Hypermobile Ehlers-Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes

Abstract

The Ehlers-Danlos syndromes (EDS) are a group of heritable, connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. There is phenotypic and genetic variation among the 13 subtypes. The initial genetic findings on EDS were related to alterations in fibrillar collagen, but the elucidation of the molecular basis of many of the subtypes revealed several genes not involved in collagen biosynthesis or structure. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. hEDS is the most common type of EDS and involves generalized joint hypermobility, musculoskeletal manifestations, and mild skin involvement along with the presence of several comorbid conditions. Variability in the spectrum and severity of symptoms and progression of patient phenotype likely depend on age, gender, lifestyle, and expression domains of the EDS genes during development and postnatal life. In this review, we summarize the current molecular, genetic, epidemiologic, and pathogenetic findings related to EDS with a focus on the hypermobile type.

1 |. HISTORY

Edvard Ehlers and Henri Danlos described variances in cutis laxa in 1908 and 1904, respectively. Ehlers-Danlos syndrome (EDS) was first named in 1946 and categorization of the EDSs followed in the late 1960’s. The EDS subtypes were then formalized in the Berlin nosology, which recognized 11 numbered subtypes of EDS.¹ As the underlying molecular basis of various subtypes emerged, the Villefranche nosology came out in 1998, consisting of six subtypes with descriptive names.² The Villefranche nosology for hEDS was originally defined as joint hypermobility with or without skin manifestations, family history, joint pain, dislocations, and systemic manifestations. The Villefranche criteria poorly defined hEDS and broadly labeled individuals with generalized joint hypermobility as having hEDS. Thus, in 2017, the EDS International Consortium proposed the 2017 International Classification for the EDSs to replace the Villefranche nosology, recognizing 13 subtypes of EDS (Table 1) with major and minor diagnostic criteria outlined for each subtype.⁷⁴ The new criteria for hypermobile EDS were more strict than previous criteria, in an attempt to better define the disease subtypes and reduce future misdiagnoses.

TABLE 1.

Description of subtypes of EDS comparing 2017 nomenclature with the Villefranche and Berlin nosology

Molecular biology of Ehlers-Danlos syndromes
Gene	Mutation(s)	Inheritance	Molecular biology	2017 EDS nomenclature	Villefranche nosology	Berlin nosology	References
ADAMSTS2	Homozygous nonsense mutations (p.(Gln225) and p.(Trp795*)), skipping in frame and out of frame of various exons, homozygous loss of function mutations (c.2927_2928delCT, p. (Pro976Argfs*42); c.669–670dupG, p. (Pro224Argfs*41); c.2751–2A>T) and compound heterozygous (p. (Met295Thrfs25*))	AR	Enzymatic component of the ECM	Dermatosparaxis EDS (dEDS)	Dermatosparaxis type	Type VIIC	3–5
AEBP1	Compound heterozygous (c,1470delC [p. Asn490_Met495delins(40)] and c,1743C>A [p.Cys581*]), homozygous (c,1320_1326del [p.Arg440Serfs*3]) homozygous splice site variant (c.1630J)1G>A), homozygous c,1925T>C p.(Leu642Pro)	AR	Regulates collagen fibrillogenesis	Classic-like EDS (clEDS)	N/A	N/A	6,7
B3GALT6	Missense and frameshift mutations, in-frame deletions, start codon mutations, splice site mutations and in-frame duplication. Homozygous and compound heterozygous mutations. The following are the most commonly reported: p.(Pro67Leu), p. (Thr79Ala), p.(Arg232Cys), p.(Asp207His), p. (Phel86Leu), p.(Arg6Trp) p.(Glu265Asp), p. (Ser309Thr), p.(Glul74Alafs*266), p.(Metl?)	AR	Post-translational modification of proteins including proteogylcans	Spondylodysplastic EDS (spEDS)	EDS progeroid type	N/A	8–13
B4GALT7	c.808C>T, p.(Arg270Cys); c,122T>C, p. (Leu41Pro); c.421C>T, p.(Argl41Trp); c.557C>A, p.(Alal86Asp); c.617T>G, p. (Leu206Pro); c.641G>A, p.(Cys214Tyr); c.277dup,p.(His93Profs*73); c.970T>A, p. (Cys324Ser)	AR	Post-translational modification of proteins including proteoglycans	Spondylodysplastic EDS (spEDS)	EDS progeroid type	N/A	14–19
C1R	Heterozygous missense and in-frame insertion/ deletion variants; p.Asp290Gly, p.Gly297Asp, p.Leu300Pro, p.Arg301Pro, p.Tyr302Cys, p. Ile306_Cys309delinsArgArg p.Cys309Trp, p. Cys309Trp, p.Cys338Arg, p.Cys358Phe, p. Trp364Cys, p.Cys371Trp, p. Arg401_Tyr405delinsHisValIle, p.Trp435Arg	AD	Complement immune system	Periodontal EDS (pEDS)	EDS periodontitis	Type VIII	20
CIS	Heterozygous missense and in-frame insertion/deletion variants p.Cys294Arg, p.Val316del	AD	Complement immune system	Periodontal EDS (pEDS)	EDS periodontitis	Type VIII	20
CHST14	Loss of function, missense, frameshift and nonsense mutations p.(Pro281Leu), p. (Val49*), p.(Arg213Pro), p.(Tryr293Cys), p. (Arg29Gfs*113), p.(Lys69*), p. (Glnl 13Argfs*14), p.(Argl35Gly), p. (Leul37Gln), p.(Cysl52Leufs*10), p. (Phe209Ser), p.(Arg218Ser), p. (Gly228Leufs*13, p.(Glu262Lys), p. (Arg274Pro), p.(Met280Leu), p.(Cys289Ser), p.(Trp327Cfs*29), p.(Glu334Glyfs*107)	AR	Post-translational modification— conversion of sulfate to dermatan sulfate	Musculocontractural EDS (mcEDS)	N/A	N/A	21–23
C0L1A1	c.934C>T, p.(Arg312Cys); c,1720C>T, p. (Arg574Cys); and c.3277C>T, p. (Argl093Cys)	AD	Structural ECM component	cEDS with vascular fragility, vEDS	Classical type, vascular type	Typel/II/IV	24–26
C0L1A1	Splice site mutations that lead deletions of exon 6 (intron 5–2A>G/T; intron 5-lG>A/C/ T; exon 6-lG>A/C)	AD	Structural ECM component	Arthrochalasia EDS (aEDS)	Athroscorasia type	Type VIIA/B	27–29
C0L1A2	c.213dupC,p.(Arg99*) homozygous, six splice site mutations (two homozygous (c.3105+ 2T>C and c.3601G>T)) and two compound heterozygous (c.70+717A>G; c.1404+1G>A and c.540+5G>A; c,1404G>C)	AR	Structural ECM component	Cardiac-valvular (cvEDS)	N/A	N/A	30–33
	Splice site mutations that lead deletions of exon 6						34
C0L1A2	(intron 5–2A>G; intron 5-lG>A/C; exon 6-lG>A; intron 6+lG>A/T/C; intron 6+2T>C/G)	AD	Structural ECM component	Arthrochalasia EDS (aEDS)	Athroscorasia type	Type VIIA/B	29,35–39
C0L3A1	p.(Gly637Ser)	AD	Structural ECM component	Hypermobile EDS (hEDS)? One Family	Hypermobility type (EDS-HT)	Type III	40
C0L3A1	Glycine substitutions, splice-site insertions/ deletions, in-frame insertions/deletions, haploinsufficiency, nonglycine missense variants in the triple helix, nonglycine missense variants and in-frame insertions/ deletions, in the N- or C-terminal	AD	Structural ECM component	Vascular EDS (vEDS)	Vascular type	Type IV	41,42
C0L5A1	Mutations leading to nonsense mediated mRNA decay, haploinsufficiency and structural mutations	AD	Structural ECM component	Classical EDS (cEDS)	Classical type	Type I/II	26,43
COL5A2	Structural mutations and splice site mutations	AD	Structural ECM component	Classical EDS (cEDS)	Classical type	Type I/II	26,43
C0L12A1	Heterozygous missense mutations that are autosomal dominant (c.7167 T>C, p. (Ile2334Thr), C.C5893T, p.(Argl965Cys), 8329G>C, p.(Gly2777Arg), C.G8357A, p. (Gly2786Asp)) and a homozygous frameshift mutation that is autosomal recessive (c.8006 +1 G>A, p.(2567Asp>Phefs*2)	AR or AD	ECM component	Myopathic EDS (mEDS)	N/A	N/A	44–46
DSE	Homozygous loss of function, missense mutations (p.(Arg267Gly), p.(Ser268Leu))	AR	Biosynthesis of dermatan sulfate	Musculocontractural EDS (mcEDS)	N/A	N/A	23,47
FKPB14	Duplication (c.362dup, p.(Glul22Argfs*7), homozygous deletion (c,197+5_197+ 8delGTAA), compound heterozygous mutations	AR or compound heterozygosity	ER folding/transport of collagen	Kyphoscoliotic EDS (kEDS)	Kyphoscoliosis type	Type VI, Type VIA	48–51
LZTS1	p.(His211Gln)	AD	Tumor suppressor	Hypermobile EDS (hEDS)? One Family	Hypermobility type (EDS-HT)	Type III	52
PRDM5	c. 1517_1527dell 1, p.(Val506Glufs*5); c.974delG, p.(Cys325Leufs*2); c.711_714delTGTT, p.(Val238Alafs*35); c,1768C>T, p.(Arg590*); c.320A>G, p. (Tyrl07Cys); c,17T>G, p.(ValôGly); C.93+ 1G>A	AR	Collagen synthesis	Brittle cornea syndrome (BCS)	N/A	N/A	53–55
PL0D1	p.Ile454IlefsX2, p.Ala667Thr, and p.His706Arg, homozygous for exons 10–16 duplication, p. Ile454IlefsX2, homozygous for p.Arg319X	AR	ER folding/transport of collagen	Kyphoscoliotic EDS (kEDS)	Kyphoscoliosis type	Type VI, Type VIA	56–64
SLC39A13	Homozygous 9-bp in-frame deletion in exon 4	AR	Zinc transporter	Spondylodysplastic EDS (spEDS)	EDS progeroid type	N/A	65–67
ZNF469	5294delA, 9527delG, Cys 3339Tyr, Glul392Ter	AR	Collagen synthesis	Brittle cornea syndrome (BCS)	N/A	N/A	68–73

