Classical EDS (cEDS, prevalence 1;20,000, (7) autosomal dominant, mostly variants in COL5A1 or COL5A2, rarely specific variants in COL1A1)

The major criteria of classical EDS are (i) generalised joint hypermobility and (ii) skin hyperextensibility and atrophic scarring. Drivers of the diagnosis in childhood are often the tendency to bruise easily, as well as skin fragility leading to splitting of the skin where there is a skin laceration extending through the epidermis and dermis. Subsequent impaired wound healing results in atrophic scars. These are characterised by thin, wrinkly scar tissue, hence the old term “cigarette paper or papyraceous scarring”. Atrophic scarring is often most noticeable on forehead, knees and shins and can occur even after mild trauma for example with parents reporting their child falling on a soft carpet leading to splitting of the skin and subsequent impaired wound healing with atrophic scarring. Individuals, particularly in families with multiple affected family members, will often manage their own wounds with adhesive tapes (steri-strips) and only when strictly necessary attend the A&E to seek medical assistance for sutures given the increased frequency of injuries. Occasionally, the extent of skin injury requires skin grafting. In case of deep skin wounds, double layered stitching is recommended [8]. Interestingly, surgical incisions often heal well without atrophic scarring. For painful bruising with swelling often Tranexamic acid is advised to have at home for when needed. This is applicable to all individuals with rare EDS types who are prone to painful bruising with swelling. It is often reported by adults that the frequency of accidents leading to skin splitting is high from toddlerhood and decreases from young adulthood. Many mention that being cautious is the main reason for this along with a general reduction in physically boisterous activities.

In young children, the hyperextensibility of the skin can easily be missed, as the skin is also still very elastic and needs to be pulled with some force before it becomes clear how far it can stretch. Testing skin hyperextensibility at stretched elbows and other areas of the body for example dorsum of the hand and neck, often gives a clear indication about presence of hyperextensibility.

In childhood, generalised hypermobility with or without (sub)luxations and joint pains are often noted. Adults tend to often develop joint pains due to osteoarthrosis starting from as early as thirties. They often consider this their main problem and therefore specialist rheumatology and physiotherapy input can be very valuable.

Further data from larger cohort studies should provide more clarity regarding frequency of cardiovascular complications including arterial aneurysms/dissections which so far are considered rare [9]. Importantly, several heterozygous variants causing Glutamic acid>Lysine changes in COL3A1 have been reported to cause clinical features of classical EDS with a hyperextensible skin and skin fragility but also generalised tissue fragility as seen in vascular EDS [10].

Vascular EDS (vEDS, prevalence 1;50,000 [11], autosomal dominant, mostly variants in COL3A1, rarely specific Arg>Cys variants in COL1A1)

Vascular EDS is one of the most well-known types of EDS due to presence of generalised tissue fragility. Major criteria include (i) arterial aneurysm and/or dissection, (ii) sigmoid colon perforation in absence of diverticular disease or other colon pathology, (iii) uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears and (iv) carotid-cavernous sinus fistula (CCSF) formation in the absence of trauma. Referrals for assessment for vEDS can therefore come from a variety of different specialties including Haematology, Rheumatology, Vascular surgery, Cardiology, Respiratory medicine, Intensive care medicine, and Paediatrics.

There are multiple minor diagnostic criteria, most typically the combination of easy and/or spontaneous bruising, bruising at unusual locations, and translucent thin skin with visible veins. However, it needs to be emphasized that there are individuals who do not have clear features of vEDS on physical examination and nevertheless have generalised tissue fragility. Therefore, vEDS remains a diagnosis that without positive family history can sometimes be only made after a (major) complication in the proband has occurred. Also, it is important to emphasize that the intrafamilial and interfamilial variability in this condition is striking regarding clinical features on physical examination, (age at) occurrence of clinical events, and type of clinical events. Importantly, management through an expert service has been shown to have a favourable effect on survival [12, 13]. Management consists of lifestyle advice including seeking support in acute situations, recommending aerobic exercise whilst still being able to hold a conversation, and advising against isometric exercise. An emergency card with explanation about vEDS for medical health care professionals should be provided. Pharmacological therapy includes blood pressure lowering medication such as Celiprolol [12] or combined therapy with beta blocker and angiotensin II receptor blocker [13]. Regular cardiovascular imaging is recommended, and it is important to advise on conservative management above invasive or endovascular procedures unless unavoidable [4, 14]. Due to the risk of death during pregnancy of 5.3 % in women with vEDS [15], obstetric management should take place in tertiary obstetric centres [13]. International guidance regarding pregnancy management in vEDS has been published through the ERN network VASCERN (https://vascern.eu/).

