1 INTRODUCTION

The Ehlers-Danlos syndromes (EDS) are a group of inherited connective tissue disorders with variable cutaneous fragility, joint hypermobility and systemic manifestations.¹ The term ‘Ehlers-Danlos Syndrome’ encompasses a group of 13 subtypes with marked clinical and genetic heterogeneity arising from defects in fibrillar collagens and other extracellular matrix proteins.² Following the latest 2017 EDS international classification, one additional subtype has been proposed, classical-like type 2 EDS (clEDS2), caused by variants in the AEBP1 gene.^{3, 4} All EDS subtypes exhibit significant cutaneous features within the major and/or minor clinical criteria (Table 1). Furthermore, cutaneous signs may sometimes be the first clinical feature and are a helpful characteristic in EDS subclassification and establishing an accurate diagnosis, prognosis and management. Thus, this review focuses on the skin manifestations in EDS to support clinicians in their clinical assessments.

2 CLASSICAL EHLERS DANLOS SYNDROME

Classical EDS (cEDS) usually has typical skin signs with some variations due to genetic penetrance and individual expression.³ Over 90% of cEDS cases are caused by heterozygous pathogenic variants in COL5A1 or COL5A2, which dysregulate the collagen assembly of fibrillar collagens.⁵ A specific mutation (p.Arg312Cys) in COL1A1 results in a phenotype of cEDS but with a propensity to vascular rupture.⁶ These mutations can cause an array of skin features, as well as mucocutaneous, ocular and facial features, which may assist in a clinical diagnosis.⁷

2.1 Skin hyperextensibility

This refers to the ability to stretch the skin beyond its normal range. Differentiation between the normal population, patients with hypermobile spectrum disorders and EDS using skin extensibility remains challenging, even for experts. In EDS, the elasticity of the skin is preserved, allowing the extended skin to recoil back to its original position.¹ It has been suggested that there is a stress-strain curve, whereby patients with EDS have skin hyperextensibility secondary to the alignment of dermal collagen bundles in the line of force.⁸ This allows for an initial extension of skin when pinched, but stops any further skin deformity when considerable additional force is applied. Furthermore, a correlation between skin hyperextensibility and increasing joint hypermobility has been shown, which may be variable depending on ethnicity.⁸ For cEDS patients, skin hyperextensibility has been shown to be greater than in healthy controls, with the skin lifting more than 1.5 cm from the dorsal surface of the non-dominant distal forearm or dorsum of the hand (Figure 1a).¹ Skin hyperextensibility is most easily assessed over the elbows, lateral neck and knees and extensibility of 3 cm or more at these sites is suggestive of cEDS.⁹ Lesser degrees of extensibility affect the other EDS subtypes.

3 VASCULAR EHLERS DANLOS SYNDROME

Vascular EDS (vEDS) is caused by heterozygous pathogenic variants in COL3A1, which result in defective or reduced secretion of collagen III by skin fibroblasts.¹⁵ Type III collagen is widely distributed in the dermis of the skin, pleuro-peritoneal linings, pelvic ligaments, intestinal tract (including the gingiva), as well as in venous and arterial walls, strongly reflecting the areas affected in vEDS.¹⁵ It is particularly important to recognize this subtype due to the high risk of arterial, as well as colonic rupture with some cases documented prior to adolescence.¹⁶ During pregnancy uterine rupture can occur with associated mortality.¹² There may be no family history as de novo mutations occur in up to 50% of cases.¹⁷

3.1 Translucent skin

Whilst vEDS patients do not usually have significant skin hyperextensibility, most commonly show skin translucency due to a decrease of collagen as a consequence of reduced type III dermal collagen, secondary to a COL3A1 mutation.¹⁸ Dermal thinning is most evident over the dorsum of the hands, upper chest and shoulders (Figure 2a). When thinning occurs over the face, hands and feet, with fine wrinkling, it is referred to as acrogeria.¹⁹ Wrinkling is a consequence of a lack of skin turgor, secondary to a lack of collagen, which is needed to hold water within the skin. Acrogeria is also a feature seen in some premature ageing syndromes and Loeys-Dietz syndrome, and to a lesser degree in Periodontal EDS (pEDS) and clEDS.¹⁹

4 PERIODONTAL EHLERS DANLOS SYNDROMES

Periodontal EDS derives its name from the prominence of oral and mucosal features, namely severe and intractable periodontitis with onset in childhood or adolescence.³ This leads to the loss of keratinized gingiva and gingival recession.^{3, 13} It appears to be caused by heterozygous gain-of-function mutations in C1R or C1S, which encode the first components of the classical complement pathway.²² The mechanism of periodontal thinning is presently unclear, but increased collagen degradation mediated by complement changes is possible.