Note: Gene mutation, inheritance pattern, molecular biology, nomenclature, and references are listed.

Similar to hEDS, hypermobility spectrum disorders (HSD) are a poorly recognized group of connective tissue disorders that involve a spectrum ranging from asymptomatic hypermobility or hypermobility affecting only one joint, to generalized joint hypermobility, subluxations, and dislocations. Patients with symptomatic joint hypermobility that do not meet the criteria for hEDS are often labeled as HSD. Prior to the 2017 criteria, patients may have been categorized as having joint hypermobility syndrome (JHS) or benign joint hypermobility syndrome (BJHS), both of which overlap phenotypically and may be indistinguishable from hEDS.⁷⁵ Due to the lack of a genetic marker for hEDS or HSD/JHS and similarity in clinical and molecular phenotype, the two diagnostic labels are often grouped together. Unless further genetic discoveries are able to accurately separate patients into different subgroups, it has been recommended that JHS and hEDS should be viewed as one.⁷⁶ Due to reclassifications of EDS subtypes, hEDS may also be referred to as EDS III or grouped with HSD or JHS in the literature reflected in this review.

2 |. EPIDEMIOLOGY

Generalized joint hypermobility, impacting four or more joints, has been reported to be present in anywhere from 12% to 28% of children, adolescents and young adults.^77–83 This has been shown to be both age and gender specific, where females and children tend to be more hypermobile.^{79–82,84–86} It is important to note that joint hypermobility alone is somewhat common in the general population and may be present with no complications, especially in children.^78,79,82,85 Furthermore, there are forms of acquired hypermobility that may be present in ballet dancers, gymnasts, wrestlers, cheerleaders, and other athletes where hypermobility is trained and is not indicative of a connective tissue disorder.⁸⁷

There is an unexpected female predominance in hEDS despite suspected autosomal dominant inheritance.⁸⁸ It is possible that women may be more frequently diagnosed due to a higher severity of symptoms than men. This may be explained by muscle mass and ligament stiffness being controlled by sex and leading to greater joint stability in men, as it is already known that women are more flexible than men.⁸⁹ Additionally, women are also known to engage the medical system earlier than males.⁸⁹ Understanding the protective factors that lead to reduced penetrance in men may be a key component of treating hEDS.

The exact prevalence of hEDS has proved challenging to determine due to changes in categorization of subtypes and lack of a clear diagnostic test for hEDS. EDS as a whole has been estimated to impact 1 in 5,000 people worldwide, however, there is limited evidence to support this statistic.⁹⁰ Demmler et al recently reported the combined prevalence of hEDS and HSD to be 1 in 500 people in Wales with 70% of the diagnosed being women, suggesting that hEDS/HSD prevalence has been grossly underestimated.⁹¹ With the spectrum of severity, variation in symptom presentation and the lack of an effective clinical diagnostic test, it is not uncommon for patients to go years undiagnosed with hEDS. Because of this, it can be assumed that the actual prevalence of hEDS is higher than reported. This highlights the need for a better understanding of the genetics and biology of hEDS to develop accurate diagnostic tools that will allow for accurate detection and epidemiological reports.

3 |. DIAGNOSTIC CRITERIA

Current diagnostic guidelines indicate major and minor criteria for each EDS subtype. Due to the heterogeneity and overlap of phenotype among subtypes, a genetic diagnosis is preferred for all subtypes, except hEDS. The presence of criteria 1, 2, and 3 (Table 2) must all be met for a clinical diagnosis of hEDS. Criterion 1 includes generalized joint hypermobility, to be assessed by the Beighton score with ≥6 out of 9 for children and adolescents, 5 out of 9 for adults up to 50 yr of age and 4 out of 9 in adults over 50. Limitations such as prior surgery or joint injury should be taken into consideration, as well as history of hypermobility; a five-point questionnaire was developed for this purpose (Table 3).⁹² A “yes” answer to two or more of the questions would suggest joint hypermobility and add one additional point to the Beighton score.⁷⁴ For criterion 2, patients must meet two or more of the following; must have systemic manifestations of a more generalized connective tissue disorder, positive family history and/or musculoskeletal complications. Criterion 3 requires all of the following: absence of unusual skin fragility that would prompt consideration for another type of EDS, exclusion of other heritable and acquired connective tissue disorders, exclusion of alternate diagnosis that may also include joint hypermobility.⁷⁴

TABLE 2.

EDS diagnostic checklist listing the three main criterion

Criterion 1: Generalized joint hypermobility

Beighton score:

≥6 in prepubertal children and adolescents

≥5 in pubertal men and women up to age 50

≥4 men and women over the age of 50

If one point below cut off two or more “yes” answers to the five point questionnaire should be considered (Table 3).

