Ehlers–Danlos Syndromes

Literature and regulatory information updated: 6 October 2026.

International classification of 2017 and updates: hypermobile, classical, vascular, kyphoscoliotic, arthrochalasia, dermatosparaxis and musculocontractural types

0. Initial Reference Table

1. Introduction

Ehlers–Danlos syndromes constitute a clinically and genetically heterogeneous group of inherited connective tissue disorders affecting the skin, ligaments and joints, blood vessels and internal organs. Their unifying triad comprises joint hypermobility, skin hyperextensibility and tissue fragility, with easy bruising and abnormal wound healing; however, severity, inheritance pattern and threat to life differ substantially between types [1, 2]. EDS skin is extensible and elastic, returning to its initial position after traction, unlike cutis laxa, in which it is redundant, pendulous and poorly elastic — a distinction obscured for decades by the disease's historical name [2].

The first description attributed to the condition is that of the Dutch surgeon Job van Meekeren, who in 1682 reported a young Spanish man able to stretch the skin of his chin down to his chest. In 1901, the Danish dermatologist Edvard Ehlers described a patient with joint laxity, hyperextensible skin and a cutaneous bleeding tendency, and in 1908 the French physician Henri-Alexandre Danlos added molluscoid pseudotumours over the elbows and knees, both still under the designation “cutis laxa” [2]. The vascular form had its own history: Georg Sack proposed status dysvascularis in 1936, Gottron described “familial acrogeria” in 1940, Barabas introduced the entity into the English-language literature in 1967 (Sack–Barabas syndrome), and Beighton designated it “type IV” in his 1969 and 1979 reviews [8]. The kyphoscoliotic form was described in 1972 by Pinnell and colleagues as “hydroxylysine-deficient collagen disease”, the first inherited connective tissue disorder with a demonstrated enzymatic defect [26].

Nosology evolved through successive stages. Initial classifications numbered types with Roman numerals (types I to XI); the Villefranche revision (1997) reduced these to six types with major and minor criteria and descriptive names (classical, hypermobility, vascular, kyphoscoliosis, arthrochalasia and dermatosparaxis) [2, 4]. In 2017, the International Consortium on Ehlers–Danlos Syndromes and Hypermobility Spectrum Disorders published the classification currently in use, with 13 clinical types, major and minor criteria and minimum suggestive criteria for each, and with the rule that, except for hEDS, definitive diagnosis of any type requires identification of the causal variant [1, 2]. The same publication introduced the concept of hypermobility spectrum disorders (HSD) for people with symptomatic hypermobility who do not meet hEDS criteria [27].

Clinically, hypermobile EDS is by far the most frequent form, outnumbering all other forms combined; classical and vascular forms are the most frequent among those with a known molecular basis, and kyphoscoliotic, arthrochalasia, dermatosparaxis and musculocontractural forms are rare or very rare [2, 4]. The vascular form occupies a distinct position because it carries a risk of arterial, intestinal and uterine rupture and reduced life expectancy, and is the only form with pharmacological therapy tested in randomised trials [13, 14, 28]. This article describes the seven entities within its scope, with separate subsections whenever justified by clinical differences, and mentions the remaining types of the 2017 classification in the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1 General principles

The 2017 classification recognises a biochemical pattern: autosomal dominant forms usually result from variants in fibrillar collagen genes (types I, III and V), whereas autosomal recessive forms result from deficiencies of collagen-modifying or -processing enzymes or proteins involved in glycosaminoglycan and extracellular matrix biosynthesis [1, 2]. The following table summarises the genetic basis of the 13 clinical types of 2017 and subsequent additions.

Source: Malfait et al. 2017, reproduced in the Oxford Desk Reference (Box 3.13), with subsequent additions recorded in GeneReviews® [1, 3, 4].

2.2 Hypermobile EDS

No genetic, epigenetic or metabolomic basis for hEDS has yet been identified, and no molecular test establishes the diagnosis; genetic heterogeneity is presumed [3, 29]. Transmission observed in families is compatible with autosomal dominant inheritance with variable expression, and disease is more severe and more frequently diagnosed in females, who account for more than 90% of cases diagnosed after puberty [2, 3]. Heterozygous TNXB variants have been described in a small subgroup of people with joint laxity and soft skin overlapping hEDS, but do not explain most cases; recessive tenascin X deficiency accounts for fewer than 5% of cases previously labelled hypermobility-type EDS and should be suspected particularly when 21-hydroxylase deficiency coexists, owing to a contiguous deletion on chromosome 6p21.3 [3, 30]. In 2025, exome sequencing analysis of 15 kallikrein family genes, including a recurrent missense variant in KLK15, associated this matrix protease with connective tissue and immune signalling changes in hEDS families and a murine model; it remains a candidate gene without clinical validation and does not change the current diagnostic rule [31].

2.3 Classical EDS

In more than 90% of patients with the complete phenotype, cEDS is caused by heterozygous variants in COL5A1 (9q34.3) or COL5A2 (2q32.2), encoding the proα1 and proα2 chains of type V collagen; GeneReviews® attributes 81% of cases to COL5A1, 16% to COL5A2 and 3% to COL1A1 c.934C>T, p.(Arg312Cys), with the gene unknown in fewer than 10% of cases [2, 7]. Collagen V is a minor fibrillar collagen, present mainly as the heterotrimer [α1(V)]2α2(V) in skin, bone and tendon, forming heterotypic fibrils with collagen I and regulating their diameter through its partially retained amino-terminal propeptide. The proposed pathogenic mechanism is “functional” collagen V haploinsufficiency, through loss of expression of one COL5A1 allele (nonsense or frameshift variants), inefficient trafficking of mutant protein in the endoplasmic reticulum or deficient incorporation of mutant chains into heterotrimers; COL5A2 variants predominantly exert a dominant negative effect [7]. The ultrastructural consequence is fibrils with irregular diameters and lobulated outlines, the “collagen flowers” seen on transmission electron microscopy [7]. COL5A1 c.1588G>A, p.(Gly530Ser) may modify disease in heterozygosity and cause it in homozygosity [7]. However, this variant is classified in ClinVar as benign or likely benign by several laboratories (NM_000093.5; VCV000038863), so its presence in heterozygosity neither establishes nor excludes cEDS diagnosis and should not be used for predictive testing [7, 32]. The historical division between type I (gravis) and type II (mitis) corresponds to variable expression of the same allelic disease [2].

2.4 Vascular EDS

vEDS results from heterozygous variants in COL3A1 (2q32.2), encoding the α1(III) chain of type III procollagen, a major structural component of skin, vessels and hollow organs [8]. Procollagen III is a homotrimer of 1,466-amino-acid chains, with an amino-terminal propeptide containing 10 cysteines, a minor triple-helical domain, telopeptides, a major triple-helical domain of 342 Gly-Xaa-Yaa triplets and a 253-amino-acid carboxy-terminal propeptide containing chain recognition and selection sites [8]. Most pathogenic variants substitute a larger residue for a glycine in Gly-X-Y triplets; approximately one-quarter occur at splicing sites, particularly the 5' donor site, causing exon skipping; partial deletions and null variants causing haploinsufficiency are less frequent (approximately 5%) [5, 8]. More than 1,500 disease-associated COL3A1 variants have been identified [8].

The dominant negative mechanism explains substitution variant severity: in a heterozygote producing similar quantities of normal and abnormal chains, only 1/8 (1/2 × 1/2 × 1/2) of trimeric molecules contain three normal chains, while the remaining 7/8 incorporate at least one mutant chain and function abnormally [4]. Structurally altered chains fold slowly, undergo excessive post-translational modification, are retained in the endoplasmic reticulum and are poorly secreted; with null variants, the cell produces half the quantity of structurally normal collagen III [8, 28]. No alteration of the TGFβ pathway has been demonstrated in vEDS patients' dermal fibroblasts, distinguishing this entity from Marfan and Loeys–Dietz syndromes [5]. Rarely, arginine-to-cysteine substitutions in COL1A1 — NM_000088.4:c.934C>T, p.(Arg312Cys); c.1720C>T, p.(Arg574Cys); and c.3277C>T, p.(Arg1093Cys), designated R134C, R396C and R915C in the original article using triple-helix numbering — cause a phenotype prone to iliac or femoral dissection in young adults [2, 4, 33]. The notation “c.3227C>T”, appearing in secondary sources, does not correspond to this variant in the reference transcript and should be read as c.3277C>T (see 5.10) [32, 33].

For laboratory purposes, fibrillar collagen genes of the same clade (COL1A1, COL1A2, COL2A1, COL3A1, COL5A2) follow a “legacy” 52-exon nomenclature derived from COL1A2; in COL3A1, exons equivalent to COL1A2 exons 4 and 5 are fused (exon 4/5), and some laboratories still number residues from the first glycine of the triple helix, which, combined with HGVS (Human Genome Variation Society) nomenclature starting at p.Met1, creates confusion when interpreting old reports [8].

2.5 Kyphoscoliotic EDS

kEDS has two genes. PLOD1 (1p36.22) encodes lysyl hydroxylase 1 (LH1; procollagen-lysine 2-oxoglutarate 5-dioxygenase 1), which hydroxylates lysine residues in collagen -Xaa-Lys-Gly- sequences. Hydroxylysine serves as a carbohydrate attachment site and is indispensable for intra- and intermolecular pyridinoline cross-link formation; its deficiency compromises these links and tissue mechanical stability [10]. The mechanism is loss of function; the most frequent variant is an 8.9 kb duplication of exons 10 to 16 resulting from homologous recombination between identical 44 bp Alu sequences in introns 9 and 16, with an allele frequency of approximately 30% in probands; c.955C>T, p.(Arg319Ter) is frequent in the Arab population, and c.1533C>G, p.(Tyr511Ter) is the third most frequent [10]. Enzyme deficiency produces a characteristic increase in the urinary deoxypyridinoline (lysylpyridinoline) to pyridinoline (hydroxylysylpyridinoline) ratio [10, 34].

FKBP14 (7p14.3) encodes FKBP22, an endoplasmic reticulum-resident peptidyl-prolyl cis-trans isomerase of the FK506-binding immunophilin family, catalysing collagen III folding and interacting with collagens III, VI and X, but not collagens I, II or V [11]. This specificity explains the combination of vascular fragility (as in vEDS, through collagen III) and myopathy (as in collagen VI-related dystrophies) [11, 35]. Most variants cause loss of function; the c.362dupC, p.(Glu122ArgfsTer7) duplication accounts for approximately 70% of alleles and shares a common haplotype [11]. Patients' fibroblasts show normal collagen I, III and V biosynthesis and secretion but matrix disorganisation (collagens I, III and VI, fibronectin, tenascins, thrombospondin), loss of α2β1 and α5β1 integrin receptors and dilated endoplasmic reticulum cisternae containing flocculent material [11]. Urinary cross-links are normal in FKBP14-related kEDS [11, 29].

2.6 Arthrochalasia EDS

aEDS is caused by heterozygous variants in COL1A1 (aEDS type 1, OMIM 130060) or COL1A2 (aEDS type 2, OMIM 617821) causing complete or partial loss of exon 6, which contains the procollagen I N-proteinase cleavage site; the amino-terminal propeptide is not removed and pN-collagen molecules are incorporated into fibrils, which become irregular [1, 19, 29]. Dermal electron microscopy shows fibrils with angulated outlines and variable diameters, with complementary diagnostic value [36].

2.7 Dermatosparaxis EDS

dEDS is autosomal recessive and caused by biallelic variants in ADAMTS2 (5q35.3), encoding procollagen I N-proteinase (ADAMTS-2), the enzyme cleaving the amino-terminal propeptide domain of types I, II and III procollagen. Without this activity, the procollagen I amino-terminal propeptide is not removed, pN-collagen is incorporated into fibrils, and these form irregular, ribbon-like and branched structures, with markedly reduced dermal tensile strength — the same lesion as in bovine, ovine and canine dermatosparaxis, which gave the disease its name [37, 38]. Molecular identification in 1999 demonstrated that human type VIIC EDS and bovine dermatosparaxis share the same genetic basis [37].

2.8 Musculocontractural EDS

mcEDS is autosomal recessive and caused by biallelic variants in CHST14 (15q15.1; mcEDS-CHST14, approximately 82% of cases) or DSE (6q22.1; mcEDS-DSE, approximately 18%) [12]. Both genes participate in dermatan sulphate biosynthesis: dermatan sulphate epimerase (DSE) converts glucuronic acid into iduronic acid in the chondroitin precursor chain, and dermatan 4-O-sulphotransferase 1 (D4ST1, encoded by CHST14) transfers a sulphate group from 3'-phosphoadenosine-5'-phosphosulphate to carbon 4 of N-acetylgalactosamine [12]. Loss of either enzyme makes decorin's side chain chondroitin sulphate (linear) rather than dermatan sulphate (curved); because decorin dermatan sulphate chains maintain collagen fibril spatial organisation, dermal fibrils, compact and regular in controls, become dispersed in mcEDS-CHST14 [12]. This was the first human disease attributed to a dermatan sulphate biosynthesis defect, initially described as adducted thumb–clubfoot syndrome (Dündar syndrome) [39, 40]. In Japan, three founder variants (p.Pro281Leu, p.Phe209Ser and p.Tyr293Cys) were found in 20, 10 and 5 families, respectively [12, 41].

2.9 Genotype–phenotype correlations

The most consistent correlations are those in vEDS. In Pepin et al.'s retrospective series of more than 1,200 patients (2014), survival was longer with null variants and shorter with donor-site splicing variants causing exon skipping and triple-helical glycine substitutions by bulky residues (valine, aspartic acid, glutamic acid or arginine); variant position in the triple helix had no discernible effect [8, 42]. Null variant carriers have an approximately 15-year delay in complication onset, life expectancy close to the general US population and fewer obstetric and intestinal complications [8, 43]. In the French series, glycine-to-serine or -arginine substitutions appeared to have a better course than substitutions by valine or aspartic acid, and variants in N- or C-terminal regions were associated with fewer digestive complications [5, 43]. COL3A1 variants substituting lysine for glutamic acid in the triple-helical domain cause an overlap phenotype with thin, hyperextensible skin, bruising and intramuscular haematomas, with rare major arterial dissections [8, 44]. Biallelic COL3A1 variants cause predominantly anterior polymicrogyria, usually with normal intelligence and death from arterial events by the beginning of the third decade; parents are usually heterozygotes with mild forms [8, 28]. In cEDS, COL5A2 variants appear associated with the more severe end of the spectrum, with no other established correlations [7]. No clinically relevant correlations have been described in kEDS or mcEDS; in mcEDS, joint and skin manifestations, constipation, hypotonia and motor delay are significantly less frequent in the DSE than the CHST14 form (p < 0.01) [10–12].