Kyphoscoliotic EDS, Prevalence 1:100,000, Biallelic variants in PLOD1 or FKBP14.

Kyphoscoliotic EDS is a well-known type of EDS and PLOD1 variants were the first reported recessive cause of a monogenic EDS type. Major criteria include (i) congenital muscle hypotonia, (ii) congenital or early onset kyphoscoliosis (progressive or nonprogressive), and (iii) GJH with dislocations/subluxations. Rupture of medium-sized arteries has been reported as part of the minor criteria, and therefore cardiovascular surveillance should be available to affected individuals [16].

The skin features in PLOD1-kEDS are similar to those seen in cEDS, with presence of skin fragility, atrophic scarring and easy bruisable skin which are part of the gene-specific minor criteria. There are reports of individuals without congenital or early onset kyphoscoliosis in whom the initial clinical diagnosis was thought to be cEDS [16]. A minority of individuals with PLOD1 kEDS was reported to have scleral rupture after minimal trauma [17]. Eye protection is recommended to avoid accidental damage during physical activities.

FKBP14-kEDS is different in that skin fragility is often absent, and individuals often have widespread follicular hyperkeratosis as well as congenital hearing impairment (sensorineural, conductive, or mixed) [18].

Arthrochalasia EDS, Prevalence < 1:1,000,000, autosomal dominant, variants in COL1A1 or COL1A2 that lead to complete or partial deletion of exon 6

The clinical hallmark of aEDS is (i) congenital bilateral hip dislocation in conjuction with (ii) severe generalised joint hypermobility and (sub)luxations [19, 20]. There is a genotype-phenotype relationship in that musculoskeletal features, including liability to fractures, tend to be more severe in individuals with COL1A1 variants. Access to musculoskeletal services can address their needs, and the condition is often well managed through services that also have experience with osteogenesis imperfecta (OI) which is the most common manifestation of heterozygous pathogenic variants in COL1A1 or COL1A2 [19]. People with aEDS can have skin features as seen in individuals with cEDS, including hyperextensible skin which is the third major criterium (iii).

Dermatosparaxis EDS (dEDS, prevalence <1:1,000,000, biallelic variants in ADAMTS2

With only 15 individuals reported in childhood – with an age range from birth to 16 years – and one patient being followed-up to adulthood (19 years), the clinical criteria for dEDS are extensive comprising 9 major criteria. In the authors opinion the most important features are (i) extreme skin fragility with congenital or postnatal skin tears, (ii) characteristic craniofacial features as seen in figure 2D (iii), redundant almost lax skin with excess folds at the wrists and ankles, and (iv) severe bruisability with a risk of subcutaneous hematomas and haemorrhage. Tissue fragility has been noted in some individuals with bladder rupture likely due to bladder diverticulae, and diaphragmatic rupture following vomiting. In adulthood one individual also developed diaphragmatic rupture with hiatus hernia (###, personal communication).

Brittle Cornea Syndrome, biallelic variants in ZNF469 or PRDM5

As the name suggests, all the major features of individuals with Brittle Cornea Syndrome (BCS) relate to the eye, and particularly the cornea. They include (i) thin cornea with or without rupture, (ii) early onset, progressive keratoconus or(iii) keratoglobus and (iv) blue sclerae. The latter can of course be identified on physical examination, taking into consideration that blue sclerae in the first 12 months can still be physiological and can also be seen in individuals with other inherited tissue conditions. Mixed hearing loss can also be present, as well as musculoskeletal features such as developmental dysplasia of the hip, scoliosis, and joint hypermobility. Dhooge et al point out that individuals who do not present with symptoms related to corneal fragility are at risk of diagnostic delay and emphasize the importance of identifying features of an inherited connective tissue condition. This is a reason for inclusion of the BCS-related genes in inherited connective tissue disorder gene panels [21].