Criterion 2: Two or more of the following features (A, B, or C) must be present

Feature A (five must be present):

•  Unusually soft or velvety skin

•  Mild skin hyperextensibility

•  Unexplained striae distensae or rubae at the back, groin, thighs, breasts and/or abdomen in adolescents, men or prepubertal women without a history of significant changes in weight

•  Bilateral piezogenic papules of the heel

•  Recurrent or multiple abdominal hernias

•  Atrophic scarring involving at least two sites without the formation of papyraceous and/or hemosideric scars

•  Pelvic floor, rectal and/or uterine prolapse in children, men or nulliparous women without history of morbid obesity or predisposing medical condition

•  Dental crowing and high or narrow palate

•  Arachnodactyly (positive Walker sign or Steinberg sign on both sides)

•  Arm span to height ratio ≥1.05

•  Mitral valve prolapse

•  Aortic root dilatation with Z-score >+2

Feature B:

•  Positive family history (one or more first degree relatives meeting current criteria for hEDS)

Feature C (must have at least one):

•  Musculoskeletal pain in two or more limbs, recurring daily for at least 3 months

•  Chronic, widespread pain for ≥3 months

•  Recurrent joint dislocations or joint instability in the absence of trauma

Criterion 3: All of the following must be met

•  Absence of unusual skin fragility, which should prompt consideration of other types of EDS

•  Exclusion of other heritable and acquired connective tissue disorders. In patients with an acquired connective tissue disorder, additional diagnosis of hEDS requires meeting both features A and B of criterion 2. Feature of criterion C cannot be counted in this situation

•  Exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity. Alternative diagnoses may include: neuromuscular disorders (e.g., Bethlem myopathy), other hereditary connective tissue disorders (e.g., Loeys-Dietz syndrome, Marfan syndrome, other types of EDS) and skeletal dysplasias (e.g., osteogenesis imperfecta)

TABLE 3.

The five-point questionnaire⁹¹

1. Can you now (or could you ever) place your hands flat on thefloor without bending your knees?

2. Can you now (or could you ever) bend your thumb to touchyour forearm?

3. As a child, did you amuse your friends by contorting yourbody into strange shapes or could you do the splits?

4. As a child or teenager did your shoulder or kneecapdislocated on more than one occasion?

5. Do you consider yourself double-jointed?

Although a Marfanoid habitus is known to be associated with Marfan syndrome, it is commonly seen in other heritable disorders of connective tissue. Arm span to height ratio, upper segment to lower segment ratio, high or narrow palate, dental crowding, ectopia lentis, and pes planus are commonly evaluated in hEDS. Arachnodactyly, or spider fingers, is also common in Marfanoid habitus and a sign of connective tissue disorders.⁹³ The Steinberg sign, also known as the thumb sign, in which the thumb extends past the palm of the hand in a closed fist and Walker-Murdoch, or wrist sign, in which the thumb and fifth finger overlap around the wrist are typically used to asses arachnodactyly. The Beighton criteria was designed to be a nonsubjective measurement of joint hypermobility but is often criticized for not including other relevant joints where hypermobility may be present. It is recommended that other joints that are commonly affected in patients with hEDS, such as the hips and shoulders, are not excluded during clinical assessment.⁷⁴

De Wandele et al emphasized that nonmusculoskeletal complaints are extremely common in hEDS and greater awareness of the heterogeneity of symptoms is necessary for diagnosis and treatment.⁹⁴ It is essential that physicians recognize signs of hypermobility and ligament laxity early on and make necessary recommendations and referrals to prevent chronic joint damage and complications of the disease. Patients who do not meet enough criteria for hEDS are often diagnosed with HSD or may lose a previous diagnosis after the new 2017 criteria, despite hEDS/HSD being indistinguishable in regard to severity of symptoms.^95,96 Because of this, the 2017 diagnostic criteria have received much criticism.⁹⁵

4 |. PHENOTYPE

Hypermobile EDS presents heterogeneously and varies in degree of severity. Multiple body systems may be impacted, and the presence of several comorbidities is common, including widespread chronic pain, autonomic dysfunction, mast cell activation syndrome (MCAS), psychological disorders and gastrointestinal dysfunction. The natural history of hEDS progression has been described by Castori et al, in a continuum of three overlapping phases.⁸⁸ The first includes ligament laxity in children without complaining of pain, despite sometimes frequent dislocations and subluxations, occasionally, problems persist and lead to complaints of pain. The second phase is termed the pain phase which begins in the 20s, where joint hypermobility may decrease but pain worsens. The third phase, stiffness phase, is later in life and results in limited joint motion and reduction of vertebral curves with chronic pain.⁸⁸

4.1 |. Musculoskeletal manifestations

The main features of hEDS consist of musculoskeletal complications resulting from hypermobility and joint instability. Hypermobility of the joints is due to laxity of ligaments, joint capsules, and tendons.⁹⁰ Instability can occur in any joint and can lead to early complications such as subluxations, dislocations, sprains, soft tissue lesions and later complications such as tendonitis, tendon ruptures, muscle and ligament tears, muscle tension and spams, osteoarthritis and chronic joint pain in both children and adults.^{74,88,97–100} It is not uncommon for patients to have multiple joint complications occurring simultaneously or for patients to experience a domino effect of existing instability impacting surrounding joints.⁹⁹ Recurrent dislocations are not uncommon, but reduction may occur spontaneously and without difficultly.¹⁰¹ Ligament laxity has been indicated in soft tissue lesions such as ganglion cysts.¹⁰² Other soft tissue lesions may include molluscoid pseudotumors, spheroids, and piezogenic papules.^74,103

There have been conflicting studies suggesting that hEDS may lead to an increased incidence of fractures or lower bone mineral density (BMD). Infants with EDS were found to have no increased fracture risk, while ambulatory older children with EDS had an increased risk.¹⁰⁴ Unlike other connective tissue diseases such as osteogenesis imperfecta (OI), there is little evidence to suggest that hEDS alone should be viewed as a brittle bone disease or as an explanation for multiple fractures presenting in infants or children.^105,106 Focusing on adults, it was found that vertebral fractures have been reported at a higher incidence in hEDS and classical EDS (cEDS) patients.¹⁰⁷ In further studies, when evaluating a patient population with hEDS or cEDS, reduced bone mineral density and a higher prevalence of general bone fractures have been reported,^108,109 but normal BMD and increase in vertebral fractures was also reported. ¹⁰⁷ EDS has been indicated to have no influence on bone fragility or fracture healing as well.¹⁰¹ However, in a Chilean population with JHS, 26% of patients had osteoporosis, but interpretation of this data is confounded by the absence of a reported control population for comparison.¹¹⁰ Additionally, altered proprioception and gait mechanics may lead to an increased susceptibility of falls, accounting for the reported fracture incidence. It is also possible that patients with hEDS have lower bone mineral density due to deconditioning, rather than a direct mechanism influencing bone integrity.