3. Clinical Spectrum and Manifestations by System

3.1 Comparative overview

Sources: Oxford Desk Reference (Box 3.12), Smith's, Síndromes Genéticas: Reconhecer para Tratar (Box 14.1.1) and GeneReviews® [2–4, 7, 8, 10, 12, 29].

3.2 Hypermobile EDS

hEDS is characterised by generalised joint hypermobility, joint instability, pain, soft and mildly hyperextensible skin with atrophic scars and easy bruising, dental crowding, abdominal hernias, pelvic organ prolapse, marfanoid habitus, mitral valve prolapse and aortic root dilatation [3]. It is the only EDS form dominated by manifestations not directly attributable to connective tissue, such as postural orthostatic tachycardia syndrome (POTS) and other dysautonomic manifestations, mast cell activation disorders, migraine, gastrointestinal complaints and adverse drug reactions; disease may be progressively disabling and significantly affects mood and mental health [2, 29].

Musculoskeletal system. Subluxations, dislocations and soft tissue injuries may be spontaneous or follow minimal trauma, with acute pain persisting for hours or days; they may affect the extremities, spine, costovertebral and costosternal joints, clavicular joints and temporomandibular joints. Compensation for instability leads to abnormal movement patterns, reduced function and fear of movement (kinesiophobia) [3]. Osteoarthritis, tendinopathies and bursitis occur earlier than in the general population; temporomandibular dysfunction is relatively frequent, degenerative hip disease may cause femoroacetabular impingement, and recurrent patellar dislocation contributes to chondromalacia [3, 4]. Hypermobility is greater in young people and females [3].

Pain and fatigue. Pain varies in age at onset, location, duration, quality and response to therapy. Distinct types include myofascial pain (with palpable spasm and tender points consistent with fibromyalgia, particularly paravertebral), neuropathic pain (electric, burning or tingling, radicular, peripheral or periarticular, with reduced small fibres on skin biopsy), pain from tissue injury, gastrointestinal and urogynaecological visceral pain and osteoarthritic pain [3]. Fatigue and sleep disturbance frequently accompany pain; the Oxford Desk Reference notes that the risk of widespread pain, autonomic dysfunction and chronic fatigue has not been studied systematically at population level [30].

Skin and haemostasis. Skin is soft, with piezogenic heel papules, atypical striae (back, chest, axillae), atrophic scars and spontaneous bruising that may be mistaken for abuse [3, 45]. Prolonged bleeding, epistaxis, gingival bleeding and menorrhagia may occur; bleeding time may be prolonged, and von Willebrand factor and platelet function abnormalities have been described, with capillary fragility contributing [3].

Gastrointestinal system. Functional disorders, now termed disorders of gut–brain interaction, are frequent and underdiagnosed: gastro-oesophageal reflux and gastritis resistant to maximum proton pump inhibitor doses, early satiety and delayed gastric emptying (worsened by opioids), irritable bowel syndrome, rectocele, rectal prolapse and haemorrhoids. They are associated with autonomic and mast cell manifestations and nutritional deficiencies; abdominal vascular compression syndromes, such as median arcuate ligament syndrome and superior mesenteric artery syndrome, should be considered when pain is otherwise unexplained [3].

Cardiovascular system. Atypical chest pain, palpitations and orthostatic intolerance with syncope or presyncope are frequent; orthostatic hypotension and postural tachycardia may be documented during consultation, by 24-hour ambulatory monitoring or tilt testing [3]. Mitral valve prolapse was observed in 7% of 258 patients with hEDS or HSD and is mild and non-progressive. Aortic root dilatation was recorded in 15% of the same cohort but only approximately 2% of 95 children with hEDS or cEDS and 62 adults with hEDS [3]. In an earlier study of 71 patients, 6 of 29 (20%) with hEDS had aortic root dilatation, rarely of clinical significance [4].

Other systems. In the oral cavity, a high, narrow palate, dental crowding, reflux-related dental erosion and ineffective local anaesthetics; severe early-onset periodontitis is not typical and suggests pEDS [3]. Laryngeal inflammation, dysphagia and dysphonia, obstructive sleep apnoea, insomnia and periodic limb movements occur. Eye manifestations include xerophthalmia, high myopia (more than −6 dioptres), increased lens curvature, eyelid laxity and convergence insufficiency [3]. Neurological manifestations include: headache, intracranial hypertension and hypotension (cerebrospinal fluid fistula), Chiari I malformation, craniocervical instability with cervicomedullary syndrome, dystonia, tethered cord, Tarlov cysts, entrapment and small-fibre neuropathies [3]. Mast cell activation disorders (asthma, urticaria, gastroenteritis, mast cell activation syndrome, anaphylaxis) and primary immunodeficiencies (complement and immunoglobulin deficiencies) have been described, as have increased frequencies of autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety and depression [3]. Many patients report experiences of disbelief from healthcare professionals, with trauma associated with clinical encounters [3]. Pelvic floor manifestations, including urinary and faecal incontinence, prolapse, pelvic pain and dyspareunia, are reported by 20% to 75% of female patients, alongside dysmenorrhoea and menorrhagia [3].

Additional findings from the French protocol. Striae may be horizontal and wide, particularly on the back, and appear during growth unrelated to weight changes; healing, which is slower, worsens with topical or systemic corticosteroids. In the eye, besides xerophthalmia and myopia, there are vitreous abnormalities and minor lens opacities, and increased corneal refractive power may help to recognise mild forms. Dysphonia is relatively frequent, and nasofibroscopy may show vocal cord incoordination or hypotonia, cricoarytenoid subluxation or loss of pharyngeal tone. Hearing loss is more prevalent in children with non-vascular EDS than in the paediatric population, but is usually mild and does not require hearing aids. The oral mucosa is thin and fragile, with easy wounds under dental appliances, and tooth mobility is increased. Memory and attention complaints are reported, probably favoured by fatigue and pain, as are exertional dyspnoea and respiratory blocks that remain poorly studied. Preliminary studies suggest a higher frequency of coeliac disease, eosinophilic oesophagitis and Crohn's disease, without a demonstrated association. Some studies suggest skeletal fragility in adults with non-vascular EDS, including radiological vertebral fractures, but osteoporosis is only established in the kyphoscoliotic and spondylodysplastic forms. The protocol estimates that mild aortic root dilatation, usually non-progressive and not requiring treatment, may occur in up to one third of children and young adults with hEDS, a proportion higher than in the cohorts cited in the cardiovascular paragraph (see the divergences in section 7.9) [23].

Pregnancy. An international survey (947 women; 1,338 pregnancies) recorded increased incidences of pre-eclampsia, eclampsia, premature rupture of membranes, preterm delivery, antepartum and postpartum haemorrhage, hyperemesis gravidarum, shoulder dystocia, caesarean wound infection, postpartum psychosis, post-traumatic stress disorder and precipitate labour [3].

In children. A child may have delayed fine and gross motor milestones, be described as “clumsy” and, in more marked cases, have infantile hypotonia; there is no intellectual impairment [30].

3.3 Classical EDS

Skin. Skin is hyperextensible — stretching easily and returning after traction — and soft, velvety or doughy to the touch. It is fragile, with dermal rupture after minor trauma, particularly over pressure points (knees, elbows) and exposed sites (shins, forehead, chin), and sutured skin or mucosal incisions may dehisce [7]. Wound healing is poor: scars widen, thin and become pigmented, acquiring a “cigarette-paper” appearance (papyraceous, atrophic and haemosiderotic) [7, 29]. Other findings include molluscoid pseudotumours (fleshy lesions over scars at pressure points), subcutaneous spheroids (small, hard, mobile bodies in the forearms and shins, sometimes calcified and radiographically visible), painful piezogenic papules, elastosis perforans serpiginosa, acrocyanosis and chilblains [2, 7]. The face may show epicanthic folds, excess eyelid skin, widened forehead scars and a pale, prematurely aged appearance [2].

Joints and muscle. Hypermobility is usually generalised, affecting large and small joints, and becomes apparent when the child starts walking; dislocations (shoulder, patella, fingers, hip, radius, clavicle) generally resolve spontaneously. Chronic joint pain with normal radiographs, pes planus, congenital clubfoot, temporomandibular dysfunction, scoliosis, pectus, genu and hallux valgus are frequent. Primary muscle hypotonia with mild motor delay, fatigue and cramps are common in children [2, 7].

Haemostasis. Spontaneous bruises recur in the same areas, leaving brown haemosiderin pigmentation on the shins and knees, and there is a tendency to prolonged bleeding (for example, after toothbrushing) despite normal coagulation [7, 29]. Bruising usually begins when the child starts walking [23].

Tissue fragility. Inguinal, umbilical, hiatus and incisional hernias, recurrent rectal prolapse in early childhood, anal or uterine prolapse and cervical insufficiency in pregnancy [2, 7].

Cardiovascular system. Structural cardiac malformations are rare. Mitral, and less frequently tricuspid, prolapse has little clinical impact. Aortic root dilatation is more frequent in young people and rarely progresses; in one study, 14 of 42 patients (33%) with cEDS had root dilatation [4, 7]. There is a risk of spontaneous rupture of large arteries, much lower than in vEDS; a Portuguese case was published of spontaneous distal aortic dissection in a 39-year-old woman with a novel COL5A1 frameshift variant [7, 46].

Teeth. Dentinogenesis abnormalities with short or bulbous roots and tooth mobility, and pulp calcification that may complicate endodontic treatment [7].

Eye. The only corneal abnormality described is corneal thinning, with ultrastructural features that justify ophthalmological surveillance [23].

Pregnancy. Premature rupture of membranes and prematurity are approximately twice as frequent when the fetus is affected; breech presentation is more frequent in the affected hypotonic fetus and may cause neonatal hip or shoulder dislocation; fetal growth restriction, perineal lacerations, postpartum haemorrhage, pelvic prolapse and incontinence may occur [4, 7]. In Lind and Wallenburg's Dutch series, postpartum haemorrhage and perineal wound complications were more frequent in women with EDS (19% versus 7% and 8% versus less than 1%, respectively) [4].

3.4 Vascular EDS

vEDS is characterised by arterial, intestinal and uterine fragility, thin translucent skin, easy bruising, characteristic facies (thin lip vermilion, micrognathia, a narrow pointed nose, prominent eyes due to deficient facial adipose tissue, sunken cheeks) and an aged appearance of the extremities, particularly the hands (acrogeria) [8, 28]. Facial features are present in fewer than 30% of patients and may be absent in young children [5, 28]. Skin is thin, friable and translucent — with a visible venous network on the chest and abdomen — but not markedly hyperextensible [5, 28]. Hypermobility is usually limited to small joints; large-joint hypermobility, characteristic of common forms, is unusual [5].

Children. Approximately 60% of those diagnosed before 18 years are identified through a positive family history, and approximately 15% of these had already experienced a major complication at testing. Of 121 children tested without a family history, 65 had a major complication, at a mean age of 11 years. The four most frequent minor features in children without a major complication are distal hypermobility, easy bruising, thin skin and clubfoot. At birth, unilateral or bilateral clubfoot occurs in 8%, and hip dislocation, limb deficiency and amniotic bands in approximately 1%. Deaths in the first two decades are almost always due to spontaneous arterial rupture or dissection (60% aortic), with a male-to-female ratio of 3:1 before 20 years [8, 28].

Adults and arterial complications. Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presentation in approximately 70% of adults, as sudden death, stroke, acute abdomen, retroperitoneal haemorrhage, uterine rupture during delivery or shock [8]. Arterial ruptures may be preceded by an aneurysm, arteriovenous fistula or dissection, but frequently occur without previous dilatation — in 33% of patients with severe haemorrhagic complications in one review — complicating management [5]. Rupture sites are distributed across the chest and abdomen (66%), head and neck (17%) and extremities (17%); the aortic arch branches, descending thoracic and abdominal aorta, vertebral and carotid arteries and medium-sized arteries are particularly affected [5, 8]. Multiple ruptures or dissections, synchronous or recurrent in different arterial territories before 40 years, should prompt consideration of the diagnosis [5]. In Pepin et al.'s series (2000), approximately 80% of arterial deaths involved thoracic or abdominal vessels and fewer than 10% intracranial haemorrhage [4, 47]. Coronary dissection manifested with chest pain or “infarction” symptoms in 80% of 26 patients; chordae tendineae or ventricular rupture is rare; early-onset varicose veins are frequent [8, 28]. Initially described mitral prolapse was not confirmed in larger series [5]. In the US VEDS Collaborative Natural History Study cohort (557 people with a pathogenic COL3A1 variant; cross-sectional analysis published in 2026), aortopathy and iliac or visceral arteriopathy were more frequent in men (74.2% versus 57.9%), who also had higher all-cause mortality (32.3% versus 20.4%), whereas carotid–cavernous fistulas and spontaneous coronary dissections predominated in women; these are accumulated proportions in a referral cohort, rather than lifetime risks [48]. A systematic review with a UK case series (56 published cases and 10 new patients) concluded that clinical features cannot reliably distinguish vEDS-associated spontaneous coronary artery dissection from other cases, and that everyone with such a dissection should be assessed for possible vEDS, recognising that clinical assessment does not identify all cases [49].

Carotid–cavernous fistula. This affects up to 10% of patients, predominantly women, and manifests with sudden blurred vision, diplopia due to sixth nerve paresis, ocular pain, proptosis and chemosis; it almost always requires urgent intervention to preserve vision [8, 28].

Gastrointestinal complications. Gastrointestinal perforation occurs in approximately 15% of patients with an identified variant (approximately 25% in the 2000 series), rarely in null variant carriers, and predominantly involves the sigmoid colon; small-bowel and stomach perforations are rare, and iatrogenic perforation during colonoscopy has been described [5, 8, 28]. Intestinal perforation mortality (3%) is much lower than arterial mortality because surgery is generally effective; deaths mainly result from unexpected haemorrhage or arterial rupture during repair [5, 8]. Approximately 25% of all complications involve the digestive tract, and in some patients colonic perforation is the first manifestation, as in the Portuguese case published in 2025 [4, 50]. Splenic, hepatic and bladder ruptures have been described [8, 28].

Pulmonary complications. Spontaneous pneumothorax occurs in approximately 12% of patients, often as the first manifestation, through rupture of pulmonary blebs; haemothorax, haemopneumothorax and severe recurrent haemoptysis have been described, with haematomas, fibrous nodules, haemosiderosis and emphysematous changes on histopathology; one patient successfully underwent lung transplantation [5, 8].

Other manifestations. Tendon and muscle rupture, chronic subluxations, keratoconus (rare), thin translucent gingiva with gingival recession and periodontal disease, temporomandibular dysfunction, dentine abnormalities and elastosis perforans serpiginosa [8, 28]. Brazilian cases of stroke as a vEDS manifestation have been published [51].

Pregnancy. See section 7.4 and section 8.