Cardiac valvular EDS, biallelic loss of function variants in COL1A2

Cardiac-valvular EDS is a very rare EDS type as so far only 7 individuals with an age range from 6–65 years have been reported and is caused by bi-allelic loss of function (LOF) COL1A2 variants leading to mRNA decay. The main criteria are (i) severe progressive cardiac-valvular problems of mitral and aortic valve. On physical examination (ii) distal or generalised joint hypermobility is often noted as well as (iii) skin involvement with hyperextensibility, thin skin with visible veins, atrophic scarring, and easy bruising. Since then, Guarnieri et al. [22] reported on 5 previously and 2 newly diagnosed patients. They noted that the core cvEDS phenoype consists of joint hypermobility limited to, or more marked at, hands and feet (100 %), skin hyperextensibility (100 %), mitral valve insufficiency (83 %), genua recurvata (66 %), bilateral pes planus (66 %), soft/doughy/thin skin (66 %), variable atrophic scarring (50 %), easy bruising and bilateral inguinal hernia (50 %). Of course, as these percentages are based on occurrence of clinical features in a very small group of affected individuals, the description of the core cvEDS phenotype could change significantly depending on additional reported individuals with cvEDS.

Classical-like EDS (clEDS), prevalence < 1:1,000,000, autosomal recessive TNXB-clEDS & autosomal recessive AEBP1 -clEDS

In the 2017 classification, clEDS was exclusively linked to pathogenic variants in TNXB; after the identification of AEBP1- clEDS, the condition is also denoted as clEDS type 1. Affected individuals typically have a (i) hyperextensible skin without atrophic scarring and (ii) generalised joint hypermobility with or without dislocations. They often bruise very easily and are prone to haematomas (iii). Foot abnormalities are very common (81 %) including broad/plump forefoot, brachydactyly with excessive skin, pes planus, hallux valgus, and painful soles of the feet. The most specific foot abnormality was broad feet with brachydactyly. Importantly, tissue fragility has been reported including gastrointestinal fragility with oesophageal, small bowel and/or large bowel ruptures (16 %), vascular fragility leading to major events (5 %) and other fragility including tracheal rupture after intubation and defect of nasal cartilage after nose blowing (4 %). Therefore, invasive procedures are advised against unless unavoidable and should then be executed with caution and awareness of potential complications due to tissue fragility. A baseline echocardiogram of the heart is currently recommended [23–26].

AEBP1- clEDS

No specific diagnostic criteria have yet been formulated for AEBP1-EDS, also called clEDS type 2. As the name suggests, individuals with this condition share features with people with cEDS and TNXB clEDS. All individuals reported so far have GJH, hyperextensible skin, easy bruising and in the majority also atrophic scarring. Intriguingly, thinning of hair was present in 6/11 (55 %) of individuals reported by Angwin et al. [27]. A recent overview of 15 individuals with AEBP1 clEDS [28] also referencing Yamaguchi et al. [29] reported on 3/15 individuals (20 %) with arterial aneurysm/dissection, 2/15 (13 %) with aortic root dilatation highlighting the importance of cardiovascular surveillance, and 2/15 (13 %) with bowel rupture suggesting avoidance of invasive procedures unless absolutely necessary.

Myopathic EDS, prevalence < 1:1,000,000, heterozygous or biallelic variants in COL12A1

To date, 25 individuals with myopathic EDS (mEDS) from 16 families have been reported, with autosomal recessive inheritance in two families [30]. Individuals with myopathic EDS share features with Bethlem and Ullrich congenital myopathies. mEDS is clinically characterised by (i) congenital muscle hypotonia, and/or muscle atrophy, that intriguingly improves with age. In addition, (ii) proximal joint contractures (knee, hip, and elbow) can be present, as well as (iii) hypermobility of distal joints. Atrophic scarring and soft, doughy skin may be observed. As there are only few individuals reported so far, the clinical criteria are likely to become more specific with time. It can be argued that because of its strong myopathic component mEDS should be classified as a congenital myopathy rather than a rare EDS type.