4.2 |. Cutaneous/dermatological

Skin hyperextensibility is seen in many types of EDS but typically to a lesser degree than is observed in hEDS or cEDS.^111,112 Soft, velvety skin is a common feature of hEDS, and reduced dermal thickness and increased skin fragility has been reported in hEDS and cEDS patients.^74,112,113 Wound healing defects may be present and may cause atrophic scarring.^74,111 Unexplained striae without significant changes in weight may occur.^74,114 Capillary fragility causes frequent bruising with delayed resolution and deep vessel fragility can result in subcutaneous and intramuscular hematomas.¹¹¹ Patients also present with peizogenic papules (small subcutaneous fat herniations through the dermis) in the heels and wrists.^74,111 Additionally, keratosis pilaris has been reported in the hEDS population and can present in other EDS types as well.¹¹¹ Alterations in sweating, such as hypohidrosis or hyperhidrosis, are seen in some patients and may be due to an underlying autonomic dysfunction.¹¹¹

4.3 |. Gynecological manifestations

Gynecological manifestation of hEDS can range from pelvic organ prolapse (POP), to pregnancy and menstrual cycle complications. In a small sample of patients with unspecified EDS subtypes, patients experienced both urinary incontinence and history of POP.¹¹⁵ POP has also been found to be more common in patients with benign joint hypermobility syndrome.^115,116 In a patient-reported survey, infertility issues have been reported in 44% of patients with EDS, hEDS was the most affected type of EDS compared to 10% of general population.¹¹⁷ Spontaneous abortions have been reported in 28% of hEDS patients and 57% of EDS patients while impacting only 15% of the general population.^117,118 Despite some evidence of pregnancy complications, including prelabor membrane rupture, preterm labor and failure to progress in labor,¹¹⁹ other published data indicates that hEDS/JHS are associated with a normal risk of serious adverse pregnancy outcomes.¹²⁰

An increase in dislocations and symptoms at puberty, during pregnancy, postpartum and during the perimenstrual period have both been reported along with an improvement after menopause.^117,118 In the general population, ligament laxity has been shown to be influenced by estrogen, progesterone, relaxin and testosterone and has been best evaluated in the context of anterior cruciate ligament (ACL) injury in females. Knee ligament laxity and risk of ACL injury occurs more frequently during preovulatory phase and ovulatory phase of the menstrual cycle, when estrogen exceeds progesterone.^121–123 Hormonal contraceptives have been found to have a possible protective role in ACL tears.^122,124,125 The influence of hormones on ligament laxity, combined with patient-reported fluctuations in symptoms that coincide with hormonal shifts, indicate that more research is needed to establish the role of hormones in hEDS.

4.4 |. Ocular manifestations

Present in many heritable disorders of connective tissue, ocular involvement may occur in hypermobile EDS as well. Ocular involvement is typically milder in hEDS than other heritable connective tissue disorders. Thin, blue sclerae, angioid streaks, retinal detachment, ketatoglobus, keratoconus, and lens subluxation or dislocation may occur in hEDS but are more frequently reported in other connective tissue disorders.^110,126,127 Myopia is more common in the hEDS population and can be severe.¹²⁷ Stromal keratocytes are also more prevalent in hEDS patients than the general population, along with xerophthalmia (dry eye).¹²⁷ It has been suggested that an underlying autonomic nervous system dysfunction could be impacting tear production or, alternatively, tear production may be reduced due to alterations in the extracellular matrix of the lacrimal gland.^110,127 Increased eyelid laxity and prominent folds of the upper eyelid skin are also common in patients with hEDS and JHS.¹²⁸ Patients with EDS may also have an increased risk of surgical complications in ophthalmological surgeries.¹²⁹ The presence of ectopia lentis (ocular lens dislocation) should raise suspicion for other conditions, such as Marfan syndrome.

4.5 |. Oral and mandibular manifestations

Oral and mandibular manifestations, resulting from compromised oral soft tissue and orofacial structures, have been identified among hEDS patients.^96,130 Dental crowding and high or narrow palate are common features of hEDS included in the current diagnostic criteria.⁷⁴ Compromised soft tissue and orofacial structures among hEDS patients may be attributed to the altered production and organization of collagen, subsequently affecting oral mucosa and periodontium.^111,131 The increased fragility of mucosal tissue, capillaries, and perivascular connective tissues¹³² should be anticipated during dental procedures for hEDS patients, due to the high incidence of injury from oral appliances.¹³³ Compromised oral soft tissue may also present as periodontal recession, which may be exacerbated by accelerated tooth mobility among hEDS populations.^134,135

Early onset periodontitis is prevalent among a variety of EDS subtypes, inclusive of the periodontal form (type VIII).¹³⁶ Periodontal abnormalities may be considered a nonspecific consequence of heritable connective tissue disorders of various subtypes.¹³⁶ Early onset periodontitis among hEDS patients may be attributed to compromised oxygen and nutrient diffusion, resulting from abnormal composition of the extracellular matrix, therefore increasing susceptibility to bacterial pathogens.¹³¹

Alterations to the composition of the extracellular matrix subsequently compromise the ability of the extracellular matrix (ECM) to maintain tissue homeostasis and diffuse oxygen, nutrients, and other small molecules.¹³⁷ This may consequentially effect overall tissue health, and may play a role in general and regional anesthesia complications.¹³⁸ Insufficient effects of local anesthetics are not uncommon and can range from no analgesic affect to shortened affect, mostly reported at the dentist.^139,140 The precise mechanism of partial or complete failure of local anesthesia among hEDS patients is not fully understood; however, some patients experienced analgesic effects with the use of intradermal lidocaine,¹³⁹ although effects lasted for shorter durations than control groups.¹³⁷

Anatomical abnormalities in orofacial structures have been identified in hEDS populations, such as the absence of lingual and inferior labial frenula.^141,142 Subluxations and dislocation of the temporomandibular joint, along with temporomandibular disorders (TMD) are a significant occurrence in hEDS patients,^143–146 which may be attributed to vertebral posture and cervical functions of the head and neck.¹⁴⁷ As craniocervical instability has been noted among hEDS populations, muscle spasms bordering the anterior, posterior, and suboccipital triangle muscles may result in the overuse and spasm of mastication muscles, sequentially resulting in subluxation of the temporomandibular joint.¹³¹

4.6 |. Cardiovascular and autonomic dysfunction

Cardiovascular dysfunction among hEDS patients is often attributed to autonomic dysfunction, typically presenting with a constellation of both cardiac and noncardiac symptoms including tachycardia, positional hypotension, gastrointestinal dysmotility, disturbed bladder function and sweating regulation.¹⁴⁸ Highly debilitating symptoms in hEDS patients may be attributed to compromised autonomic function, presenting as postural orthostatic tachycardia syndrome (POTS), vasovagal syncope or neurally mediated hypotension (NMH), orthostatic hypotension (OH), and orthostatic intolerance.^148,149 Recent estimates on the prevalence of both hEDS and POTS in a small study with 91 patients revealed 24% of POTS patients had generalized joint hypermobility without fully meeting clinical criteria for hEDS, while 31% of POTS patients did meet hEDS criteria.¹⁵⁰ Prior to this, the estimated prevalence of hEDS in POTS patients was between 15% and 22%,^151–153 while hypermobility spectrum disorder in POTS patients was seen at 35%.¹⁵³

The association between cardiovascular autonomic dysfunction and hEDS is not well understood, although several plausible mechanisms have been suggested in accordance with clinical experience. Possible mechanisms for cardiovascular autonomic dysfunction among hEDS patients include: low blood pressure, increased peripheral venous dilation and blood pooling, elevated circulating catecholamines, excess systemic levels of histamine, and brainstem or cervical cord impingement attributed to Chiari malformations or craniocervical instability.¹⁴⁸ Rowe et al also proposed that connective tissue laxity in hEDS increases vascular and venous compliance, impacting vasoconstriction and venoconstriction when upright.¹⁵⁴ More recently, work by Miller et al,¹⁵⁰ has supported increased arterial elasticity in these patients as a plausible reason for lower blood pressure and cardiovascular complications, although more work is still needed in this area.