Natural course. Complications are rare in childhood, but 25% of patients have their first complication by 20 years and more than 80% by 40 years; mean age at first complication in the 2000 series was 23.5 ± 11.1 years, without sex differences [4, 5]. Median survival was 48 years in the 2000 series (deaths between 6 and 73 years) and approximately 50 years in the 2014 series, five years lower in males; in a smaller Mayo Clinic series, 68% of patients treated for vascular events were alive at 50 years [5, 8, 42]. The Oxford Desk Reference reports median survival of 51 years from Pepin et al.'s data (2014) [4]. In the French cohort followed for up to 17 years, overall survival was 71.6% after a median follow-up of 5.3 years, dependent on variant type, age at diagnosis and treatment [52].

3.5 Kyphoscoliotic EDS

PLOD1-related kEDS. Characterised by congenital hypotonia (100%), early kyphoscoliosis (95%), generalised joint hypermobility with dislocations (shoulders, hips, knees, wrists), skin fragility and ocular abnormalities, with normal intelligence [10]. Pregnancy with an affected fetus may be complicated by premature rupture of membranes. Muscle weakness may be severe, with “wrist drop”, and cause upper brachial plexus paresis; mild to moderate gross motor delay occurs in approximately 60%, but walking is almost always acquired before 2 years and there is no regression [10]. Thoracic kyphoscoliosis is frequently present in the newborn and becomes moderate to severe in childhood; clubfoot (approximately 20–25%), pectus deformity (approximately 25%), osteopenia (approximately 20–25%) and marfanoid habitus (long limbs, arachnodactyly) are frequent [10]. Skin is hyperelastic, velvety and friable in all patients, with wide atrophic scars in approximately 60% and severe bruising in approximately 50% [10]. Cardiovascular manifestations include risk of aortic dilatation or dissection and medium-sized artery rupture, mitral prolapse, venous ectasia after catheterisation and prenatal or neonatal cerebral haemorrhage [10]. In the eye, bluish sclerae, refractive errors (high myopia, hypermetropia) and microcornea are frequent, whereas scleral fragility with globe rupture — described in the original cases — occurs in a minority; severe kyphoscoliosis may cause restrictive pulmonary disease with secondary pulmonary hypertension [4, 10, 29]. Nevo syndrome is now included in the kEDS spectrum [10].

FKBP14-related kEDS. The newborn presents with congenital hypotonia and weakness, feeding difficulties, poor head control and sometimes a need for respiratory support; strength improves during childhood, and most children acquire independent walking between 2 and 4 years, with adult motor decline generally compatible with independent walking [11, 53]. Usually severe and progressive kyphoscoliosis develops before the first year in two-thirds of patients (from birth to 7 years in 15 patients) and may require surgery [11]. Hypermobility is marked (mean Beighton 8/9), with foot deformities in all patients, congenital contractures in up to one-third, congenital hip dislocation in 4 of 17 and atlantoaxial instability described in three patients [11]. Hearing loss — sensorineural in approximately half, conductive in up to one-quarter — may be present at birth or develop later. Skin is soft and hyperextensible (17/23), with follicular hyperkeratosis and crossed palmar creases. Refractive errors (two-thirds), blue sclerae (one-third), hernias (11/23), cleft palate or submucous cleft with bifid uvula (7/23), speech delay (7/20) and large bladder diverticula (3/19) complete the picture; internal carotid and coeliac artery dissections in adults, hypogastric pseudoaneurysm rupture in a child, valvular insufficiency and subdural hygroma have been described [11, 53]. The oldest described patient was 53 years [11].

3.6 Arthrochalasia EDS

aEDS is characterised by severe generalised joint hypermobility with recurrent subluxations, bilateral congenital hip dislocation, skin hyperextensibility, tissue fragility with atrophic scars, easy bruising, muscle hypotonia with motor delay, kyphoscoliosis and mild osteopenia [2, 4, 29]. Dislocations are frequently painless [29]. Short stature and mild bone fragility are described, and skin involvement tends to be less marked than in cEDS [19]. In the largest published series (12 patients from 10 families), 9 had fractures (one required bisphosphonates), 5 underwent hip surgery and 3 spinal surgery, and 4 were wheelchair-dependent or unable to walk without support; of the 8 adults, most were employed, and one patient had two affected children, with preterm delivery the only complication [54].

3.7 Dermatosparaxis EDS

dEDS is distinguished by extreme skin fragility, with congenital or early lacerations after trivial trauma, redundant, pendulous, doughy, lax skin (particularly on the face and limbs), severe bruising with risk of subcutaneous haematomas and haemorrhage, and increased palmar creases [2, 4, 38]. Facies is characteristic: oedematous (“puffy”) eyelids, blue sclerae, epicanthic folds, micrognathia and a depressed nasal root, with pendulous neck skin [29, 38]. Other findings are large, late-closing fontanelles, short limbs with brachydactyly, large umbilical and inguinal hernias, premature rupture of membranes and perinatal complications, postnatal growth delay, hirsutism, dental anomalies, refractive errors and strabismus [2, 29]. Visceral and vascular fragility may cause bladder or diaphragmatic rupture [29, 38]. A milder phenotypic variant has been recognised [38].

3.8 Musculocontractural EDS

mcEDS manifests from birth with multiple congenital contractures (thumbs in adduction-flexion, clubfoot) and characteristic facies, followed with age by progressive foot deformities, dislocations, spinal deformities, skin fragility and large subcutaneous haematomas [2, 12]. The table summarises frequencies in 85 patients from two cohorts (mcEDS-CHST14 and mcEDS-DSE).

Source: GeneReviews® (combined data from Minatogawa et al. 2022) [12, 41, 55].

Digital contractures attenuate with age, but limited extension or flexion persists; median age at first dislocation is 6 years, and 80% of patients with dislocations experience their first episode by 10 years [12]. In an institutional survey of 12 patients, 67% had scoliosis with a Cobb angle ≥ 10° (one ≥ 45°), 42% thoracolumbar kyphosis ≥ 20°, 50% cervical kyphosis, 17% atlantoaxial subluxation and 83% cervical vertebral malformations [12]. The round childhood face with micrognathia or retrognathia becomes elongated, with a prominent mandible, dental crowding and asymmetry in adolescence; cleft lip or palate occurred in 3 of 50 patients [12]. Recurrent subcutaneous infections with fistula formation (buttocks, elbows) occurred in 14 of 42 patients with the CHST14 form [12]. Median age at retinal detachment is 15.5 years, and six patients became blind [12]. Large subcutaneous haematomas — scalp, buttocks, thigh, leg, knee; median first episode at 6 years — may progress to hypovolaemic shock and, associated with slow healing, led to toe amputations [12]. Hydronephrosis, bladder dysfunction, recurrent urinary infections (12/37) and nephrolithiasis or cystolithiasis (only in the CHST14 form), hypogonadism in 3 of 22, colonic diverticula with perforation — including fatal perforations at 36 and 37 years and perforations in two sisters at 25 and 24 years — and pneumothorax in 4 of 40 occur [12, 56]. Hearing loss, typically mild to moderate bilateral sensorineural, was detected in 89% of patients in an institutional series [12]. There is no significant intellectual impairment in the CHST14 form; creatine kinase may be elevated [12]. Smith's adds hydronephrosis and glaucoma as characteristic findings [2]. The French protocol distinguishes the haematomas of mcEDS, which arise mainly after minor trauma and also affect non-subcutaneous sites (scalp, spine, buttocks), from those of clEDS, which are mainly spontaneous and subcutaneous; both differ from the easy bruising of the other forms in that they may require surgery and transfusion [23].

4. Clinical Recognition and Red Flags

Recognition begins with a three-generation pedigree, with targeted questions about hypermobility, easy bruising, abnormal healing, dislocations (shoulders, patellae, temporomandibular joints, fingers), congenital hip dislocation, arthroplasties, premature cardiac death and, when vEDS is suspected, arterial or intestinal ruptures and sudden deaths in close relatives [4, 30]. Examination includes the Beighton score, asking about flexibility “tricks”, assessment of dysautonomic symptoms, skin palpation and traction, scar inspection (elbows, knees, shins, surgical scars) and recording bruises [4]. Skin is considered hyperextensible when a fold stretches more than 1.5 cm on the volar forearm or dorsum of the hand and more than 3 cm on the neck, elbows or knees; measurement should be made on the mid-volar aspect of the non-dominant forearm, without redundant folds [4, 7]. Extension exceeding 2.0 cm should suggest types other than hEDS [3]. Hypermobility should also be distinguished from hypotonia of central or peripheral origin by assessing muscle strength and reflexes [10, 30]. The French protocol proposes a standardised clinical form for the consultation and for the transmission of information between specialists — number and age of the first sprains and dislocations, Beighton and Bulbena scores (the latter with 10 items), scars, bruising with normal haemostasis, pain and its neuropathic component, autonomic, ocular, oral, digestive, respiratory, urogynaecological and obstetric symptoms, and the suspected EDS type — and emphasises that symptoms usually begin in childhood, more or less early depending on the type and severity [23].

vEDS should be suspected in any young person with unexplained arterial or visceral rupture, carotid dissection or colonic perforation; many diagnoses are made only after a catastrophic complication or at autopsy [4, 5]. In children, the vascular form may manifest with extensive bruising (the most frequent sign and often the reason for consultation), clubfoot, hip dislocation or limb deficiency [28]. In severe EDS forms, extensive mucocutaneous injuries after minimal trauma may mimic abuse, justifying inclusion of EDS in assessment of suspected non-accidental injury, alongside osteogenesis imperfecta, Menkes syndrome and glutaric aciduria [45].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Assessment of hypermobility: Beighton score and five-question questionnaire

Source: Oxford Desk Reference (Box 2.12) and GeneReviews® [3, 30]. The most frequent errors in the trunk manoeuvre are slight knee flexion, feet placed apart, palm bases not resting on the floor and hands placed too far forward of the feet; for the 5th finger, fingertip extension without metacarpophalangeal extension exceeding 90° scores no points [3].

Generalised joint hypermobility thresholds depend on age: in the Oxford Desk Reference, ≥ 6 in prepubertal children and adolescents, ≥ 5 from 15 to 50 years and ≥ 4 above 50 years [30]; in the 2017 hEDS criteria, ≥ 5 in biologically mature adolescents and adults up to 50 years and ≥ 4 above 50 years [1, 3]. Approximately 5% to 10% of school-age children are hypermobile, a proportion decreasing with age, higher in females and varying between ethnic groups [30]. In people with acquired limitation of mobility, generalised hypermobility may be accepted one point below the threshold if there are two or more positive answers to Hakim and Grahame's five-point questionnaire (5PQ): (1) can you now (or could you ever) place your hands flat on the floor without bending your knees? (2) can you now (or could you ever) bend your thumb to touch your forearm? (3) as a child, did you amuse friends by contorting your body or could you do the splits? (4) as a child or teenager, did your shoulder or kneecap dislocate more than once? (5) do you consider yourself “double-jointed”? [3]. Two or more affirmative answers suggest hypermobility with sensitivity of 80% to 85% and specificity of 80% to 90% [7].

5.2 The 2017 criteria for hypermobile EDS

Clinical hEDS diagnosis, applicable only after biological maturity, requires all three following criteria [1, 3, 29]:

Criterion 1 — Generalised joint hypermobility (Beighton ≥ 5 up to 50 years; ≥ 4 above 50 years; or one point below with positive 5PQ). People with positive 5PQ but a score two or more points below should be assessed at other joints (shoulders, hips, ankles, toes); localised or regional hypermobility points towards HSD [3].

Criterion 2 — At least two of features A, B and C:

• Feature A — five or more systemic manifestations of a generalised connective tissue disorder: unusually soft or velvety skin; mild skin hyperextensibility; unexplained striae on the back, groin, thighs, breasts or abdomen in adolescents, men or prepubertal girls without weight changes; bilateral piezogenic heel papules; recurrent or multiple abdominal hernias (hiatus hernia does not count); atrophic scars at at least two sites, without papyraceous or haemosiderotic scars; pelvic floor, rectal or uterine prolapse in children, men or nulliparous women without a predisposing cause; dental crowding and a high or narrow palate (both required); arachnodactyly (bilateral wrist or thumb signs); arm-span/height ratio ≥ 1.05; mitral valve prolapse by echocardiographic criteria; aortic root dilatation with z-score > +2 [3, 29].
• Feature B — positive family history, with at least one first-degree relative independently meeting the criteria [3].
• Feature C — at least one musculoskeletal complication: musculoskeletal pain in two or more limbs, daily, for at least three months; chronic widespread pain for at least three months; or recurrent dislocations or frank joint instability without trauma (three or more atraumatic dislocations at the same joint, or two or more at two different joints at different times, or confirmed instability at two or more sites) [3].

Criterion 3 — All of the following: absence of unusual skin fragility or other features suggesting another EDS type; exclusion of other inherited or acquired connective tissue disorders, including autoimmune rheumatological diseases (which may coexist but should not explain feature C); exclusion of alternative diagnoses with hypermobility due to hypotonia or laxity (neuromuscular disorders, other inherited connective tissue disorders, skeletal dysplasias) [1, 3]. In the official checklist, reproduced in the French protocol, a person with an acquired connective tissue disorder (for example, lupus or rheumatoid arthritis) only receives an additional diagnosis of hEDS if features A and B of criterion 2 are met; feature C (chronic pain or instability) does not count in this situation [23].

People with symptomatic hypermobility who do not meet these criteria and have no other syndrome receive an HSD diagnosis, subdivided into generalised, peripheral, localised and historical forms; the terms “familial benign joint hypermobility syndrome” and “joint hypermobility syndrome” are no longer used [3, 27]. The Oxford Desk Reference records that some literature still treats HSD and hEDS as synonyms [4]. Because the 2017 criteria were constructed for adults, the 2023 paediatric framework classifies children aged 5–18 years into eight subtypes of paediatric generalised hypermobility or paediatric HSD according to skin involvement, musculoskeletal complications and comorbidities, with reassessment using adult criteria after biological maturity [3, 20]. The checklist reproduced in the French protocol keeps a Beighton threshold of ≥ 6 for prepubertal children and adolescents, and the protocol recommends, when there is diagnostic doubt in a child, regular reassessments until the end of growth [23]. A retrospective Italian study of 327 patients previously diagnosed using Villefranche or Brighton criteria proposed making the 2017 criteria less restrictive because they classify patients with the same extra-articular manifestation profile as HSD [57]. The Ehlers–Danlos Society provides an hEDS diagnostic checklist (www.ehlers-danlos.com/heds-diagnostic-checklist) [4]. The International Consortium announced publication of an updated classification of all EDS types and HSD and recommendations for monogenic forms on 2 December 2026, followed in March 2027 by recommendations on hEDS/HSD and a diagnostic pathway; this revision is supported by an international study evaluating the 2017 criteria (326 participants across eight centres, 2022–2025). These are institutional announcements: until publication, the 2017 criteria remain the reference [22, 58].