Periodontal EDS, prevalence < 1:1,000,000, specific gain-of-function variants in C1R or C1S

Of all the different rare EDS types, pEDS is certainly the most intriguing one regarding the underlying pathogenic mechanism, which involves components of the classical pathway of the complement system. It is ultimately caused by activation of the C1r complement subunit which has collagenase function and may also lead to incomplete activation of the complement system. A pathognomonic feature in people with pEDS is (i) lack of attached gingiva which is the keratinised gingiva that connects the gingiva to the dental bone [31]. Individuals typically experience (ii) gingivitis and aggressive periodontitis leading to periodontal bone loss at a very young age with complete dental loss at an average age of 20 years. The diagnosis of lack of attached gingiva requires the very trained eye of a periodontal expert and may be easily missed. However, the history of receding gums with teeth becoming loose and falling out in combination with gum recession and (ii) presence of pretibial plaques – often symmetrical brownish discoloured plaques on the shins that can also involve the calves – are very suggestive of pEDS. In addition, imaging studies in adults with pEDS have revealed white matter abnormalities in almost all adults who underwent imaging studies; there are usually no clear neurological symptoms although symptoms such as migraines and poor memory have been recorded. Some individuals develop a hoarse or high-pitched voice. Rare complications include aneurysms/dissections and organ rupture, and cardiovascular surveillance is advised [32–33]. Excellent dental hygiene is recommended with electric toothbrushes, interdental brushes, and 3-monthly professional dental cleaning. This will limit formation of dental plaque and may reduce subsequent excessive C1r/C1s activation that leads to severe periodontitis and loss of periodontal bone and consequently teeth [31–32]. However, whilst this may reduce the degree of the inflammatory response, the underlying activation remains.

Musculocontractural EDS, prevalence < 1;1,000,000, biallelic variants in CHST14 and DSE

Individuals with mcEDS are usually diagnosed in childhood as they have multiple congenital contractures specifically adduction-flexion contractures and/or talipes equinovarus in combination with specific craniofacial features and characteristic skin features including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling. Individuals with mcEDS can develop multiple complications of which some are also part of the minor criteria. An international review of 66 individuals with recessive CHST14 variants was published in 2022 [34] as well as review on 14 individuals with mcEDS due recessive DSE variants [35] which should guide revision of gene specific criteria formulated in 2017.

Spondylodysplastic EDS, prevalence <1:1,000,000, biallelic variants in B3GALT6, B4GALT7 and SCL39A13

Individuals with spondylodysplastic EDS are also often diagnosed in childhood due to major features of (i) short stature, (ii) muscle hypotonia (ranging from severe congenital, to mild later-onset) and (iii) bowing of limbs leading to a suspicion on a skeletal dysplasia. The associated cutaneous skin features are important in the diagnostic process and likely the reason why this condition is classified as a monogenic EDS type. These features consist of skin hyperextensibility, doughy skin and thin translucent skin. As there are three different genetic causes that lead to spEDS there are gene-specific criteria as well.

OIEDS1, OIEDS2 and COL1-related overlap disorder condition

In 2020 Morlino et al. [36] coined the term COL1 overlap disorder pertaining to individuals with previously reported OIEDS1 and OIEDS2 due to combined symptoms of osteogenesis imperfecta type 1 (non-deforming OI with blue sclerae) and Ehlers Danlos syndromes due to structural COL1A1 and COL1A2 variants without fulfilling the clinical criteria for these conditions. Major criteria for COL1-related overlap disorder were defined as (i) blue sclerae, (ii) flatfoot with valgus deformation of the hindfoot, (iii) generalised joint hypermobility according to age, (iv) significantly soft and doughy, and/or hyperextensible skin. Minor criteria consisted of (i)dolichostenomelia in adults, (ii) hearing loss, (ii) short stature, (iv) two or more atrophic scars, (v) two or more fractures in pre-pubertal age, (vi) two or more joint dislocations, (vii) two or more fractures injuries and/or ruptures of ligaments, tendons and/or muscles. Genetic testing of COL1A1 and COL1A2 genes was encouraged in presence of ≥3 major criteria or one major and ≥ 4 minor criteria.

Venable et al. [37] subsequently reported on a cohort of 34 individuals with (likely) pathogenic variants in COL1A1/2 with an initial diagnosis of OI, unspecified EDS, and interestingly, hypermobile EDS. They suggested that features such as easy bruising, vascular fragility, and striae as well as positive family history could be incorporated in the COL1-related overlap disorder criteria. They also argued for a comprehensive checklist to document full fracture history, dental history, wound healing abnormalities, physical exam with Beighton scoring, sclerae colour, and texture/extensibility of the skin, essentially describing the clinical assessment by a specialist in inherited connective tissue conditions.

Figure 1:

Decision tree to determine likelihood of a diagnosis of a monogenic EDS type in an individual referred with generalised joint hypermobility without a medical or family history with vascular and/or hollow organ rupture.