Cardiac valve abnormalities, including mitral valve prolapse (MVP), may occur in patients with hEDS and is considered in the diagnostic criteria (Table 2).^74,88,155 Aortic Root dilation (ARD) is also included in hEDS diagnostic criteria and has been reported to occur in some individuals with hEDS (Table 2).^74,155–157 In a study of 15 patients evaluated with joint hypermobility syndrome, 13 were found to have increased aortic compliance that correlated with an increase in age and 10 were identified as having MVP.¹⁵⁸ Despite the inclusion of MVP and ARD also in hEDS diagnostic criteria, they are not seen as frequently as in connective tissue disorders with vascular complications such as vascular Ehlers-Danlos syndrome (vEDS), cEDS, Marfan syndrome, and Loeys-Dietz syndrome.¹⁵⁹

In retrospective chart review of adults age 15 and older with hEDS, BJHS and cEDS, 6.4% and 1.6% were found to have MVP and ARD (Z-score ≥2), respectively.¹⁶⁰ Inclusion criteria for the study were based on a diagnosis of EDS, cEDS or BJHS and at least one echocardiogram. This study had several limitations including a change in diagnostic criteria during the study period, variability in clinician interpretation of echocardiograms and the timing of echocardiogram evaluation. Cardiac abnormalities like MVP and ARD typically develop later in life and echocardiography at an early time point in some of these patients may not reflect their current cardiac pathology.

Pediatric patient data suggests that ARD and MVP are less common in hEDS than previously reported with MVP occurring in less than 1% of patients and no ARD identified in the hEDS cohort.¹⁶¹ In the same study, there were no vascular abnormalities reported in vEDS patients. Routine echocardiography may only be necessary in patients with cardiac symptoms or family history of aortic disease or MVP.¹⁶¹ Another vascular pathology, Raynaud’s phenomenon, is correlated with joint hypermobility and EDS, as well as other connective tissue disorders.^{88,96,101,110,162} Raynaud’s phenomenon is a recurrent vasospasm that occurs due to stress or cold temperatures, leading to decreased blood flow to the fingers or toes. Raynaud’s phenomenon is also reported in more than half of POTS patients.¹⁶³ However, acrocyanosis may also be a plausible explanation for similar symptoms in this patient population.^88,101,164

4.7 |. Immunological manifestations

Non-IGE mediated hypersensitivity, such as histamine intolerance and mast cell activation disorders, often referred to as mast cell activation syndrome (MCAS) are comorbid clinical manifestations among hEDS patients.^165–167 Mast cells that reside in the connective tissue produce tryptase, while mast cells in the gut secrete both tryptase and chymase.¹⁶⁵ Mast cell activation disorders are described as an increased number of mast cells, increased mast cell activity, or both. This leads to abnormal degranulation in the presence of inappropriate stimuli and can potentially impact all organ systems.¹⁶⁷ Histamine, tryptase and chymase are the main chemical mediators released by mast cells that may lead to allergy-like symptoms in patients. Elevated serum tryptase is often used in the diagnosis of MCAS.¹⁶⁵ However, symptoms may occur alongside normal plasma histamine and serum tryptase levels; for this reason, diagnostic criteria is initially suspected on clinical grounds, in the presence of symptoms including flushing, cholinergic urticaria, angioedema, hypotension, diarrhea, and rhinitis¹⁶⁵ Patients often experience fluctuations in the frequency, duration, and intensity of symptoms, with trends of increasing intensity.

Mast cells are known to modulate connective tissue metabolism. Both chymase and tryptase positive cells have been identified in the papillary dermis of patients with signs of connective tissue dysplasia, mimicking hEDS symptoms.¹⁶⁸ Although tryptase positive cells were similar in numerical density in the patient and control groups, chymase positive cells had significant increased density in the patient group.¹⁶⁸ Increased chymase positive mast cells in the skin of those with connective tissue dysplasia may be a compensatory mechanism to increased collagen.¹⁶⁸ Along with MCAS, asthma is prevalent among hEDS/HSD patients.¹⁶⁹

4.8 |. Gastrointestinal

Hypermobile EDS diagnostic criteria is consistently limited to skin fragility or elasticity and hypermobile joints.² Due to the emphasis on specific joint and skin elasticity, diagnostic criteria for hEDS frequently neglects gastrointestinal manifestations, despite their high prevalence.¹⁷⁰ The frequency of gastrointestinal symptoms is higher than previously assessed among hEDS patients. While GI symptoms experienced by affected individuals are primarily functional and nonlife threatening in nature, their impact upon the patient’s quality of life is significant. Clinical assessment of gastrointestinal symptoms associated with hEDS should be constructed to address diagnosed and under-treated gastrointestinal complaints among hEDS patients.¹⁷⁰ Gastrointestinal complaints are common in EDS and generalized joint hypermobility.^88,171–173 Abdominal pain, bloating, nausea, reflux symptoms, vomiting, constipation and diarrhea are commonly experienced GI symptoms.¹⁷¹ In a widespread survey inquiring about GI symptoms among hEDS populations, 79.3% of participants reported gastroesophageal disease (GERD), 48% reported symptoms congruent with irritable bowel syndrome, and 36% reported motility issues, specifically functional constipation.¹⁷⁰ Dysmotility and delayed gastric emptying (gastroparesis) was highly reported, which may be attributed to the high prevalence of dysautonomia among hEDS patients.^171,174

Gastrointestinal physiological studies by Mayo Clinic surveyed 36 EDS patients of various subtypes, a majority of whom presented with type III (hypermobile type): 28% of patients who underwent colonic transit studies had abnormal results, with either slow or fast transit.¹⁷² There is currently no standardized clinical assessment nor care guidelines for the management of hEDS-related gastrointestinal symptoms.¹⁷⁴ Anatomical abnormalities among hEDS patients may be attributed to structural changes in collagen located in the smooth muscle of gastrointestinal pathology, presenting as diverticulosis, rectoceles, and prolapse. Celiac disease is also reported to be more prevalent in hEDS.¹⁷⁵ Recurrent abdominal pain, chronic gastritis and constipation/diarrhea was reported by hEDS patients.¹⁷⁶

4.9 |. Neurological manifestations

Neurological manifestations can be serious in hEDS and may require surgical intervention. Chiari malformation Type I may occur in hEDS patients and can be associated with recurrent cerebrospinal fluid leak.^177,178 Spinal instability is also prevalent and may present in various ways. Atlantoaxial instability (AAI) and craniocervical instability (CCI) are spinal manifestations directly due to ligament laxity.¹⁷⁹ Additionally, spinal instability in the form of spondylolisthesis was reported in 10% of patients.¹⁰⁰ Cervical and thoracic instability and discopathy in EDS can lead to a loss of the normal cervical lordosis and myelopathy.¹⁷⁹ Scoliosis, neck and back pain are also expected in hEDS.¹⁰⁰ Tethered cord syndrome (TCS) may also be present in EDS due to abnormalities in filum terminale, although the exact prevalence of TCS in the EDS population is unknown.¹⁷⁹

It has been suggested that neuropathic pain in EDS is associated with axonal polyneuropathy and compression neuropathy.¹⁸⁰ Nerural conditions such as small fiber neuropathy¹⁸¹ and peripheral nerve entrapments may develop.¹⁸² Brachial plexopathies and sciatic neuropathies have been reported in EDS and may require surgical decompression.^99,183–185 It is possible that dislocations and subluxations due to ligament laxity may stretch or apply pressure to peripheral nerves resulting in neuropathy or plexopathy.¹⁸⁶ Headache and migraine were shown to be commonplace hEDS patients.^187–189 Headache may be a result of ligament laxity and AAI and CCI, or a separate entity. Potential associations between Idiopathic intracranial hypertension and EDS may also be related and can contribute to headaches.¹⁷⁹