5.3 Classical EDS

There are no sufficiently agreed clinical criteria for definitive diagnosis; cEDS should be suspected with the major criteria of skin hyperextensibility and atrophic scars, or with generalised joint hypermobility and/or three or more minor criteria [7, 17]. The version in Síndromes Genéticas: Reconhecer para Tratar (Villefranche criteria) requires three major criteria and one minor [29]. Minor criteria are: easy bruising, soft doughy skin, skin fragility, molluscoid pseudotumours, subcutaneous spheroids, hernias, epicanthic folds, hypermobility complications (sprains, dislocations, pain, flexible pes planus) and a first-degree relative with cEDS [7]. Diagnosis is confirmed by identifying a heterozygous variant in COL5A1, COL5A2 or COL1A1. The recommended approach is: (1) COL5A1 and COL5A2 sequencing (sequencing detects 99% of variants; 1% are deletions/duplications); (2) if negative and the panel does not include COL1A1, targeted testing for COL1A1 c.934C>T; (3) COL5A1/COL5A2 deletion/duplication analysis; alternatively, exome or genome [7]. Without a variant, COL5A1 null allele testing in fibroblast complementary DNA (possible only if the proband is heterozygous for an informative polymorphism) may demonstrate loss of expression of one allele; transmission electron microscopy with “collagen flowers” supports but does not confirm diagnosis [7].

5.4 Vascular EDS

There are no agreed clinical diagnostic criteria; the 2017 criteria guide the decision to test [1, 8]. vEDS should be considered with one (particularly two) major criteria or several minor criteria, especially before 40 years [8]. Major criteria: arterial rupture, dissection or aneurysm at a young age; intestinal rupture (particularly sigmoid) without risk factors; uterine rupture in the third trimester; carotid–cavernous fistula without trauma; family history of vEDS with a known COL3A1 variant [8, 28, 29]. Minor criteria: easy bruising (spontaneous, at unusual sites), thin translucent skin, characteristic facies, acrogeria, spontaneous pneumothorax or haemopneumothorax, small-joint hypermobility, tendon or muscle rupture, clubfoot, congenital hip dislocation, chronic subluxations, early varicose veins, gingival recession and keratoconus [8, 29]. Two major criteria have high specificity; two minor criteria justify referral for genetic assessment [28, 29].

Diagnosis is established by identifying a heterozygous pathogenic or likely pathogenic COL3A1 variant; a variant of uncertain significance neither confirms nor excludes it [8]. Sequencing detects more than 95% of variants and targeted deletion/duplication analysis approximately 1%; if DNA sequencing is negative, RNA sequencing from cultured fibroblasts may reveal intronic variants inserting new sequences [8]. When the phenotype is typical (gastrointestinal rupture, multiple ruptures in different arterial territories), COL3A1 alone may be tested; in other cases, a heritable thoracic aortic disease panel or exome with gene filtering is preferable, given overlap with Loeys–Dietz syndrome, Marfan syndrome and non-syndromic forms [5]. Expanded panels identify pathogenic variants in 4% to 27% of patients with heritable aortic disease, at the cost of approximately 20% variants of uncertain significance [5]. Biochemical analysis of fibroblast-synthesised procollagen III (sodium dodecyl sulphate polyacrylamide gel electrophoresis after radiolabelled proline incorporation) identifies more than 95% of patients but has limited availability and is now used mainly to characterise splicing variants [8, 28].

5.5 Kyphoscoliotic EDS

Major criteria: congenital muscle hypotonia; congenital or early-onset kyphoscoliosis (progressive or not); generalised joint hypermobility with dislocations or subluxations. General minor criteria: skin hyperextensibility, easy bruising, medium-sized artery rupture or aneurysm, osteopenia, blue sclerae, hernia, pectus deformity, marfanoid habitus, clubfoot and refractive errors. Specific minor criteria: for PLOD1, skin fragility (friable skin, poor healing, wide atrophic scars), scleral and ocular fragility and rupture, microcornea and facial dysmorphism; for FKBP14, congenital hearing loss (sensorineural, conductive or mixed), follicular hyperkeratosis, muscle atrophy and bladder diverticula [1, 10, 11]. Minimum suggestive criteria are congenital hypotonia and early kyphoscoliosis associated with generalised hypermobility or three minor criteria [10, 29].

In kEDS-PLOD1, diagnosis is established by biallelic PLOD1 variants; sequencing identifies approximately 67% and deletion/duplication analysis approximately 33% of variants, so testing for the exon 10–16 Alu duplication should form part of first-line analysis [10]. If only one variant or variants of uncertain significance are identified, the urinary deoxypyridinoline/pyridinoline ratio by high-performance liquid chromatography — approximately 6.0 in kEDS-PLOD1 against approximately 0.2 in normal individuals — is a sensitive, specific and inexpensive test [10, 29, 34]. Fibroblast lysyl hydroxylase activity (below 25% of normal) and electrophoresis with accelerated migration of underhydroxylated chains are complementary methods [10, 29]. In kEDS-FKBP14, sequencing identified variants in all 24 patients studied; the urinary ratio is normal, separating the two forms; creatine kinase is normal or slightly elevated; muscle biopsy shows non-specific myopathic changes and lower-limb MRI may show fatty degeneration of rectus femoris and soleus, but none of these examinations is necessary for diagnosis [11].

5.6 Arthrochalasia EDS

Major criteria: bilateral congenital hip dislocation; severe generalised joint hypermobility with recurrent subluxations; skin hyperextensibility. Minor criteria: muscle hypotonia, kyphoscoliosis, mild radiological osteopenia, tissue fragility with atrophic scars and easy bruising [1, 4]. Diagnosis is suggested by bilateral congenital hip dislocation associated with severe generalised hypermobility or skin hyperextensibility and confirmed by COL1A1 and COL1A2 sequencing with exon 6 analysis [1, 29]. In a series of 12 patients from 10 families, most had COL1A1 or COL1A2 variants causing complete or partial exon 6 loss, and COL1A1 variants were associated with greater musculoskeletal severity [54].

5.7 Dermatosparaxis EDS

Major criteria: extreme skin fragility with congenital or early lacerations; characteristic facies; redundant, almost lax skin with excessive wrist and ankle folds; increased palmar creases; severe bruising with risk of subcutaneous haematomas and haemorrhage; umbilical hernia; postnatal growth delay; short limbs, hands and feet; perinatal complications due to connective tissue fragility [1, 38]. Diagnosis rests on severe skin fragility with the facies and other features and is confirmed by biallelic ADAMTS2 variants [29]. Dermal electron microscopy with irregular, “hieroglyphic” or “ribbon-like” fibrils and biochemical demonstration of pN-collagen in fibroblasts support diagnosis [37, 38].

5.8 Musculocontractural EDS

mcEDS should be suspected with two major criteria — multiple congenital contractures (thumb adduction-flexion and/or clubfoot), characteristic facies present at birth or in early childhood (large, late-closing anterior fontanelle, short downslanting palpebral fissures, hypertelorism, blue sclerae, low-set rotated ears, short nose with hypoplastic columella, long philtrum, thin upper vermilion, small mouth, high palate, micrognathia) and skin features (hyperextensibility, bruising, fragility with atrophic scars, increased palmar creases) — with supportive minor criteria (dislocations, pectus, spinal deformities, tapered fingers, progressive foot deformities, large haematomas, constipation, colonic diverticula, pneumothorax, nephrolithiasis, hydronephrosis, cryptorchidism, strabismus, refractive errors, glaucoma) [1, 12]. Diagnosis is confirmed by biallelic CHST14 or DSE variants; all described variants are in coding regions and detectable by panel or exome, with no described intragenic deletions [12].

5.9 Practical algorithm

1. Characterise the phenotype: Beighton and 5PQ, skin extensibility and texture, scar type, bruising, signs of arterial, visceral or ocular fragility, congenital contractures, hypotonia and kyphoscoliosis, congenital hip dislocation and facies [1, 4].
2. Signs of vascular or visceral fragility → urgent COL3A1 testing (or heritable aortic disease panel) and vEDS precautions until results [5, 8].
3. Marked skin fragility, contractures, congenital hypotonia or other rare-type features → multigene EDS panel or exome (including COL5A1, COL5A2, COL1A1, COL1A2, COL3A1, TNXB, PLOD1, FKBP14, ADAMTS2, CHST14, DSE, B4GALT7, B3GALT6, SLC39A13, ZNF469, PRDM5, COL12A1, C1R, C1S, AEBP1); urinary cross-links for congenital kyphoscoliosis [1, 10].
4. Hypermobility with soft skin and systemic manifestations, without fragility → apply 2017 hEDS criteria or the paediatric framework; genetic testing serves only to exclude alternative diagnoses [3, 20].
5. Supplementary investigations: echocardiography with aortic root measurement in cEDS, vEDS and kEDS; thoracic and abdominal aortic and iliac artery MR angiography in vEDS; skin biopsy for electron microscopy and fibroblast culture only as second-line [4].
6. Initial assessment common to non-vascular EDS (French protocol): radiography of the whole spine (EOS, if available) and echocardiography in all patients, unless contraindicated; ophthalmological examination and dental examination with orthopantomography and assessment of the temporomandibular joint in all; laboratory tests according to the patient to exclude alternative diagnoses (inflammatory markers, autoimmunity, haemostasis, TSH, creatine kinase, calcium-phosphate metabolism); osteoarticular radiographs, densitometry, ultrasound, MRI or CT, cerebral MR angiography, Doppler ultrasound of the supra-aortic trunks, electromyography, muscle or spinal MRI and dynamic radiographs or CT of the cervical spine only in the presence of symptoms [23].
7. 2017 criteria not met: look for warning signs of another diagnosis (vascular, ophthalmological, muscular, neurological, psychomotor delay, bone abnormalities, growth disorders, body habitus) and, if present, request chromosomal microarray (array comparative genomic hybridisation), a panel or an exome; without these signs, consider HSD, chronic dysfunctional pain syndromes or rheumatological diseases [23].

The French protocol recommends that genetic testing be requested in a genetics clinic, ideally with experience in EDS, and discussed at a multidisciplinary meeting. A panel is indicated when the 2017 criteria for a non-vascular type are met, may be offered in hEDS so as not to miss mild forms of cEDS or clEDS, and is not recommended in HSD, given the very low yield and the frequency of variants of uncertain significance; in the other types, the yield is high and interpretation easier. Skin biopsy does not allow routine confirmation of the diagnosis. The diagnosis, which often follows a long journey without answers, should be communicated with a systematic offer of psychological support [23].

5.10 Genetic test limitations and report content

Test sensitivity depends on method and variant type. The detectable variant percentages cited in previous subsections (for example, 99% by sequencing in cEDS, more than 95% in vEDS, approximately 67% in kEDS-PLOD1) refer to the proportion of known variants identified by each technique in already confirmed patients, rather than the probability of a positive test in someone with clinical suspicion [7, 8, 10]. In kEDS-PLOD1, approximately one-third of variants are duplications or deletions, particularly the exon 10–16 Alu duplication, invisible to sequencing without copy-number analysis; in cEDS and vEDS, deletions and duplications are rare (approximately 1%), but deep intronic COL3A1 variants are revealed only through fibroblast RNA sequencing or procollagen III biochemical analysis [7, 8, 10]. No intragenic deletions have been described in mcEDS [12]. Parental leucocyte DNA does not detect exclusively germline mosaicism, described in cEDS and in at least 1% of apparently de novo vEDS families [7, 8]. There is no confirmatory test in hEDS: a negative panel serves only to exclude alternative diagnoses, and a variant of uncertain significance in a collagen gene confirms neither hEDS nor another type [3].

The report should indicate the gene, versioned reference transcript, HGVS complementary DNA and protein nomenclature, zygosity (heterozygosity in dominant forms; biallelic variants in recessive forms, ideally demonstrated to be in trans through parental studies), classification under ACMG/AMP criteria and method limitations [59]. The MANE Select transcripts (version 1.5) for this article's genes are: COL5A1 NM_000093.5; COL5A2 NM_000393.5; COL1A1 NM_000088.4; COL1A2 NM_000089.4; COL3A1 NM_000090.4; TNXB NM_001365276.2; PLOD1 NM_000302.4; FKBP14 NM_017946.4; ADAMTS2 NM_014244.5; CHST14 NM_130468.4; DSE NM_013352.4; AEBP1 NM_001129.5; C1R NM_001733.7; and C1S NM_001734.5 [60]. The PLOD1 and FKBP14 GeneReviews® chapters still use NM_000302.3 and NM_017946.3, but the cited variants retain their numbering on the MANE transcript and are classified in ClinVar: PLOD1 c.955C>T, p.(Arg319Ter) and c.1533C>G, p.(Tyr511Ter), pathogenic; FKBP14 c.362dup, p.(Glu122ArgfsTer7), pathogenic or likely pathogenic [10, 11, 32]. Three numbering systems coexist in collagen genes: triple-helix residue numbering, old cDNA numbering and current HGVS starting at p.Met1. The same COL1A1 variant appears as R134C, c.1053C>T in the 2007 article and NM_000088.4:c.934C>T, p.(Arg312Cys); R915C corresponds to c.3396C>T in old numbering and c.3277C>T, p.(Arg1093Cys) in current numbering. Added to these is the “legacy” 52-exon nomenclature (section 2.4). Old reports should be converted before comparing results between relatives or laboratories [8, 33]. ClinVar classification also differs between these rare variants: p.(Arg312Cys) is pathogenic or likely pathogenic, without conflicts; p.(Arg1093Cys) has conflicting classifications; and p.(Arg574Cys) has a single submission as a variant of uncertain significance. They should therefore not be treated as equivalent in predictive testing [32].

A variant of uncertain significance does not become pathogenic because a patient has a suggestive phenotype, responds to treatment or shows partial segregation in a small family. In vEDS, late penetrance of null variants and the existence of asymptomatic carriers in the eighth and ninth decades make unaffected relatives poorly informative, and segregation studies are described as research until attaining the weight required by the criteria [8, 59]. A VUS should not be used for predictive testing, prenatal diagnosis or to release relatives from surveillance; in these cases clinical decisions rest on phenotype and, with suspected vEDS, precautions remain until clarification, for example through RNA studies or procollagen III biochemistry [8].

5.11 Minimum criteria for the remaining types of the 2017 classification

The types mentioned only in the differential diagnosis (section 6.1) also have major, minor and minimum suggestive criteria, which the French protocol reproduces from the 2017 classification; in all of them, definitive diagnosis requires the causal variant [1, 23].