4.1 Pretibial plaques

Pigmented pretibial shin plaques are suggestive, but not specific for pEDS and are common in vEDS and cEDS (Figure 3a). Histologically there are fibrosis and haemosiderin deposits and overlap and resemblance to necrobiosis lipoidica. Individuals with pEDS also exhibit skin hyperextensibility and fragility with atrophic scars and may also have prominent vasculature, and/or acrogeria.²²

5 DERMATOSPARAXIS EHLERS DANLOS SYNDROME

In dermatosparaxis EDS (dEDS), the skin is extremely and prematurely fragile with congenital or postnatal tears and sagging around the wrists and ankles (Figure 3b).²³ Palmar wrinkling, atrophic scarring, marked bruising with subcutaneous haematomas, soft doughy skin and postnatal growth retardation with short limbs, hands and feet may also be present.³ Craniofacial features can occur at birth or later in childhood and include prominent eyes with oedematous eyelids, blepharochalasis, epicanthal folds, large fontanelles and delayed closure.³

6 HYPERMOBILE EHLERS DANLOS SYNDROME

Hypermobile EDS (hEDS), which overlaps with hypermobility spectrum disorders relies on a clinical diagnosis as no consistent or common genetic cause has yet been identified.²⁴ Furthermore, the current diagnostic criteria for hEDS were designed to identify patients with a consistent phenotype for gene discovery.³ Cutaneous alterations are much milder in all respects than those in cEDS. The diagnostic criteria include mild skin hyperextensibility, soft skin, unexplained striae (such as striae distensae or rubrae at the back, groin, thighs, breasts and/or abdomen) and mild atrophic scarring involving at least two sites and without the formation of truly papyraceous and/or haemosiderin scars seen in cEDS.³ True skin fragility, such as the propensity to have an open wound due to trivial trauma, is not a typical feature of hEDS. Significant joint hypermobility and associated complications such as chronic pain, and dislocations are key.²⁵ Bilateral piezogenic papules affect the medial and lateral aspects of the ankles of the foot and represent herniation of underlying soft tissue but are not specific to hEDS. Additional features such as easy bruising, haematomas, blue sclerae and delayed wound healing were also noted in a cross-sectional review of joint hypermobility syndrome/hEDS.²⁶ The differential diagnosis of hEDS includes clEDS and Cardiac-valvular EDS (cvEDS).

7 CLASSICAL-LIKE EHLERS DANLOS SYNDROME

Autosomal recessive TNXB mutations cause classical-like EDS (clEDS), with cutaneous features resembling cEDS with hyperextensibility, easy bruising and/or slow wound healing.²³ It has also been noted that some clEDS patients exhibit oedema in the legs in the absence of cardiac failure.^{3, 27} The critical difference between clEDS compared to cEDS is the absence of atrophic or atypical scars. Acrogeric skin thinning, pelvic prolapse and various foot deformities including pes planus and hallux valgus are non-specific findings.³ The latter can also be seen in vascular and arthrochalasia subtypes.

8 RARER EHLERS DANLOS SYNDROMES SUBTYPES WITH CUTANEOUS FEATURES

Cardiac-valvular EDS is an important subtype and is accompanied by aortic and/or mitral valve pathology.²³ Cutaneous features resemble cEDS with hyperextensibility, atrophic scarring and bruising. Variants affecting the alpha 2 chains of type I collagen result in cardiac valve pathology.²⁸ In other cases, the clinical phenotype of these variants cause in severe osteogenesis imperfecta type II/III.²⁹ Given the possible clinical overlap between cEDS and cvEDS, a baseline echocardiogram should be considered for cEDS patients to screen for cardiac pathology that may indicate a missed diagnosis of cvEDS. The subtype may also present with pectus excavatum, inguinal hernias and foot deformities.³

Arthrochalasia EDS can present with skin hyperextensibility, but atrophic scarring and bruising have previously been listed as minor non-specific features. Congenital bilateral hip dislocation with generalized joint hypermobility, hypotonia, kyphoscoliosis and mild osteopenia are present. Furthermore, a crisscross patterning of the palms and soles has also been noted in some cases.²³ In musculocontractural EDS congenital adduction-flexion contractures are found, as well as talipes equinovarus with skin hyperextensibility, bruising, fragility with atrophic scars and increased palmar wrinkling.³ Furthermore, peculiar tapered, slender fingers, hyperalgesia to pressure and fistula formation due to recurrent subcutaneous infections has been noted in this subtype.²³

In kyphoscoliotic EDS the major clinical features of congenital muscle hypotonia and kyphoscoliosis present in infancy or childhood alongside generalized hypermobility.¹ Cutaneous signs are relatively non-specific but include skin hyperextensibility, easy bruising and keratosis pilaris. Features specific to heterozygous pathogenic variants in PLOD1 include fragility of skin, blue sclera and ocular issues (ocular fragility, high myopia, glaucoma and microcorneas).³⁰ Congenital hearing impairment and follicular hyperkeratosis are reported with heterozygous pathogenic variants in FKBP14.^{3, 31} Other cutaneous features described with pathogenic variants of FKBP14 include molluscoid pseudotumours, multiple isolated comedones and umbilical skin redundancy.³² Urinalysis by high performance liquid chromatography can show an increased dexoypyridinoline to pyridinoline ratio, specific for PLOD1 mutations, which is not present with FKBP14 mutations.³

