therapy [65]. The case illustrates three points: SAH in a young adult with a family history of sudden death from SAH and aortic dissection should prompt consideration of a connective tissue disorder, even without complete clinical criteria; the lesion was a dissection, not a saccular aneurysm; and the choice of non-invasive imaging accords with vEDS recommendations [8, 23]. Clopidogrel use in this patient with dissection was an individual decision by the authors: in vEDS, antiplatelets should be used only after weighing haemorrhagic risk, and the report should not be read as routine management [14].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The prognosis of a person with familial or syndromic IA depends mainly on three factors: the occurrence of SAH, with a case fatality around 35–45% and severe deficits in around 30% of survivors; the rupture risk of detected aneurysms, which is low for most small aneurysms found on screening; and, in syndromic forms, extracranial complications of the underlying disease [21, 24]. In FIA families, serial screening continues to find aneurysms at subsequent screens (8% at the second, 5% at the third and 5% at the fourth in the Utrecht cohort), and the only predictor of new aneurysms during follow-up was a previous aneurysm (HR 4.5; 1.1–18.7) [20]. The rupture risk of familial aneurysms may exceed that of sporadic aneurysms, with estimates ranging from around threefold (Utrecht, not statistically significant) to 17-fold (FIA, an indirect comparison with two events) [25, 33, 36].

In ADPKD, aneurysms detected on screening rarely rupture under surveillance (1 in 121 patients with a known IA, 1.21 per 1000 patient-years), and rupture after a negative screen is even rarer (3 in 1460, 0.39 per 1000 patient-years); two studies recorded no ruptures after preventive treatment [21]. In the Olmsted County cohort, the proportion of deaths due to IA rupture in patients with ADPKD fell from 2 in 29 (1935–1980) to 0 in 21 (1980–2016), although up to 6% of patients with ADPKD may die from aSAH [21, 25]. The main cause of death in ADPKD is cardiovascular, and early hypertension control reduces cardiovascular and cerebrovascular risk [7, 12].

In vEDS, median survival is around 50–51 years (range 10–81), five years shorter in men in the US series of around 1200 patients, with arterial rupture causing most deaths; the French cohort of 215 patients found no sex difference, probably because of ascertainment bias [8, 27, 48]. Complications recur at a rate of 1.6 events per five years [48]. In the treated French national cohort (144 patients; median follow-up 5.3 years), overall survival was 71.6% and depended on variant type, age at diagnosis and celiprolol treatment, with more than two-thirds of patients clinically silent; these observational data describe treated disease and are not comparable with historical series of untreated disease [99]. Null variants are associated with life expectancy close to the general population [8]. In SMAD3-related LDS, cumulative aortic event risk is 50% by age 54, with no aortic events in childhood, and 20% of patients presenting with joint symptoms died suddenly from dissection [15]. In MOPD II, stroke is associated with greater cognitive impairment, and chronic kidney disease and coronary disease contribute to morbidity in young adults [10].

11.2. Surveillance

Arterial surveillance in vEDS has no demonstrated benefit: there are no published efficacy data, and ruptures at sites distant from monitored regions have been described [8]. The frequency of surveillance for untreated UIAs is also not evidence-based, and in aneurysms stable for years the interval may be extended [24]. In ADPKD, the 2026 Japanese cohort supports long intervals after negative screening, whereas Kuopio data, with de novo formation of 1.3% per patient-year in patients with IA, support prolonged angiographic follow-up in that subgroup [66, 68].

12. Summary and Concluding Remarks

Saccular intracranial aneurysms occur in around 3% of adults, but their hereditary component is concentrated in two groups with different underlying patterns. In non-syndromic familial intracranial aneurysm, defined in clinical practice by two or more first-degree relatives with aSAH or an unruptured aneurysm, heredity is predominantly polygenic and interacts with smoking and hypertension; the susceptibility genes described (ANGPTL6, THSD1, RNF213, PCNT, PPIL4, CTSO) have incomplete penetrance and currently no predictive utility, so counselling rests on empirical risks: around an 11% probability of an aneurysm at initial screening and lifetime aSAH risk that may reach 20%. Screening by magnetic resonance angiography every five years, from late adolescence until the age at which treatment ceases to offer a favourable balance, is the strategy supported by the Utrecht cohorts and modelling studies, and should be preceded by counselling that includes residual risk between screens and the social consequences of diagnosis.

In syndromic forms, the aneurysm is a manifestation of a systemic vascular disease. In ADPKD, a prevalence of around 13% on screening and rupture a decade earlier than in the general population justify informing all adults and screening those with a personal or family history, according to KDIGO 2025, with discussion extended to other groups; small aneurysms detected on screening rarely grow or rupture. In vEDS, cervicocephalic lesions are frequently dissections, carotid–cavernous fistulae or pseudoaneurysms, invasive procedures carry high risk and diagnostic angiography should be avoided; celiprolol and, since ARCADE, add-on irbesartan are the only pharmacological interventions with randomised evidence, both outside the indications in prescribing information. In LDS, intracranial aneurysms affect 19–30% of patients, are small and grow slowly, and head-to-pelvis imaging at diagnosis with cerebral surveillance every two to three years is the approach recommended by the US guideline. MOPD II, NF1, coarctation of the aorta, fibromuscular dysplasia and Alagille syndrome complete the differential, and HHT is distinguished by arteriovenous malformations.

Management of an unruptured aneurysm, familial or syndromic, follows the principles of the 2022 European guideline: multidisciplinary decision-making at a high-volume centre, weighing individual rupture risk (with family history as an aggravating factor) against treatment risk, smoking cessation and blood pressure control below 130/80 mmHg. Fixed size thresholds in older sources have been replaced by this individual assessment. The main gaps are the absence of completed preventive treatment trials, absence of evidence on optimal surveillance frequency, lack of validation of risk scores in familial and syndromic forms, and lack of population data outside Western Europe, North America and Japan.

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