Source: 2017 classification, in the version of the French protocol for non-vascular EDS; OMIM according to Orphanet [1, 23]. In the minimum criterion for BCS, the protocol table gives a central thickness below 100 µm, a value that contradicts the major criterion in the same table and the protocol's own ophthalmology chapter (below 400 µm); the 400 µm threshold of the 2017 classification is adopted. For the proximal contractures of mEDS and the B4GALT7-specific criterion of spEDS, the protocol gives the shoulder instead of the elbow; the elbow of the 2017 classification is adopted. In pEDS, brown or black pretibial pigmentation is highly suggestive [23].

6. Differential Diagnosis

6.1 Between EDS types

hEDS is the most frequent diagnosis and also the most susceptible to overdiagnosis. Mild cEDS forms may be mistaken for hEDS, and diagnosis may be revised if more marked skin manifestations develop in the patient or a relative; among patients with the full cEDS skin phenotype, approximately 90% have a COL5A1 or COL5A2 variant, but no consistent variants have been found in patients with intermediate skin involvement [3]. Distinction between rare types rests on the following features [3, 7, 10, 12]:

6.2 Other disorders with hypermobility, skin or arterial fragility

The French protocol divides the differential diagnoses into two groups, according to whether or not there is intellectual disability: epileptic seizures and global developmental delay are very rare in non-vascular EDS and should point towards genetic, metabolic or chromosomal syndromes, or towards periventricular nodular heterotopia if there is epilepsy [23].

7. Treatments and Risk Management Strategies

7.1 Common principles

No EDS form has approved disease-modifying therapy; management is multidisciplinary, preventive and directed at manifestations [3, 7, 29]. General measures include physiotherapy to strengthen joint-stabilising muscles, orthoses for recurrent sprains or dislocations, pain control (non-steroidal anti-inflammatory drugs for mild to moderate pain; selective serotonin reuptake inhibitors and low-dose tricyclic antidepressants for more severe pain), cognitive behavioural therapy, acupuncture and transcutaneous electrical nerve stimulation (TENS), sleep hygiene for chronic fatigue and lifestyle changes (diet and physical exercise) [29]. Repetitive activities and obesity exacerbate hypermobility; swimming, cycling and walking are preferable to high-impact activities (for example, trampolining), and contact-sport injury risk is increased [30].

Wound healing requires specific surgical technique in forms with skin fragility (cEDS, kEDS, dEDS, mcEDS): close dermal wounds without tension, preferably in two layers, use generous deep sutures, retain skin sutures for twice the usual duration and secure adjacent skin with adhesive tape to prevent scar widening; in young children, padding or bandages over the forehead, knees and shins, and football shin guards or ski socks with shin protection in active children [2, 7, 10]. The French protocol adds that sutures should be non-absorbable, more numerous and closer together, reinforced with adhesive strips, kept for about 15 days and removed alternately (every other suture) by a nurse, who monitors healing; staples and skin glue are not recommended. These rules are mandatory in cEDS and in rare forms with marked skin fragility and are adapted, in hEDS, to any history of poor healing. It also recommends a helmet and custom-made foam protection in young children, avoiding excessive sun exposure, which accelerates skin ageing, and discussing surgical removal of molluscoid pseudotumours when the cosmetic impairment has a significant psychological impact [23].

7.2 Hypermobile EDS

Management recommendations were published by the international consortium in 2017 and updated in subsequent reviews, summarised in GeneReviews® [3, 18, 62].

Musculoskeletal. Individualised exercise to increase axial and limb muscle strength and tone, proprioception and joint stability, emphasising movement patterns and function; orthoses and splints for alignment and control; occupational therapy for wide-grip utensils and ergonomics, and assistive devices (wheelchair or scooter, appropriate mattress, soft cervical collar) [3, 62]. In a randomised physiotherapy trial in 26 children and adolescents with hypermobility and knee pain, exercise into hyperextension produced similar pain improvement and greater psychosocial improvement than exercise restricted to neutral position [3]. Surgery may be necessary when conservative treatment fails or structural pathology is present (impingement, dysplasia, spinal cord or radicular compression with deficit), and failure to recognise hypermobility may be associated with poorer outcomes; prolotherapy showed safety and efficacy in one study [3].

Pain. Physical and occupational therapies, dry needling, behavioural and complementary therapies are most frequently reported as helpful; among drugs, non-steroidal anti-inflammatory drugs, paracetamol and opioids are reported as most beneficial, with scarce or contradictory data on magnesium, muscle relaxants, duloxetine, gabapentin and tricyclics [3].

Haemostasis. Platelet abnormalities may respond to tranexamic acid or mefenamic acid; desmopressin may help in severe bleeding or as surgical prophylaxis; vitamin C, folate and vitamin B12 deficiencies should be sought [3].

Gastrointestinal. Gastritis and reflux may require a proton pump inhibitor twice daily before meals, a high-dose H2 antagonist at bedtime (for example, famotidine 20–40 mg), sucralfate 1 g four times daily and antacids; investigation and treatment of Helicobacter pylori and small intestinal bacterial overgrowth; treatment of delayed gastric and colonic emptying; Doppler assessment for vascular compression syndromes if abdominal pain persists unexplained [3]. The American Gastroenterological Association clinical practice update (2025; expert recommendations without systematic review or formal evidence grading) adds that gastroenterologists should ask about hypermobility and use the Beighton score as screening in disorders of gut–brain interaction; that POTS and mast cell activation syndrome testing should target patients with suggestive manifestations rather than all hEDS/HSD patients; that mast cell activation requires serum tryptase to rise by 20% above baseline plus 2 ng/mL, sampled 1–4 hours after the episode; that coeliac disease may be investigated earlier; that incomplete evacuation symptoms justify anorectal manometry, balloon expulsion testing or defecography; and that treatment follows that for functional and motility disorders in the general population, with special diets only under nutritional supervision to avoid harmful dietary restrictions [21].

Cardiovascular (dysautonomia). Avoid abrupt postural changes, use compression stockings and garments, strengthening exercise, sodium and water supplementation (electrolyte tablets) and, if necessary, beta blockers, midodrine, fludrocortisone or ivabradine initiated by a clinician experienced in autonomic medicine [3]. Significant aortic root dilatation and vascular compression syndromes require referral; root growth of 0.5 cm or more in one year indicates intervention [3].

Mast cell, oral and neurological manifestations. Trigger avoidance, H1 and H2 antihistamines, acetylsalicylic acid, ketotifen, montelukast and sodium cromoglicate; monoclonal biological therapy in severe cases under specialist guidance [3]. Usual periodontal treatment, anticipating reduced response to local anaesthetics and intolerance of prolonged head positions; intraoral splints for temporomandibular dysfunction; craniocervical stabilisation and spinal surgery only in experienced centres [3].

Mental health. Validation of symptoms is central because many patients have been accused of malingering or diagnosed with primary psychiatric disease; psychological counselling, cognitive behavioural therapy and antidepressants are useful, and autism spectrum disorder and attention-deficit/hyperactivity disorder receive usual treatment [2, 3].

To avoid. High-impact activities (for example, American football), chiropractic manipulation or unadapted yoga, poorly tolerated drugs or excipients (analgesics with slow transit; vasodilators in orthostatic intolerance), adhesives and topical agents on fragile or allergic skin [3].

7.3 Classical EDS

Sports placing excessive load on joints (contact and combat sports, football, running) should be avoided [7]. In pregnancy, surveillance throughout gestation and the puerperium is recommended because of laceration, postpartum haemorrhage and uterine or bladder prolapse risk; ascorbic acid (without defined guidance in the third trimester); physiotherapy for pelvic instability; surveillance of fetal growth restriction and cervical insufficiency through cervical length measurement; surveillance for preterm delivery in the third trimester; early episiotomy in vaginal delivery; and desmopressin and tranexamic acid prophylaxis, with postpartum oxytocin, because of bleeding risk [7].

7.4 Vascular EDS

Organisation of care. The initial task is to establish an organised team — family physician, vascular surgeon, general surgeon, cardiologist, pulmonologist and geneticist — responsible for scheduled care and contingency plans. Patients should carry documentation of the diagnosis (MedicAlert® bracelet, emergency letter or “vEDS passport”) and seek immediate care for any sudden unexplained pain, which should be investigated with clinical examination and non-invasive imaging [5, 8, 9]. International consensus recommends confirming the COL3A1 variant before applying the diagnosis, centralising care at a referral centre whenever possible, maintaining normal blood pressure and treating hypertension aggressively [9].

Pharmacological therapy. Celiprolol, a long-acting β1 blocker with partial β2 agonist activity, is the only drug with benefit demonstrated in a randomised vEDS trial [5, 28]. BBEST (Beta-Blockers in Ehlers-Danlos Syndrome Treatment), a multicentre, randomised, open-label trial with blinded event assessment, included 53 clinically diagnosed vEDS patients (33 with a COL3A1 variant) at eight French and one Belgian centre, randomised to celiprolol for five years or no treatment; it was stopped early for benefit after mean follow-up of 47 months, with arterial events (rupture or dissection, fatal or non-fatal) in 5 of 25 (20%) treated patients against 14 of 28 (50%) controls (HR 0.36; 95% CI 0.15–0.88; p = 0.040) [13]. However, event rates remained high in the treated group, and clinical selection of patients without molecular confirmation limits extrapolation [5, 16]. In the French cohort of 144 molecularly diagnosed patients followed for up to 17 years, 90.3% were taking celiprolol at study end; treated patients had better survival (p = 0.0004), with a dose-dependent effect — maximum protection at 400 mg/day versus less than 400 mg/day (p = 0.003) [52]. A 2025 systematic review (323 participants) confirmed reduced major vascular events, with dizziness and hypotension as adverse effects, and emphasised response variability [67]. The first non-European series, a retrospective Japanese cohort of 26 molecularly diagnosed adults, all treated with celiprolol and followed for a mean of 96.6 months, recorded one death (hepatic artery rupture) and vascular events in 11 patients, without association with genotype or dose; 61.5% reached 400 mg/day. Without a control group, this series describes the course during treatment but does not measure efficacy [68].

In 2025, a French multicentre, randomised, double-blind, placebo-controlled trial over 2 years (ARCADE in registry NCT02597361, with 61 enrolled patients) evaluated irbesartan in 57 adults with vEDS receiving stable celiprolol: the composite endpoint (fatal or non-fatal arterial event, or new or worsening arterial lesion on head-to-pelvis CT angiography or peripheral Doppler ultrasound) occurred in 8 of 29 (27.6%) patients receiving irbesartan against 15 of 28 (53.6%) receiving placebo (HR 0.42; 95% CI 0.17–0.99; p < 0.05), with reduced recurrent arterial events (risk ratio 0.37; 95% CI 0.19–0.68; p = 0.002) and lesion progression across all territories, unrelated to the systolic pressure reduction (5.4 mmHg); 11 hypotensive episodes occurred, with dose reduction in 4 patients [14].

Enzastaurin, a protein kinase C β inhibitor, was studied in a phase 3 trial (PREVEnt, NCT05463679), suspended by sponsor decision since 2024 (“indefinite hold by company”), without results [72]. Drugs targeting extracellular matrix organisation and the autophagy–lysosome pathway are in preclinical investigation [8].

Surgery and procedures. Many symptomatic arterial events are self-limiting; dissection or rupture management should be conservative whenever possible, with surgery reserved for life-threatening complications, using a targeted approach and minimal exploration, preferring endovascular techniques in experienced hands and “judicious hypohydration” to avoid the cycle of complications associated with overhydration [5, 8, 16]. Outcomes are better when the surgeon knows the diagnosis, but morbidity remains high: complications in 46% of 31 Mayo Clinic patients and 33% of 9 Johns Hopkins patients; in a retrospective analysis, mortality was 30% in open surgery, 24% in endovascular procedures and 39% overall [5]. In a retrospective review of splenic artery aneurysms and dissections, the endovascular approach had fewer complications and deaths than open surgery [8]. Anaesthetic precautions include cross-matching adequate blood quantities, avoiding intramuscular premedication, adequate peripheral venous access and avoiding arterial lines and central venous catheters (or using ultrasound guidance if indispensable), atraumatic intubation, prevention of hypertensive surges and caution with neuraxial anaesthesia; rectal temperature measurement and intramuscular injections are contraindicated, and tourniquets should be avoided [5, 16]. Intestinal perforation requires urgent surgery, usually partial colectomy with colostomy (Hartmann's operation) and restoration of continuity 3–6 months later; proximal recurrence led some authors to recommend partial or total colectomy at the first episode, but prophylactic colectomy adds unnecessary risk for most patients [8]. Elective surgery should be discouraged unless there is substantial benefit; varicose vein stripping may have severe complications, but elective repair of at-risk vessels can be performed safely in specialised centres [8, 28]. Endovascular repair may help in significant aortic dilatation [4].

Surveillance. Initial arterial imaging is common practice, using MR angiography, low-radiation CT angiography or ultrasound; there is no consensus on the benefit of serial surveillance, which should weigh induced anxiety against detection of treatable lesions. With a normal vascular tree, re-examination every 18–24 months is usual practice; international consensus proposes annual surveillance where feasible. Blood pressure should be measured regularly [5, 8, 9]. Conventional arteriography should be avoided (risk of puncture-site dissection and injection-pressure aneurysm) and reserved for planned therapeutic procedures, such as embolisation or stenting [8, 28]. Invasive gastrointestinal assessment has no benefit because no abnormality precedes rupture [8].

To avoid. Collision sports, extreme weightlifting, scuba diving and violent sports; activities with sudden blood pressure increases; routine colonoscopy without symptoms or a strong colorectal cancer family history (virtual colonoscopy also involves insufflation; alternatives: faecal DNA testing, capsule endoscopy); antiplatelet agents (acetylsalicylic acid, clopidogrel), vitamin K antagonists and non-steroidal anti-inflammatory drugs unless risks and benefits are carefully weighed [4, 5, 8, 28]. Moderate recreational exercise has not been shown to be harmful [8].