4.10 |. Sleep, fatigue, pain, and psychological impact

Chronic fatigue and chronic pain are prevalent in hEDS.^{173,189–193} Poor sleep quality, pain, orthostatic intolerance, physical deconditioning and muscle weakness may be possible causes for chronic fatigue.^154,194,195 Joint pain is often associated with subluxations, degenerative joint disease and hypermobility but can be both acute and chronic.^{189,196–198} About one third of children with hEDS reported chronic back pain, arthralgias and myalgias, which increased to two thirds of patients by age 20 and almost all patients over age 40, indicating that pain progresses over time.^176,189 A significant number of patients with fibromyalgia have joint hypermobility.^199,200 The relationship between joint hypermobility and fibromyalgia may be relevant in widespread pain. An increased sensitivity to pain, generalized hyperalgesia, has also been reported in hEDS and HSD.²⁰¹ When investigating pain in hEDS patients, Leone et al recently revealed that hEDS patients may have a deficit in endogenous pain inhibitory control.²⁰²

Sleep problems such as insomnia and poor sleep quality are common in children and adults with hEDS.^203–205 In 26% to 42% of children and 32% of adults, obstructive sleep apnea has been reported.^203,206,207 Psychological manifestations of hEDS have been focused mainly on anxiety and depression, which have both been described in hEDS/JHS patient population.^208–210 It is unknown whether these are a result of living with a chronic disorder and pain, or if there is another explanation for the relationship. Chronic pain, mood disorders, anxiety, disordered sleep, and comorbid conditions can have significant impacts on social life, and overall quality of life. Poor quality of life has been reported by children and adults with hEDS/JHS.^{190,205,211,212} A proposed association between joint hypermobility and neurodevelopment disorders including autism spectrum disorders (ASD), has been suggested.^213,214 Immune mediated and endocrine mediated symptoms were also reported to occur at a higher rate in patients with ASD and hEDS than ASD alone.²¹⁵

4.11 |. Development and proprioception

Often, EDS is first noticeable during childhood. Although all babies are hypermobile, there may be some signs of EDS during infancy. Children may delay in walking and have coordination issues and clumsiness.^216,217 Clumsiness was reported by almost half of hEDS patients regardless of age.¹⁷⁶ Because many patients have muscular hypotonicity due to ligament laxity, babies might be diagnosed as “floppy infant,” where EDS as a differential diagnosis should be considered.¹⁰¹ Hypotonia is often accompanied by poor postural control and impaired proprioception. Poor postural control has been described in EDS and joint hypermobility due to excess joint movement as stretched or lax ligaments are unable to align the body properly.^218–220 This can lead to abnormal stress on the joints, pain and long-term musculoskeletal complications.²²¹

Proprioception is necessary for maintaining joint stability. Proprioceptive impairment is very prevalent in hEDS/JHS and has been shown to be correlated with patients’ Beighton score in some cases, but not in others.^222–226 Abnormal, nonphysiological gait pattern has also been observed in hEDS/JHS due to biomechanical consequences of hypermobility and is associated with an increased frequency of falls.^220,227

5 |. GENETICS

The genetic basis for most of the EDS subtypes are well characterized and were initially discovered to be involved in production and processing of the collagen extracellular matrix (ECM). More recently, the discovery of the genetic etiology of several subtypes has revealed that not all types are directly involved in collagen biosynthesis (Table 1). However, for the majority of EDS genes, their involvement in the synthesis, folding, transport and post-translational modification of ECM components, namely collagen, tenascin, proteoglycans and dermatan sulfate overwhelmingly points to ECM alterations as a generalized theme in EDS pathogenesis. Hypermobile EDS, on the other hand, has challenged researchers and very little is known about the underlying biology. An autosomal dominant pattern of inheritance has been observed, however, at this time there have been no definitive gene candidates identified.

The genetic etiology of hEDS is largely unknown. A few reports have been published identifying gene variants involved in hEDS, but the majority of hEDS cases are of unknown genetic origin. A mutation in COL3A1 in a single family with autosomal dominant hEDS phenotype was identified that led to reduced collagen secretion and over modification of collagen.⁴⁰ The family’s affected individuals had a glycine 637 to serine substitution in COL3A1, similar to what has been observed in vEDS; however, patients lacked vascular phenotype. There have been no other reports of this COL3A1 variant in hEDS. As compared to those with a clinical diagnosis of vEDS, those with a pathogenic variant in COL3A1 were less likely to have hypermobility.

In a multigenerational Belgian family with hEDS phenotype, genome wide linkage analysis identified a chromosomal locus, 8p22–8p21.1 A heterozygous missense variant in the LZTS1 gene was confirmed in all affected individuals and none of the unaffected. Screening of hEDS patients revealed 3 additional LZTS1 variants.⁵² LZTS1 encodes leucine zipper tumor suppressor 1, and pathogenic variants in this gene are associated with several types of cancer. Other potentially more plausible candidate genes in this chromosomal locus were tested, but excluded when analyzed more closely. To date, data supporting the role of LZTS1 in hEDS is very limited and lacks conclusive evidence for its involvement in connective tissue biology. Additional research is needed to determine the pathogenicity of these variants and care should be taken to extrapolate causation between this gene and disease phenotype.

More recently, Lyons et al revealed that copy number alterations in TPSAB1, encoding alpha-tryptase was found to be associated with increased basal serum tryptase levels in 35 families with symptoms related to autonomic dysfunction, gastrointestinal disorders, allergic and cutaneous symptoms, and connective tissue abnormalities.²²⁸ A gene dose effect relating to copy number and basal serum tryptase levels was also reported. However, not all affected individuals met diagnostic criteria for dysautonomia, MCAS or hEDS and elevated basal serum tryptase is considered relatively common in the general population.

Tenascin X is an extracellular matrix protein that is important for collagen organization. It is encoded by the TNXB gene. TNXB is part of the complex RCCX module, composed of RP1, RP2, C4A, C4B, CYP21A2 and pseudogene CYP21AP, TNXB and pseudogene TNXA. The RCCX module contains pseudogenes, tandem copy number variation and promotes gene rearrangements and deletions. Tenascin X deficiency has been indicated in a recessive form of EDS in which patients meet major and minor diagnostic criteria of classical EDS.²²⁹ The Tenascin X deficient patients were found to have truncating mutations or deletions in TNXB.^229,230 This has since been reclassified as classic-like EDS, a rare, autosomal recessive type of EDS.²³¹ Some other point mutations in TNXB have also been suggested to cause hEDS or classic-like EDS (clEDS).^231–233 TNXB haploinsufficiency has been identified in patients with an autosomal dominant form of hEDS who did not have the easy bruising and skin hyperextensibility as seen in TNX deficient EDS.²³⁴ Patients with TNX haploinsufficiency and point mutations have distinct abnormalities in elastic fibers and normal collagen appearance.²³³ It is likely that this only represents a small group of patients with hEDS.²³⁴ Interestingly, in a small study, there was evidence to indicate that some hEDS/JHS patients may have reduced serum TNX concentration compared to healthy controls, without any discernible mutations in TNXB.²³⁵ Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder causing 21-hydroxylase deficiency. Some patients with CAH will have a mutation or deletion in CYP21A2 that also affects TNXB, leading to contiguous deletion syndrome (CAH-X).²³⁶ TNXA/TNXB chimeras have been identified in which TNXB exons are replaced with TNXA.^236–238 These patients have phenotypic characteristics of both hEDS and CAH. The tenascin x protein has been proposed to be essential for collagen I deposition by dermal fibroblasts and important for maintaining the distance between collagen fibrils by forming bridges through direct interactions with collagen fibrils.^239–242

6 |. MOLECULAR BIOLOGY

6.1 |. Collagen fiber analysis

Collagens are among the most abundant proteins in the body and a major component of skin, bone, tendons and ligaments. Collagens are an integral part of the ECM and provides structure and support throughout the body. Fibrillar collagens are transcribed as three alpha chains which are then modified and assembled into a triple helical conformation known as procollagen. After further modification by enzymes like lysyl hydroxylase and procollagen peptidase, the collagen fiber is then incorporated into a cross-linked fibril that is part of the ECM. Collagen fibril analysis has been performed on patient dermal biopsies to investigate possible changes in collagen structure and appearance but has provided limited information in regard to hEDS.