Brittle cornea syndrome causes a thin cornea, keratoconus and keratoglobus with myopia and deafness, whilst limited skin signs include soft, velvety and translucent skin, without atrophic scarring.^{3, 23} Myopathic EDS displays congenital muscle hypotonia and joint contractures are major features along with hypermobile small joints, whilst skin changes can include softness and atrophic scarring.¹ Spondylodysplastic EDS presents with progressive short stature in childhood, with hypotonia and bowing of limbs.³ Skin hyperextensibility and softness can be present, with thin and translucent skin.

Ehlers Danlos syndromes cases caused by AEBP1 autosomal recessive pathogenic variants are limited but are considered a classical-like EDS (clEDS2) due to the significant clinical overlap with cEDS, including skin hyperextensibility, atrophic scarring and generalized joint hypermobility. The mode of inheritance and early-onset osteopenia are helpful points of differentiation. Specific cutaneous features per subtype can be found in Supplementary Information (see Fig. S1).

9 HISTOLOGICAL FEATURES IN DIFFERENT EHLERS DANLOS SYNDROMES SUBTYPES

In addition to cutaneous findings, both light and transmission electron microscopy (TEM) of skin biopsy samples are helpful in some subtypes,³³ although not diagnostic on their own, as these findings are largely qualitative (Table 2).³⁴ A recent analysis of TEM in 24 patients with a definitive diagnosis of monogenic EDS noted that 17 (71%) had an abnormal biopsy report.³⁵ They also noted that no TEM findings were specifically associated with any EDS subtype, although collagen flowers were present in most patients with a genetically confirmed diagnosis of cEDS.³⁵ These results also need to be interpreted with patient age and current treatment in mind, as a thin dermis can also result from photoageing of skin or from prolonged use of topical corticosteroids.³⁶ If TEM is not easily available, preliminary light microscopy is helpful when stained for collagen and elastin, particularly for vEDS and cEDS.

This review highlights those skin signs helpful to a potential EDS diagnosis in some EDS subtypes, particularly cEDS, vEDS, pEDS, dEDS and clEDS2 subtypes. In patients with signs of cEDS such as skin hyperextensibility, fragility and atrophic scarring there are other differentials to consider including clEDS, AEBP1-related EDS and cvEDS. Vascular EDS patients typically have translucent skin, though this can be seen in other subtypes and may lack large joint hypermobility and may instead have hypermobility of smaller joints. Periodontal EDS patients typically have severe premature and progressive periodontitis presenting in early childhood and pretibial plaques may be seen but are not pathognomonic as these can overlap with cEDS and vEDS. Dermatosparaxis EDS patients have extreme, premature skin fragility with resultant redundant, skin laxity. These subtypes may present in the dermatology clinic and in the case of vEDS, if unrecognized can have life-threatening complications. Clinicians can identify signs suggestive of these EDS subtypes on skin examination, but features can overlap between subtypes. Skin biopsies for light and electron microscopy provide additional evidence to further support the need for formal DNA analysis. Genotyping is becoming increasingly accessible and is an important addition to the dermatologist's tool kit. This is especially true for vEDS, where confirmation of diagnosis allows for predictive testing of other at-risk family members, affording appropriate early intervention, in the prevention of the severe internal manifestations of the disorder. For all subtypes where the genetic basis is known, reproductive options such as pre-implantation genetic testing may be facilitated, with appropriate counselling.

AUTHOR CONTRIBUTIONS

Nastasha Stembridge: Data curation (Equal); Formal analysis (Lead); Investigation (Lead); Writing – original draft (Equal); Writing – review & editing (Supporting). Brent J. Doolan: Formal analysis (Equal); Resources (Equal); Writing – review & editing (Lead). Mark E. Lavallee: Writing – review & editing (Supporting). Ingrid Hausser: Writing – review & editing (Supporting). F. Michael Pope: Writing – review & editing (Supporting). Suranjith L. Seneviratne: Writing – review & editing (Supporting). Ingrid M. Winship: Writing – review & editing (Supporting). Nigel P. Burrows: Conceptualization (Equal); Methodology (Lead); Supervision (Lead); Writing – original draft (Equal); Writing – review & editing (Supporting).

CONFLICT OF INTEREST

All authors of this manuscript certify that they have no affiliations with or involvement in any organization of entity with any financial interest or other equity interest or non-financial interest in the materials discussed in this manuscript.