Pregnancy. Maternal mortality was historically high: in Pepin et al.'s series (2000), 81 women had 183 pregnancies, with 167 term live births, three stillbirths, ten miscarriages and three elective terminations; 12 women died peripartum or in the following two weeks (five from uterine rupture during labour, two from vascular rupture during delivery and five from postpartum vascular rupture) [4, 47]. In the largest study (more than 500 pregnancies in 253 women), mortality was approximately 5.3% per pregnancy, half the women had no complications, and the most frequent were third- or fourth-degree lacerations (20%), arterial dissection or rupture (9.2%), uterine rupture (2.6%) and surgical complications (2.6%); survival did not differ between women with and without children, suggesting age, rather than pregnancy itself, is the main risk factor [5, 73]. Preterm delivery (up to 19%) is more frequent when the fetus is affected because of membrane fragility [5]. In a retrospective Dutch multicentre cohort published in 2026 (43 women with a pathogenic or likely pathogenic COL3A1 variant, nine with haploinsufficiency variants; 121 pregnancies), there were no deaths, arterial dissections or uterine ruptures during the perinatal period; 19% of pregnancies ended in miscarriage, more frequent with glycine substitutions, 19.1% of live births were preterm, 34 of 43 women delivered vaginally (only one of the seven who knew their diagnosis), and eight severe perineal lacerations and six postpartum haemorrhages occurred. The authors propose shared decision-making rather than advising all women with vEDS against pregnancy; however, absence of fatal events in 43 women does not demonstrate zero risk and contrasts with approximately 5% mortality per pregnancy in the US series, collected using a different ascertainment method [73, 74]. Current practice tends towards planned caesarean delivery at 36–38 weeks (or before 37 weeks), at a high-risk obstetric centre with a vascular surgeon present, accepting the risk of haemorrhage and abdominal organ injury; intervention may be stratified by variant type because complications are rare with null variants and women with glycine-to-alanine substitutions have had several uncomplicated pregnancies [8, 28]. Elective caesarean delivery has not been established to reduce mortality because uterine rupture may occur before labour [4]. Irbesartan should be discontinued as soon as pregnancy is confirmed [71].

7.5 Kyphoscoliotic EDS

There are no published guidelines; measures are based on GeneReviews® chapters [10, 11]. Physiotherapy to strengthen large muscle groups, particularly the shoulder girdle (preventing recurrent shoulder dislocation), with swimming recommended; orthoses for unstable joints; orthopaedic kyphoscoliosis treatment, including surgery, which is not contraindicated but should account for vascular risk, possible atlantoaxial instability and primary myopathy in the FKBP14 form; protection and a helmet during sports; suturing technique described in 7.1; corrective lenses and retinal laser for impending detachment; careful hernia repair; hearing aids in the FKBP14 form; cleft palate repair [10, 11]. Cardiovascular measures include strict blood pressure control to reduce rupture risk, a beta blocker for aortic dilatation (celiprolol may be considered by extrapolation from vEDS, outside approved indications) and antimicrobial prophylaxis according to American Heart Association recommendations for mitral prolapse; vascular surgery is high-risk [10, 11]. Sports overloading joints (gymnastics, long-distance running), collision sports, extreme weightlifting, hypertension and arteriography (except to locate life-threatening bleeding before surgery) should be avoided [10, 11]. Pregnancy carries increased risk of miscarriage, premature rupture of membranes and arterial rupture; echocardiographic aortic root surveillance and delivery at a centre with a high-risk perinatologist are recommended. Two women with kEDS-PLOD1 had seven pregnancies (three miscarriages and four healthy children, three delivered vaginally at term and one at 24 weeks) without maternal complications; no pregnancies have been described in the FKBP14 form [10, 11].

7.6 Arthrochalasia EDS

There are no formal recommendations; management of congenital hip dislocation, recurrent subluxations, kyphoscoliosis and osteopenia follows usual orthopaedic practice, with rehabilitation, orthoses and adapted suturing techniques. In the 12-patient series, 5 underwent hip surgery, 3 spinal surgery, 1 received bisphosphonates and 2 of 10 echocardiograms showed probably unrelated abnormalities; the authors emphasise scarce adult management data and the need for multidisciplinary follow-up [54].

7.7 Dermatosparaxis EDS

There is no enzyme replacement or disease-modifying therapy; management is preventive: protecting skin from trauma, careful tension-free wound closure with prolonged scar support, avoiding contact sports, timely hernia surveillance and treatment, and attention to visceral and vascular fragility during any surgery or anaesthesia [19, 38].

7.8 Musculocontractural EDS

Contact or competitive sports should be avoided and, in patients with pressure hyperalgesia, upper-arm sphygmomanometry and tight tourniquets during blood sampling [12]. Abdominal pain in adolescents and young adults with mcEDS-CHST14 justifies computed tomography in addition to radiography because of colonic perforation risk even without diverticula [56]. Only one pregnancy has been recognised in a woman with mcEDS-CHST14; premature rupture of membranes, birth canal laceration and haemorrhage risks are anticipated, so pregnancy and delivery should be managed at a perinatal centre, with planned caesarean delivery reasonable [12].

7.9 Organ- and system-based management in non-vascular EDS

The French national diagnosis and care protocol for non-vascular EDS, prepared by the reference centre for constitutional bone diseases and the OSCAR filière, endorsed by the French societies for pain management, physical and rehabilitation medicine and internal medicine and published by the HAS in 2020, applies to all EDS types except vEDS. The literature on which it is based consists mainly of case reports and case series, with few comparative studies, so that most recommendations express expert opinion. Unless otherwise stated, the measures apply to all non-vascular types, with intensity adjusted to the degree of tissue fragility of each [23].

Rehabilitation. The aims are to prevent and limit the consequences of hypermobility, reduce pain, recover or compensate for limitations (walking, grasping, sphincter control), adapt school and working life and promote autonomy; occupational therapy and psychomotor therapy complement physiotherapy. Osteoarticular treatment includes, as appropriate, treatment of scoliosis (physiotherapy, bracing, surgery), orthoses, image-guided injections and prevention of osteoporosis. Cardiovascular and musculoskeletal training should be individualised and supervised by an adapted physical activity professional; competitive gymnastics, repeated lifting of heavy loads and contact or pivoting sports are not recommended. The standard physiotherapy prescription includes massage, postural work, isometric strengthening of the stabilisers of the proximal joints — from inner range to outer range, without going beyond the end of mid-range —, gradual introduction of concentric work avoiding eccentric work, heat before and massage after exercise, cautious proprioceptive re-education with manual resistance, progressive aerobic reconditioning without ballistic movements, warm-water hydrotherapy, a long-term home programme and respiratory training for dyspnoea and respiratory blocks. TENS and proprioceptive orthoses (insoles, compression garments, lumbar support, knee supports, ankle supports) may be kept on during the sessions. Repeated movements and high loads worsen pain, manipulations are contraindicated and the patient can be taught to reduce a shoulder or patellar dislocation [23].

Rheumatology, neurology and mental health. Joint and myofascial pain, of mechanical rhythm, peripheral (shoulders, elbows, wrists, fingers, knees, ankles) and axial (spine, pelvis), is associated with bursitis, tendinitis, synovitis, tenosynovitis and fasciitis; searching for trigger points guides the treatment of myofascial syndrome. Osteoporosis should be sought and treated in the presence of risk factors (sedentary lifestyle, corticosteroid therapy) or fractures from minimal trauma, and vitamin D deficiency, frequent in these often sedentary patients, should be corrected. Image-guided corticosteroid or hyaluronic acid injections, adjusted to age, may relieve pain. Headaches are treated as migraine (triptans at usual doses, caffeine, acupuncture, hypnosis, meditation), but atypical symptoms require exclusion of arterial dissection, Chiari malformation, spinal instability, low-lying tethered cord, abnormal movements, neuromuscular disease and Tarlov cysts. Memory and attention complaints justify neuropsychological and language assessment. Psychological distress, frequent particularly in hEDS because of the absence of a confirmatory test, and often linked to lack of information, loss of quality of life and poorly controlled pain, benefits from psychological or psychiatric support with a cognitive-behavioural orientation [23].

Pain and fatigue. Pain should be assessed at every consultation, after reviewing previous treatments. The protocol proposes a visual analogue or numerical scale for intensity, the DN4 questionnaire to identify neuropathic pain and the NPSI for its intensity, the HIT-6 for the impact of headaches, the HAD scale for emotional impact and the Brief Pain Inventory for multidimensional assessment. In children, observer assessment is used under 4 years (EVENDOL, NFCS, FLACC), the revised faces scale (FPS-R) from 4 to 6 years, the paediatric visual analogue scale from 6 to 8 years and the numerical scale from 8–10 years, with a body pain map and assessment of sleep, anxiety and depression, school absenteeism, isolation and family impact. Treatment is multidisciplinary and combines analgesics from all three steps, muscle relaxants and topical agents (doses in the table in section 7.3); antidepressants or antiepileptics used as background treatment for neuropathic pain also serve to avoid excessive opioid use. An equimolar mixture of nitrous oxide and oxygen (EMONO) helps to reduce a dislocation or subluxation or to control acute pain after the patient has reduced it. In children, few analgesics have a paediatric authorisation, and in paediatric hEDS the priority is prevention. Non-pharmacological measures proposed include hypnosis, sophrology, relaxation, meditation, acupuncture, mesotherapy, heat or cold, TENS, splints or compression garments and joint offloading without prolonged use of crutches, with regular follow-up at a chronic pain clinic. Subcutaneous lidocaine injections, intermittent oxygen therapy, antiparkinsonian drugs, baclofen and levocarnitine have no efficacy demonstrated in randomised trials or comparative studies, are off-label uses without established safety and are not recommended. Fatigue is multifactorial (muscular, proprioceptive, dysautonomic, pain-related); anaemia, nutritional deficiencies, drug effects, sleep disorders, allergies and thyroid dysfunction should be sought and corrected, and there is no evidence to justify drugs for fatigue [23].

Orthopaedics. Multiple or severe sprains and dislocations may lead to surgery, but the indication should be discussed at a multidisciplinary meeting and only arises once rehabilitation, analgesia and stabilisation measures have been exhausted, because the main complaint is pain, which surgery rarely resolves and may worsen in hEDS. Surgery should spare the articular surfaces and be performed by an experienced surgeon, with small incisions, short immobilisation and early proprioceptive rehabilitation. Recurrence, haemorrhage, poor healing, infection, adhesions and worsening pain are frequent and functional results limited; bone healing is normal, although sometimes slower, and the skin should be protected during the operation (stop sutures to prevent extension of the incision, tension-free closure and late suture removal) [23].

Source: French protocol for non-vascular EDS [23].

Eyes, ears, mouth and temporomandibular joint. An initial ophthalmological examination is recommended in all types, with refraction, corrected visual acuity, corneal diameter, biomicroscopy, tear film break-up time or Schirmer test, fluorescein staining, intraocular pressure, fundoscopy, optical coherence tomography and orthoptic assessment, complemented by pachymetry, confocal microscopy, corneal topography and visual field testing according to the findings. There is no validated schedule, but regular follow-up with visual fields, topography and slit lamp is proposed. In hEDS, the examination guides the treatment of xerophthalmia and myopia; in kEDS, bilateral reduced acuity, myopia, astigmatism and ocular hypertension with minimal visual field change responding to treatment have been described. In BCS, recognition before the first rupture is decisive: continuous ophthalmological follow-up with topography, polycarbonate protective glasses, contraindication of violent sports and information to the patient, the family and the school. Refractive and accommodative errors are treated with orthoptics (surgery if insufficient), and visuospatial difficulties may require prisms. Dental examination, clinical and with orthopantomography, and examination of the temporomandibular joint are recommended in all, with assessment of mouth opening, chewing, the masticatory muscles and cervical posture. The ENT examination includes laryngoscopy and audiogram according to symptoms, and dysphagia may justify oesophageal manometry. Dental care should be early, with meticulous hygiene; the response to local anaesthetics is often reduced; orthodontics uses light forces and prolonged retention; implants are difficult in pEDS; before any surgical procedure, coagulation is checked and suturing is done with care. In temporomandibular dysfunction, the basis is postural work (joint, cervical and thoracic spine), relief of masticatory muscle spasms and sometimes splints; surgery is reserved for extreme cases with an anatomical lesion. Speech and language therapy treats dysphonia and dysphagia [23].

Heart and vessels. A baseline echocardiogram is recommended in all patients, complemented by CT angiography or MR angiography if necessary, avoiding endovascular investigations; the frequency depends on the results. Cardiovascular assessment and follow-up imaging are particularly important in cEDS, dEDS and kEDS, whose risk of vascular complications is much lower than in vEDS (where they affect about half of patients), and in carriers of COL1A1 c.934C>T, p.(Arg312Cys), with a notable risk of dissection or rupture; as in vEDS, aneurysms and dissections mainly affect large and medium-calibre arteries. In cEDS, the protocol recommends complementing echocardiography with vascular imaging, preferably thoraco-abdomino-pelvic CT angiography in adults or at the end of growth. In types with arterial risk, non-invasive imaging surveillance follows the vEDS model, and the recommendations for Marfan and Loeys–Dietz syndromes (annual imaging, antihypertensives, surgery when the aortic root diameter approaches the threshold or in acute dissection) may be applied until specific recommendations exist. In ascending aortic dilatation, the protocol accepts atenolol; without a dose defined for EDS, the Marfan syndrome doses are used by extrapolation: in children, 1–4 mg/kg/day orally, up to 250 mg/day (2024 European VASCERN/AEPC paediatric statement); in adults, the US Tenormin® label for hypertension indicates 50 mg once daily, increased to 100 mg/day if necessary, with no likely benefit above this dose [23, 75, 76]. Celiprolol has not been studied in non-vascular EDS, but the protocol considers that the benefit demonstrated in vEDS supports its use in types with an increased risk of arterial rupture or aneurysm (off-label extrapolation; dosing regimen in section 7.4). Desmopressin may be useful in the treatment or prevention of bleeding and haematomas in mcEDS and kEDS (label dose in the paragraph on anaesthesia, surgery and emergencies). When POTS is suspected, a cardiology consultation is recommended; non-pharmacological management includes avoiding prolonged standing and abrupt changes of position, elastic compression of the lower limbs, increased water and salt intake and regular low-intensity lower-limb exercise, and beta-blockers are often poorly tolerated because of low resting blood pressure. In spontaneous arterial dissection without clinical consequences in cEDS, kEDS and cvEDS, repair should be planned and as atraumatic as possible: in the endovascular approach, thin and flexible catheters and covered stent grafts; in open surgery, low-pressure intraluminal aortic balloons, protected clamps or elastic tourniquets, simple ligations, bypasses reserved for limb salvage (avoiding venous bypasses) and tension-free anastomoses with interrupted horizontal sutures. Severe valvular regurgitation is an indication for valve replacement [23].

Lung and sleep. Obstructive sleep apnoea is more frequent and should be sought in the presence of fatigue or daytime sleepiness, even with a low body mass index, by polysomnography or respiratory polygraphy; continuous positive airway pressure appears more effective than mandibular advancement devices, which are an alternative if it is not tolerated. There is a risk of pneumothorax and pneumomediastinum in some rare types, and bronchoscopy is contraindicated when the tissues are very fragile and should be cautious in other cases. The exertional dyspnoea and respiratory blocks of hEDS are assessed with a walking test and pulmonary function tests with measurement of respiratory muscle strength, and are treated with programmed physical activity and exercise reconditioning; intermittent oxygen therapy and intrapulmonary percussive ventilation have no demonstrated efficacy, are off-label uses and are not recommended, any exceptional indication being the responsibility of the respiratory physician [23].