Dermal biopsies have shown a wide variety of findings and many of the studies were performed prior to recent reclassification of EDS subtypes. In one study, biopsies were examined for collagen structure among people who clinically appeared to have EDS I, II or III and were then grouped based on collagen appearance and patient phenotype. It is important to note that this was prior to the discovery of variants related to classical and classic-like EDS so patients were characterized based on clinical phenotype alone. Some patients presented with “flower-like” collagen cross sections and “rope-like” longitudinal sections. In other patients who were more mildly affected with joint hypermobility and lacked hypertrophic scars, the dermis appeared normal.²⁴³

Flower-like collagen fibrils and collagen fibril abnormalities, including reduced collagen fibril thickness and disarray of fibrils, were found in some patients with hEDS and patients with low Beighton scores.^244–248 There was evidence that abnormal collagen appearance did not always correlate with the degree of hypermobility.^246,248 Yet, many patients do exhibit decreased collagen I to collagen III ratios.²⁴⁸ Conflicting evidence on elastic fiber changes has been reported, indicating both changed and unchanged elastic fibers.^246,247,249 Angwin et al, recently published transmission electron microscopy findings that revealed no specific collagen abnormalities associated with any subtype of EDS, except collagen flowers in most patients with cEDS.²⁵⁰ Eighty-six of ninety patients diagnosed with hEDS had what were considered normal biopsy appearance by transmission electron microscopy (TEM), despite some variations in collagen and elastin, possibly due to age variation of the patients evaluated.²⁵⁰ To date, collagen structure analysis is mostly outdated and provides limited information on the pathophysiology of hEDS. Additionally, most of the studies investigating extracellular matrix structure have focused only on collagen and elastin structure, specifically by TEM. There is a strong need for further investigation of ECM components and analysis of fibroblasts of hEDS patients.

6.2 |. The ECM and integrins

Integrins are vital components of ECM adhesion. They link the ECM proteins to the cytoskeleton and serve as mechanotransducers for various cellular process, including development, cell proliferation, cell movement and tissue homeostasis. Various types of EDS have shown changes in αvβ3, α5β1, and α2β1 integrin expression in dermal fibroblasts isolated from patients.^{231,251–254} The αvβ3 integrin is widely expressed in endothelial cells, which interacts with several proteins including vitronectin, laminin, fibronectin, fibrillin as well as collagen. Recruitment of αvβ3 integrin is also an indicator of fibroblast activation. The α5β1 integrin and α2β1 integrin are involved in ECM organization of fibronectin and fibrillar collagens, respectively.

In a small study of four hEDS and six HSD patients, dermal biopsies from both were reported to have a “myofibroblast-like” phenotype, exhibiting organized α-smooth muscle actin, increased cadherin-11 expression, αvβ3 integrin expression and enhanced cell migration. Additionally, the fibroblasts showed a decreased in CCN1/CYR61 and increased CCN2/CTGF in both hEDS and HSD compared to controls, along with an increase in MMP-9 that could help explain ECM abnormalities. ILK was found to be localized mainly in focal adhesions in hEDS and HSD cells and coimmunoprecipitated with αvβ3 integrin, suggesting they may form a complex that promotes α-smooth muscle actin assembly in hEDS/HSD. Snail1/Slug was found to be increased in expression in hEDS/HSD and localized in the cytoplasm and nucleus. Coimmunoprecipitation with αvβ3 integrin and ILK indicated Snail1/Slug enables the fibroblast to myofibroblast transition in hEDS/HSD cells through an αvβ3 integrin—ILK mediated interaction.²⁵⁵

6.3 |. Gene expression analysis

Transcriptome-wide expression analyses from five female patients’ fibroblasts with hEDS/JHS has identified numerous differentially expressed genes in pathways involved in composition and homeostasis of connective tissue (e.g., FNDC1, GPC4, MMP16, SPON2, SULF1, TGM2), inflammation (e.g., CFD, COLEC12, IGSF10, IL11, IL6, NFKBIA), cell adhesion (e.g., CLDN11, DSP, FLG, ITGA4, ITGA2, CDH10, CDH2, PCDH9, PCDHB16, PCDHB8), signal transduction (e.g., AQP9, CHRM2, CLIC2, KCNQ5, OPCML, PRLR, SLCO2A1, NPR3), and redox homeostasis (e.g., ADH1B, ADH1C, AKR1C3, GSTM5).²⁵² This study was limited in its small sample size but can guide future research to understand the pathogenicity of hEDS.

Gene expression was also investigated in women with generalized joint hypermobility. The authors found that serum levels of zinc, strontium and lithium were altered in generalized joint hypermobility (GJH) patients, along with several differentially expressed genes. GJH patients had lower COL1A1 and COL1A2. Contrary to other studies, GJH patients had higher TNXB than controls. Additionally, B3GALT6, encoding for galactosyltransferase II was elevated, while B4GALT7, also involved in galactosyltransferase was reduced compared to health controls. Recessive mutations in both B3GALT6 and B4GALT7 have been implicated in Spondylodysplastic EDS. Dermatan sulfate epimersase-1 (DSE) was found to be reduced in GJH patients and is important for biosynthesis of iduronic acid blocks which is indicated in Musculocontractural EDS. Mutations in FKBP14 are causative for kyphoscoliotic EDS and expression of FKBP14 was reduced in GJH patients. SLC39A13 which encodes a Zn exporter ZIP13, which plays a role in connective tissue development, was increased in GJH patients. Spondylodysplastic EDS is also associated with mutations in SLC39A13.⁶⁵ Further research on gene expression and serum levels may help to identify biomarkers for hEDS.

An overall view of EDS gene expression is presented in Figure 1 and detailed gene mutational analyses for each EDS subtype are presented in Table 1. While many of the collagen genes are abundantly expressed, some of the EDS genes display more specific spatial distribution. For example, Fkbp14 and Plod1, which cause kyphoscoliotic EDS are most abundantly expressed in the developing spinal column. Additionally, C1S, as part of the complement system, is expressed primarily in the developing craniofacial structures and may help explain some of the phenotypes related to oral-mandibular conditions in patients with periodontal EDS (pEDS). Interestingly, collagen 5α2 and to a lesser extent collagen 3α1, which cause classical and vascular EDS, respectively display unique neurological patterns not observed with the other genes, and may play a role in pain accentuation, pain management and/or migraines in this subset of patients.

FIGURE 1.