Digestive and urinary systems. In addition to functional disorders (section 7.2), non-vascular EDS increase the risk of recurrent hernias (hiatal, abdominal wall, inguinal), rectal prolapse, visceral ptosis, diaphragmatic hernia, megacolon and diverticulosis; a spontaneous colonic perforation should suggest vEDS and, more rarely, clEDS or cEDS, and justifies the opinion of a reference centre. Frequent comorbidities (coeliac disease, lactose intolerance, Helicobacter pylori infection) and a history of gastrointestinal bleeding should be sought. There are no validated recommendations; investigations (oesophageal manometry, pH monitoring, gastric emptying study, small bowel manometry, colonic transit time, anorectal manometry) are requested according to symptoms and endoscopy should be discussed and cautious. Proton pump inhibitors and laxatives relieve some of the symptoms (doses in section 7.2); rectocele and rectal prolapse that worsen constipation justify therapeutic education, with specialist nursing and defecation physiotherapy, or, in severe forms, surgical correction. A low-FODMAP diet may reduce pain, bloating and diarrhoea in hEDS, but is not yet recommended without gastroenterological and dietetic supervision. In surgery, ideally decided at a multidisciplinary surgical and anaesthetic meeting, the approach should be as minimally invasive as possible, although laparoscopy is difficult because of the fragility of the mesenteries and the risk of dissecting haematomas and vascular ruptures; hernias, incisional hernias and prolapses are repaired with non-absorbable meshes; prevention of postoperative evisceration and incisional hernia uses a mesh reinforcing the peritoneum (absorbable if the digestive tract has been opened) and layer-by-layer closure; silicone dressings for as short a time as possible and a continuous intradermal suture avoid skin lesions. The most frequent surgical complications are recurrent perforations, lacerations and eviscerations, recurrent hernias and digestive fistulas, more frequent than in the general population in all types, but particularly in vEDS. In the urinary system, stress or mixed incontinence, urgency, nocturia and infections are frequent; constipation, prolapses, bladder diverticula and vesicoureteral reflux should be sought, with dipstick and urine culture, urodynamic study, ultrasound and cautious cystoscopy, and pelvic floor re-education with a home programme should be offered [23].

Gynaecology, pregnancy and delivery. Typing the EDS is essential, because tissue fragility and complications differ between types. Menorrhagia, dysmenorrhoea and dyspareunia or vulvodynia are the most frequent complaints, particularly in hEDS; hormonal contraception is not contraindicated and may improve symptoms, combined oestrogen-progestogen contraceptives being preferred to progestogen implants (to be weighed according to the state of the skin and the bleeding risk) and intrauterine devices being used with caution; pelvic prolapses are frequent. In pregnancy, miscarriage, preterm delivery and ectopic pregnancy may be slightly more frequent, and the main risks are prematurity due to premature rupture of membranes and perineal laceration. The protocol proposes early ultrasound to confirm intrauterine location, cervical length measurement in the first trimester and at around 16 weeks of gestation (cerclage to be discussed if the cervix is shorter than 25 mm, without systematic prophylactic cerclage), clinical or ultrasound assessment of the cervix from 28 weeks, monthly consultations until 34 weeks and then weekly or fortnightly, and discussion with the pregnant woman, at around 32 weeks and according to the risk of preterm delivery, of fetal lung maturation with intramuscular betamethasone (in the French regimen, two ampoules of Célestène® Chronodose on two consecutive days). These two points of the 2020 protocol are French positions and do not coincide with the US obstetric recommendations, which serve as the reference: American College of Obstetricians and Gynecologists (ACOG) bulletin no. 142 accepts ultrasound-indicated cerclage in a singleton pregnancy with a previous spontaneous preterm birth before 34 weeks and a cervix shorter than 25 mm before 24 weeks, and not on the basis of an isolated measurement without that history [77]; and ACOG committee opinion no. 713 recommends a single course of corticosteroids between 24 weeks and 33 weeks and 6 days when preterm delivery is likely within the following 7 days (betamethasone 12 mg intramuscularly, two doses 24 hours apart), and not at a fixed gestational age, because the benefit diminishes when delivery occurs more than 7 days after the course [78]. Pregnancy is sometimes poorly experienced by women with hEDS, and psychological support may be offered; the end of gestation increases sprains, subluxations and mobility difficulties. Delivery may be planned; epidural analgesia is possible, episiotomy may be performed if the perineum is fragile and vaginal labour is managed as for a scarred uterus. No optimal mode of delivery has been demonstrated: elective caesarean section is preferable when the risk of complications is high, severe haemorrhage should be anticipated in patients with vascular fragility and a uterine rupture should suggest vEDS. For caesarean section, the protocol describes a cautious Pfannenstiel incision with an X stitch at each end, skin suture with 3/0 non-absorbable thread in closely spaced interrupted stitches, without staples, and removal of half the stitches at 2 weeks and the rest at 3 weeks or when healing allows. General anaesthesia should be avoided in pregnant women, particularly for caesarean section, except in vEDS or in non-vascular forms with demonstrated vascular fragility (risk of perimedullary haematoma with neuraxial block), an exception that never applies to hEDS; neuraxial block is the recommended technique, with vasopressor amines and crystalloids if necessary, avoidance of vasodilators unless vitally necessary (severe hypertension, pre-eclampsia) and non-invasive monitoring. In hEDS under prolonged locoregional analgesia, the parturient should change position frequently, using very dilute local anaesthetic with an opioid to avoid motor block, and the positioning of the legs in the stirrups, the arms and the neck should be careful. In the postpartum period, bleeding from cervical laceration, perineal laceration, episiotomy dehiscence, poor healing, uterine bleeding and infection are monitored, and the response to the Valsalva manoeuvre may be abnormal in dysautonomia. Thromboprophylaxis with enoxaparin (Lovenox®) 40 mg subcutaneously once daily for 4 to 6 weeks, combined with compression stockings for 6 to 8 weeks, is only indicated if there is a thromboembolic risk, and not systematically in a mobilising puerpera; perineal re-education is recommended to reduce the risk of vaginal prolapse and, if necessary, home support for postpartum fatigue. The protocol considers that there are no robust data showing an excess of obstetric complications attributable to hEDS [23].

Anaesthesia, surgery and emergencies. Non-vascular EDS do not alter the pharmacokinetics or pharmacodynamics of anaesthetics, but they require specific preparation: careful positioning to reduce pressure points and dislocations, intubation that is as atraumatic as possible (risk of temporomandibular dislocation and tracheal injury), attention to excessive tissue diffusion of locally acting anaesthetics and to resistance to local anaesthetics, assessment of bleeding risk and intubation difficulties, and recording of anaesthetic and bleeding history and response to blocks. Peripheral nerve block may be preferred; neuraxial block is possible, with precautions to avoid post-dural puncture headache. Intramuscular injections, central venous catheters and arterial punctures (with ultrasound guidance if essential), adhesives and shear forces on fragile skin and drugs that interfere with haemostasis should be avoided whenever possible; ventilatory pressures should be kept low to reduce the risk of pneumothorax; tourniquet use should be discussed; and fragility of the skin, mucous membranes and eyeball, spinal instability, accidental dislocations and POTS should be anticipated. All patients, even after minor surgery, should be monitored for at least 24 hours, in a facility able to treat complications; in rare types without their own recommendations, the vEDS rules are followed as a precaution (section 7.4). A systematic haemostasis work-up is recommended (prothrombin time, activated partial thromboplastin time, platelet closure time), usually normal and without predictive value for bleeding risk; heavy and prolonged menstruation may cause iron deficiency; epistaxis, petechiae, haematuria, haemoptysis and haemarthroses do not appear to be more frequent [23]. Desmopressin may transiently reduce bleeding in surgery and dental procedures [23]; without a dose defined for EDS, the US label dose for haemophilia A and type 1 von Willebrand disease (analogous condition) is 0.3 µg/kg of actual body weight, up to 20 µg, by intravenous infusion over 15 to 30 minutes, 30 minutes before the procedure, repeatable 8 to 12 hours later and, if necessary, once daily; it is approved for these indications from 3 months of age, requires fluid restriction in children and is contraindicated in current or previous hyponatraemia, polydipsia and with loop diuretics or systemic or inhaled glucocorticoids [79]. In hEDS, the surgical risk is lower than in the other types and consists mainly of delayed healing. In the emergency setting, the most frequent reasons for presentation are sprains, subluxations, dislocations and ligament ruptures, which should be documented by radiography; analgesic immobilisation (splint, orthosis) is the rule and any surgical indication should be postponed and discussed at a multidisciplinary meeting. Acute abdominal pain, subocclusion and chest pain should be investigated; faecal impaction may be treated with an enema; topical anaesthetics and peripheral blocks are sometimes ineffective [23].

Divergences between the French protocol and the other sources.

7.10 Trials, regulatory status, hierarchy of evidence and off-label use

The two positive trials cannot be compared or added through indirect comparison. BBEST was open-label, included patients without molecular confirmation and was stopped early for benefit, circumstances tending to overestimate the effect; relative reduction coexisted with events in 20% of treated patients over approximately four years [13]. ARCADE tested irbesartan in addition to celiprolol, and its composite endpoint included asymptomatic lesions detected through systematic imaging; therefore, HR 0.42 is not equivalent to a 58% reduction in ruptures or deaths, and the upper limit of the 95% CI approaches 1 [14]. Neither trial was powered to assess mortality, and the French and Japanese observational cohorts, without a randomised control group, do not measure efficacy [52, 68]. There are no randomised trials in other EDS forms: drugs mentioned in sections 7.2 to 7.9 (analgesics, desmopressin, tranexamic acid, ascorbic acid, drugs for POTS or mast cell activation) rest on observational studies, extrapolation or expert opinion.

Evidence hierarchy. This article distinguishes trials published in peer-reviewed journals (BBEST, ARCADE), sponsor information in documents submitted to the US securities regulator (DiSCOVER status and US celiprolol regulatory history, from Zevra Therapeutics' annual report and statements) and institutional announcements not yet fulfilled (international classification revision). An orphan drug or breakthrough therapy designation is not authorisation; national authorisation for arterial hypertension is not authorisation for vEDS; and authorisation does not guarantee reimbursement or access in each country.

Extrapolation and off-label use. Off-label use is defined by label wording, age and jurisdiction; extrapolation concerns the population in which evidence was obtained. Celiprolol and irbesartan are used off-label in vEDS in any country, but supported by randomised trials; in a child with vEDS, celiprolol is both off-label and an extrapolation of evidence obtained in older patients. The same reasoning applies to kEDS, where a beta blocker is proposed by analogy with vEDS (section 7.5), and drugs used for hEDS comorbidities or bleeding in cutaneous forms whose approved indications do not include EDS: when prescribed, off-label use and the extrapolated evidence should be documented. In pregnancy, angiotensin receptor antagonists are contraindicated by the label, irrespective of expected vEDS benefit [71].

8. Reproductive Options and Family Counselling

In autosomal dominant forms, when the proband appears to be the only affected person, parents should be examined for slow wound healing, abnormal scars, bruising, hypermobility, recurrent dislocations and chronic joint pain, and tested for the familial variant; an apparently negative family history may result from unrecognised mild phenotypes, reduced penetrance, early parental death or mosaicism [7, 8, 29]. In vEDS, penetrance approaches 100% in adults with substitution or exon-skipping variants, but is delayed with null variants, and null variant carriers without clinical signs in their eighth and ninth decades have been described [8]. Mosaic parents with COL3A1 variants have no known symptoms or complications to date [8].

Predictive testing in minors with vEDS was controversial because no proven prevention existed; however, 12% to 24% of carriers have a major complication by 20 years, and knowledge of the diagnosis allows restriction of risky activities, preparation for emergency responses and relief from concern in non-carriers. Among children tested before 18 years, 87% had not experienced any complication and mean age at testing was 8 years; parents rarely deferred testing until adulthood [8]. Systematic cascade testing of relatives is recommended in vEDS, given the severity of its implications, and knowledge of the diagnosis influences management of surgery, pregnancy and major complications [4, 28].

Prenatal diagnosis and preimplantation genetic diagnosis are technically possible in all forms with a known familial variant, but are rarely requested outside vEDS and severe recessive forms [4]. In cEDS, severity cannot be predicted from the prenatal result [7]. Experience with assisted reproduction techniques in women with vEDS is limited [8]. A woman with vEDS should decide whether to become pregnant before conception, with discussion of maternal risks (mortality of approximately 5% per pregnancy in the US series; no fatal events in a Dutch cohort of 43 women, see 7.4) and all options, involving high-risk obstetrics and planning delivery with the vascular surgery team present [8, 73, 74]. In women with hEDS, the preconception consultation should address musculoskeletal health and current medicines; during pregnancy, joint instability, pelvic strength, hernias and analgesia; during delivery, options, mobility and anaesthesia; and postpartum, wound healing, the pelvic floor and newborn care. In pregnant women with known aortic root dilatation, an echocardiogram each trimester is recommended [3]. Preconception referral to a high-risk pregnancy service is advised in any form of EDS [4].

In France, the protocol for non-vascular EDS provides for a genetic counselling consultation before any test and when the result is given, and recalls that genetic testing is prohibited before 18 years of age in an asymptomatic minor, unless there is a direct individual benefit for the minor's follow-up (see the divergences in section 7.9). Prenatal diagnosis and preimplantation genetic diagnosis are only legal for diseases of “particular severity” without curative treatment at the time of diagnosis; there is no list of eligible diseases, and each request, made after genetic counselling, is discussed at a multidisciplinary prenatal diagnosis centre (CPDPN), with decisions that vary according to the severity of the EDS type. Both techniques require the identified familial variant and are therefore impossible in hEDS. A preconception consultation is recommended for all women with diagnosed non-vascular EDS and addresses a history of miscarriage and ectopic pregnancy, the risk of prematurity, peripartum and postpartum complications and adjustment of therapy, particularly analgesic, with information for the partner; early assessment of infertility and preconception genetic counselling should be considered, and gamete donation, preimplantation diagnosis and early prenatal diagnosis are only discussed when a variant has been identified. In hEDS, the course during pregnancy appears unpredictable; planning should balance activity and rest and may require psychological and social support, occupational therapy, physiotherapy and rehabilitation medicine [23].

9. Special Considerations: Population Diversity and Epidemiology

EDS overall. The Oxford Desk Reference estimates a frequency of approximately 1:5,000, while the cardiogenetics chapter reports 1:10,000 to 1:25,000 for all types [4, 5]. The French protocol for non-vascular EDS adopts 1:5,000 both for the group as a whole and for hEDS [23]. The range reflects the difficulty in delineating hEDS and HSD.

hEDS. GeneReviews® cites a health-record study of the entire Welsh population for an hEDS prevalence of approximately 1:3,100 and a US hospital admission study with a similar value [3]. The Welsh article, however, measures a different quantity: point prevalence of coded diagnoses of EDS or joint hypermobility syndrome (now hEDS or HSD), 194.2 per 100,000 in 2016/2017 (approximately 1:500; 6,021 people, 70% women), with continuously increasing diagnoses over 27 years; the same article reports 20 per 100,000 for EDS in a Danish hospital-care cohort that did not include hypermobility [6]. None of these values represents prevalence confirmed by the 2017 criteria, and true prevalence is probably underestimated [3, 6]. Síndromes Genéticas: Reconhecer para Tratar reports 1:5,000 births [29]. More than 90% of postpubertal diagnoses are in women [2], and joint range varies between ethnic groups, requiring caution when applying Beighton thresholds outside the populations in which they were validated [30].

cEDS. Estimated prevalence 1:20,000, probably underestimated because mild forms (formerly type II) do not reach clinical care; Orphanet records 5 per 100,000 [7, 29, 80]. The French protocol gives 1:30,000 (section 7.9) [23].

vEDS. No sound estimates exist in any population. More than 2,000 patients have been identified in the United States, establishing a minimum of 1:150,000; the international consensus reports 1:50,000 to 1:200,000 and Orphanet 1 per 100,000 [8, 9, 83]. The criteria table of the French protocol for non-vascular EDS places it between 1 and 9 per 100,000 [23]. Clinical and insurance registry studies using co-occurrence of two major complications as a diagnostic proxy estimated approximately 1:10,000, and exome sequencing of all admissions to Mount Sinai Hospital (New York) suggested an upper bound just below 1:20,000; the general conclusion is that vEDS is more frequent than previously thought and underdiagnosed, as many families are identified only after a severe complication or death [8]. No sex differences in complications were observed in the French adult series, but deaths before 20 years are three times more frequent in males [5, 8]. In the US natural history cohort (557 patients; 44.5% male), mean age at genetic diagnosis was 30.8 years in men and 33.5 in women, and cumulative mortality and aortopathy were more frequent in men (section 3.4) [48].

kEDS. Incidence of each form is estimated at approximately 1:100,000 live births. In the PLOD1 form, many described patients originate from Turkey, the Middle East and Greece, and the p.(Arg319Ter) variant is frequent in the Arab population; parental consanguinity is common [10]. In the FKBP14 form, approximately 30 patients were known in 2019 and the c.362dupC variant shares a common haplotype, suggesting a founder effect [11].

aEDS and dEDS. Very rare forms, without a prevalence estimate; approximately 15 patients with dEDS had been described by 2016 [38, 54].

mcEDS. By 2025, 70 patients from 51 families with the CHST14 form and 15 patients from 9 families with the DSE form had been described; in Japan, prevalence of the CHST14 form was estimated at 1:2,000,000 from the frequency of the three founder variants [12]. Orphanet places mcEDS in the prevalence category below 1 per 1,000,000 [84].

Regional gaps. The consulted sources did not yield prevalence estimates for any EDS type in Portugal, Brazil, the rest of Latin America, Africa or most of Asia, which does not demonstrate that none exist; the identified literature from these regions consists of case reports, including Portuguese vEDS cases with splenic rupture and colonic perforation (section 10.4) and cEDS with aortic dissection, and Brazilian cases of stroke due to vEDS [46, 50, 51, 85]. Outside Europe and the United States, the only published series of patients with vEDS treated with celiprolol comes from Japan [68]. Availability of genetic panels, urinary cross-link tests and celiprolol varies between countries and influences diagnosis and treatment.

10. Illustrative Clinical Case

10.1 Vascular EDS: spontaneous splenic artery rupture (published case, Portugal)

A 34-year-old man diagnosed with vEDS attended the emergency department with sudden abdominal pain, rapidly progressing to haemorrhagic shock. CT angiography confirmed active bleeding from the distal splenic artery. After multidisciplinary discussion between general and vascular surgery, endovascular embolisation with multiple coils was performed through left brachial access, with haemostasis and immediate clinical improvement. He was discharged on day 27, after vaccination against encapsulated microorganisms for presumed hyposplenism [85].

Comment. The case illustrates the typical adult vEDS presentation — rupture of a medium-sized visceral artery with sudden abdominal pain — and the current preference for the endovascular route, which minimises manipulation of fragile tissues and is supported by retrospective data showing lower morbidity and mortality in splenic artery lesions [8]. Choosing arterial access away from the lesion and minimising diagnostic angiography follow recommendations to avoid unnecessary arteriography [8, 28]. Subsequent management includes confirmation or review of the COL3A1 variant (and its class, because of prognostic implications), initiation or optimisation of celiprolol, consideration of irbesartan, a written emergency plan, non-invasive arterial surveillance and cascade testing of first-degree relatives [9, 13, 14, 42].

10.2 Classical EDS with aortic dissection (published case, Portugal)

A 39-year-old woman with a history of transposition of the great arteries corrected at 18 months (Senning operation) and controlled hypertension presented with spontaneous distal aortic dissection. The clinical diagnosis of cEDS was established by the major criteria (hyperextensible skin, atrophic scars and generalised hypermobility), and molecular analysis identified a novel frameshift variant in COL5A1 [46].

Comment. Arterial dissections are rare in cEDS, but spontaneous rupture of large arteries is a recognised risk, albeit much lower than in vEDS [7]. Following dissection in a person with a cEDS phenotype, absence of a COL3A1 or COL1A1 variant with a vascular phenotype should be confirmed, and baseline echocardiography with aortic root measurement, repeated annually if abnormal, blood pressure control and physical activity counselling considered [4, 7].

10.3 Musculocontractural EDS with colonic perforation (published case, Japan)

Two Japanese sisters homozygous for the founder variant CHST14 c.842C>T, p.(Pro281Leu) — described in the article using NM_130468.3, with the same numbering in the MANE transcript NM_130468.4 and classified as pathogenic in ClinVar [32] — with a history of clubfoot, recurrent dislocations, large subcutaneous haematomas after minimal trauma and severe constipation, developed colonic perforation without diverticula [56]. The elder sister, aged 25 and after two weeks of constipation, had transverse colon perforation with faecal peritonitis and septic shock; plain radiography was inconclusive and CT showed free air; she underwent double-barrel colostomy, required ventilation and temporary tracheostomy, and returned to work three months later. The younger sister, aged 24, with mild pain in the left hypochondrium and normal radiography, underwent surgery after CT showed a small amount of free air: the splenic flexure perforation was resected, with colostomy, and she was discharged on day 23. Histopathological examination showed no specific changes at the perforation site [12, 56]. CT images (figure 1), operative findings (figure 2) and histology (figure 3) can be consulted in the original open-access article: https://pmc.ncbi.nlm.nih.gov/articles/PMC10218258/ .

Comment. In mcEDS, visceral fragility may manifest without prior diverticula, and fatal perforations have been described at 36 and 37 years. The authors recommend abdominal computed tomography, rather than radiography alone, for abdominal pain in patients with mcEDS-CHST14 between adolescence and the fourth decade [12, 56].

10.4 Vascular EDS revealed by sigmoid perforation and arterial lesions interpreted as vasculitis (published case, Portugal)

A 25-year-old man with recurrent atraumatic shoulder dislocations, whose mother had died young following an unexplained acute gastrointestinal episode, attended the emergency department of a Viseu hospital with an acute abdomen; CT showed pneumoperitoneum and free fluid (figure 1 of the article), and laparotomy revealed sigmoid perforation with faecal peritonitis, treated with sigmoidectomy and delayed anastomosis; histology described perforated diverticulosis [50]. Postoperatively he had left renal infarction due to renal artery thrombosis (figure 2), radial artery occlusion and pulmonary thromboembolism; abdominal angiography showed hepatic, perigastric and mesenteric artery microaneurysms (figure 3), interpreted as polyarteritis nodosa, and the patient was discharged on anticoagulation and corticosteroids. He returned on day 27 with a left colonic wall haematoma distal to the anastomosis (figure 4), treated with washout, drainage and a protective ileostomy, complicated by an enterocutaneous fistula. Only during follow-up did MRI showing non-specific leukoencephalopathy prompt genetic testing, identifying a COL3A1 variant; positron emission tomography showed no vasculitis, and anticoagulation and corticosteroids were discontinued [50]. The figures can be consulted in the original open-access article: https://pmc.ncbi.nlm.nih.gov/articles/PMC12291538/ .

Comment. The report does not specify the variant in HGVS nomenclature, transcript, zygosity or ACMG/AMP classification, so, under the requirements in section 5.10, the molecular diagnosis cannot be verified from the article [50]. The case combines several warning signs from section 4 — colonic perforation without risk factors in a young person, sudden abdominal death in a parent, recurrent dislocations and multiple visceral arterial lesions — and shows how vEDS may be mistaken for vasculitis and exposed to procedures that recommendations advise avoiding or weighing cautiously, such as conventional angiography and anticoagulation [8, 28]. The approaches described are those of a single case report and do not constitute a recommendation.

11. Prognosis and Long-Term Follow-Up

Overall prognosis. Life expectancy is generally normal in most types; potentially fatal complications are concentrated in vEDS and, to a lesser extent, kEDS and mcEDS [29]. In hEDS, disease may become progressively disabling through pain, fatigue and comorbidities, with marked impact on quality of life and mental health; hypermobility is not a major cause of degenerative joint disease, but instability predisposes to injury and early osteoarthritis [2, 4, 30]. In cEDS, aortic root dilatation is rarely clinically significant and rupture risk is much lower than in Marfan syndrome [4]. In vEDS, median survival is approximately 48 to 51 years in historical series, but has improved with early diagnosis, celiprolol and care in specialist centres (71.6% survival after a median 5.3 years in the French cohort, with more than two-thirds of patients clinically silent) [4, 5, 52]. In kEDS-PLOD1, life expectancy may be normal, but vascular rupture is the principal fatal complication, and severe kyphoscoliosis may cause restrictive lung disease, recurrent pneumonia and heart failure; in the FKBP14 form, it is unknown whether survival is reduced [10, 11]. In mcEDS, survival into adulthood is possible, with risk of colonic perforation, severe haematomas and blindness [12].

For the non-vascular types, the French protocol defines a common initial assessment and, in most domains, states that there is no validated follow-up schedule; the frequency and modalities of follow-up are individual [23].

Transition from paediatric to adult care should include transfer of the emergency plan and education of the young person to recognise warning signs in forms with vascular risk; in children with symptomatic hypermobility, reassessment against adult criteria after biological maturity [8, 20]. International registries (for example, the Ehlers-Danlos Society global registry) and patient associations — Ehlers-Danlos Society, Ehlers-Danlos Support UK, Hypermobility Syndromes Association and national associations — are resources for patients and families [3, 4, 30]. In the European Union, vEDS falls within the medium-sized arteries working group of the VASCERN European Reference Network, and EDS overall within ERN ReCONNET (rare and complex connective tissue and musculoskeletal diseases), which maintains a list of EDS patient organisations; the British charity Annabelle's Challenge also supports vEDS [24, 25, 86].

In France, non-vascular EDS are followed at the reference centre for constitutional bone diseases (constituent sites at Hôpital Necker-Enfants Malades, in Paris, and Hôpital Raymond-Poincaré, in Garches) and at 13 competence centres (Caen, Clermont-Ferrand, Lyon, Marseille, Montpellier, Nancy, Paris-Lariboisière, Paris-Trousseau, Perpignan, Poitiers, Strasbourg, Toulouse and Tours), integrated into the OSCAR health filière (rare diseases of bone, calcium and cartilage); two therapeutic education programmes were validated by the regional health agencies in 2019, in Garches and in Lyon, and the family doctor coordinates follow-up and renews therapies initiated by specialists. Full (100%) coverage as an off-list long-term condition is justified when there are costly and prolonged treatments, in particular admissions to a rehabilitation centre, and the health insurance fund may exceptionally reimburse non-reimbursed expenses (podiatry, Murphy rings). Disability is recognised by the Maison départementale des personnes handicapées (MDPH), which awards, according to age and situation, the education allowance for a child with a disability, the disability compensation benefit (human and technical aids, adaptation of housing and vehicle), the disability card, the school life assistant and the personalised schooling plan, and the allowance for adults with disabilities; social security provides daily allowances (up to 3 years), therapeutic part-time work and an invalidity pension; above 60 years, the personalised autonomy allowance is requested from the local council; and parents may request a daily parental presence allowance from the family allowance fund. Schooling should be maintained in mainstream settings, close to the family, with adapted physical education that is not systematically contraindicated and, often, an individualised reception plan; at work, occupational medicine adapts the workstation and working hours (teleworking, proximity of premises, wheelchair during crises), with the support of a social worker. The French patient associations are AFSED, UNSED and SED 1+ [23].

12. Summary and Final Considerations

The Ehlers–Danlos syndromes encompass 13 clinical types in the 2017 classification, with additional entities described subsequently. hEDS, by far the most frequent form, still lacks a known genetic basis and is diagnosed exclusively by rigorous adult clinical criteria, with a specific paediatric framework and HSD as the category for symptomatic patients who do not meet those criteria; the 2025 KLK15 data open a molecular hypothesis that is not yet validated. In more than 90% of cases, cEDS results from functional collagen V haploinsufficiency due to COL5A1 or COL5A2 variants and is defined by hyperextensible skin with papyraceous scars; treatment is preventive and symptomatic. vEDS, caused by COL3A1 variants, is the most life-threatening form: arterial, intestinal and uterine ruptures arise mainly between the second and fourth decades, survival depends on variant class, celiprolol and, more recently, added irbesartan reduced arterial events in randomised trials, and management rests on an organised team, an emergency plan, avoidance of unnecessary invasive procedures and specialist pregnancy planning. Rare recessive forms — kEDS (PLOD1, FKBP14), dEDS (ADAMTS2) and mcEDS (CHST14, DSE) — and the dominant aEDS form (COL1A1/COL1A2, exon 6) are recognised by specific combinations of congenital hypotonia and kyphoscoliosis, extreme skin fragility, congenital contractures or congenital hip dislocation, and require molecular confirmation, multisystem surveillance and counselling on a 25% recurrence risk. For the non-vascular forms, the 2020 French national protocol systematises the common initial assessment (spinal radiography, echocardiography, ophthalmological and dental examinations), organ-based management, anaesthetic and obstetric precautions and organisation in reference centres, and advises against treatments without demonstrated efficacy, such as intermittent oxygen therapy. In 2026, a Dutch cohort without maternal deaths or uterine ruptures reopened the discussion of pregnancy counselling, celiprolol remained unauthorised for vEDS in any jurisdiction (DiSCOVER trial ongoing), and the International Consortium announced a classification revision for December 2026. Relevant gaps persist: epidemiological data for Portugal, Brazil and most non-European regions, studies of arterial surveillance efficacy and disease-modifying therapies for non-vascular forms.

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