Section in situ hybridization of EDS genes. Messenger RNA expression of EDS genes on sagittal mouse sections at E14.5. Purple staining reveals expression of mRNAs showing widespread expression of EDS genes in regions of connective tissue development. Numbers correspond to specific anatomical locations (red: neural tissues, teal: craniofacial tissues, yellow: thoracic/abdomen tissues). 1, Roof of midbrain; 2, mesencephalic vesicle; 3, ventral part of midbrain; 4, pons; 5, choroid plexus within central part of lumen of fourth ventricle; 6, dorsal part of medulla oblangata; 7, upper lip; 8, Meckel’s cartilage; 9, dorsal surface of tongue; 10, cartilage primordium of nasal bone; 11, right ventricle of the heart; 12, aortic valve and ascending aorta; 13, mitral valve; 14, cartilage primordium of the palatal shelf; 15, lower thoracic dorsal root ganglion; 16, apical part of caudal lobe of right lung; 17, right dome of diaphragm; 18, diencephalon; 19, median circumvallate papilla/cartilage primordium of basisphenoid bone; 20, evidence of ossification within cartilage primordium of basioccipital bone (cilvus); 21, lumen of urogenital sinus (future bladder); 22, liver; 23, costal cartilage of ribs

6.4 |. Model systems

Mouse models have provided insight into the underlying molecular biology of some EDS subtypes revealing abnormal ECM synthesis, deposition, and/or organization.^256,257 For example, a conditional knockout of Col5a1 in tendon and ligaments resulted in joint laxity, abnormal gate and early onset osteoarthritis associated with abnormal collagen structure and organization.²⁵⁸ Additionally, knocking out a known gene for mcEDS in mice, CHST14, provided functional evidence for the glycosaminoglycan, dermatan sulfate, in connective tissues.²⁵⁹ More recently, knock in mice with heterozygous mutations in Col3a1 mimicking patient genetics, revealed abnormal signaling through the PLC/IP3/PKC/ERK pathway and that inhibition of these targets may prevent death due to aortic rupture.²⁶⁰ Despite TNXB not encoding for collagen or any enzyme involved in collagen modification, it was revealed to play a role in collagen deposition though studies involving inactivation of Tenascin-X in a murine model of EDS.²⁴⁰ Tenascin-X knockout mice also exhibit mild muscular features and evidence of increased ECM turnover.²⁶¹ Using an in vitro model, there was evidence of wound healing defects involving up-regulated TGF-β1 and increased MMP activity in mouse embryonic fibroblasts lacking Tenascin-X.²⁶² Although, some models for studying a few EDS subtypes exists, there are currently no established model system for studying hEDS. It is intriguing that nearly all of the genes that have thus far been identified for the various subtypes of EDS are related to the extracellular matrix. These genes are primarily related to collagen isoforms themselves or collagen synthesis (ZNF469, PRDM5), intracellular folding or transport of collagens (PLOD1, FKBP14), post-translational modifications of glycosaminoglycans such as proteoglycans or dermatan sulfate (B4GALT7, B3GALT6, CHST14) or the synthesis of dermatan sulfate (DSE), or other noncollagen, ECM genes (TNXB, ADAMTS1). The correlation of gene-phenotype relationship to particular subtypes of EDS indicates that each of these genes likely have unique cell-specific expression domains and/or levels that are required for normal development and homeostasis within affected tissues in each of the EDS subtypes as discussed above and shown in Figure 1.

The lack of hEDS models is likely based on a lack of genetic knowledge around the causes of hEDS in the human population, further underscoring the necessity for large-scale genetic analyses in this EDS patient group. Only through a combination of this genetic knowledge with animal models will the field be able to advance understanding for the etiology and pathogenesis of the disease.

7 |. MANAGEMENT

Early diagnosis of hEDS allows for disease monitoring and management. Although there are no therapies approved to treat hEDS, symptoms of hEDS and comorbidities can be managed through physical therapy, exercise, lifestyle modification, medication and when needed, surgical intervention. Physical therapy is a crucial part of hEDS management. Treatment is aimed at treating problems due to joint laxity and instability, often seen with muscle weakness from underuse of key muscles and proprioception.²⁶³ Therapy is used both preventatively to prevent subluxations and as a treatment for acute injury.²⁶⁴ It is not uncommon for patients to seek treatment for multiple issues at once, for extended periods of time. The use of stretching exercises should be limited due to risk of subluxation and dislocation. Physical therapy should include manual therapy for overactive muscles and an emphasis on core and trunk stabilization.²⁶⁵ Posture reeducation and joint awareness using biofeedback are important to improve proprioception and poor posture due to ligament laxity.²⁶⁵ Adaptive lifelong activity and fitness is recommended at every stage of life for patients EDS. Daily exercise consistent with mild strength training, proprioception, dynamic joint stability, flexibility, and cardiovascular exercise is beneficial in most cases. Aquatic therapy has been noted to be very helpful in treating the more severely affected patients. There are various pharmacologic therapies that may ease the suffering of certain aspects of the EDS patient. Other anecdotal treatments such as meditation, massage, kinseotaping, CBD oil, mindfulness, acupuncture, dry needling, and so forth, need more evidence-based research to ascertain their effectiveness. Early recognition and appropriate treatment of issues with nutrition, sleep function, mobility, chronic pain, and psychologic conditions is important for successful holistic treatment of EDS patients. Additionally, bracing of unstable joints including finger splints, knee and ankle stabilizing braces and cervical collars is sometimes recommended.^99,265,266 Instability, weakness and pain may result in the need for part time or full-time mobility aids. Frequent chiropractic care and spinal manipulation are generally not recommended for patients with joint hypermobility, ligament laxity, connective tissue disease, or spinal instability.^267–270 Surgical intervention for orthopedic issues involving hEDS should always be carefully considered and failure rate of surgical repair and postoperative complications are higher in EDS patients.^99,271 The risks and benefits of surgery should always be taken into careful consideration. Slow wound healing may require careful surgical closure with extra precautions.²⁷² Medications for pain, inflammation, and management of comorbid conditions including MCAS and POTS are frequently prescribed.^3,98,99,148

8 |. CONCLUDING REMARKS AND PERSPECTIVES

Modification of the ECM likely play a major role in impairing the mechanical stability of the affected tissues in EDS patients. These ECM alterations likely feedback to the cells, resulting in altered mechanosensing and cell phenotype, probably through an integrin-dependent mechanism. As a consequence, propagation of altered mechanical, cellular and physiological result in a chronic, feed-forward disease responses with profound effects on tissue damage and instability. Stabilizing the ECM environment may set in motion positive mechanical cues that can revert cell and physiological phenotypes with long-term benefits for patients. This highlights the necessity for careful physiotherapy while taking into consideration already compromised connective tissues. While this concept may apply broadly for EDS, its application to hEDS is not yet known. The clinical spectrum of hEDS has been described for decades, with significant advancements made in recent years in regard to diagnostic guidelines, knowledge of comorbidities, treatment options, and awareness among healthcare practitioners. However, most of the available data on the underlying biology of hEDS is broad in scope and lacks clear information regarding genetic pathways that contribute to disease etiology and pathogenesis. Establishing this information will not only provide molecular pathways for hEDS but also other diseases that affect musculoskeletal, ocular, neurological, and cardiovascular tissues. To date, basic sciences discoveries on EDS diseases are woefully lacking. Collective research networks should continue identifying genetic factors that contribute to disease. But, we as a scientific community most move these genetic discoveries into appropriate, genetically accurate animal models to understand the molecular, biochemical, mechanical, and physiological mechanisms that contribute to disease origin and its progression. Without this fundamental knowledge, diagnostic tools and more effective or curative therapeutics for hypermobile EDS and EDS disease subtypes will remain enigmatic.

EDS patients may endure years without proper diagnoses and/or treatments. Increased awareness in the medical community is needed to ensure proper care for this group of affected individuals. This medical deficiency may originate during training as medical students are taught “when you hear hoofbeats, look for horses not zebras.” This means to look for the more common diagnosis and not the rare one. As such, the zebra has become the symbol for EDS. Just like zebras in the wild, no two EDS zebras have the same stripes. All patients’ symptoms and experiences are different, but the community comes together as a group of zebras, called a dazzle. A mission of this review is to inform the scientific and lay community of the necessity for increased awareness and involvement in connective tissue disease societies like the EDS society. This, in turn, will lead to a brightening, or dazzling of research and provide new hope to patients with these life altering diseases.²⁷³