ArticlePDF AvailableLiterature Review

Hypermobile Ehlers‐Danlos Syndrome and disorders of the gastrointestinal tract. What the Gastroenterologist needs to know

June 2022
Journal of Gastroenterology and Hepatology 37(9)

June 2022
37(9)

DOI:10.1111/jgh.15927

License
CC BY-NC-ND 4.0

Authors:

Phoebe Thwaites

Monash University (Australia)

Rebecca Burgell

Monash University (Australia)

Background: Hypermobile Ehlers-Danlos Syndrome (hEDS) and the hypermobility spectrum disorders (HSD) can be challenging to diagnose and manage. Gastrointestinal symptoms and disorders of gut-brain interaction are common in this cohort and multifactorial in origin. Aims: The primary aim of this review is to arm the gastroenterologist with a clinically useful understanding of HSD/hEDS, by exploring the association of gastrointestinal disorders with HSD/hEDS, highlighting current pathophysiological understanding and providing a pragmatic approach to managing these patients. Methods: Literature relevant to the gastrointestinal system and hypermobile Ehlers-Danlos Syndrome was systematically searched, critically-appraised and summarized. Results: Diagnosis is based upon clinical criteria and a genetic basis is yet to be defined. The prevalence of many gut symptoms, including abdominal pain (69% vs 27%, p<0.0001), postprandial fullness (34% vs 16%, p=0.01), constipation (73% vs 16%, p<0.001) and diarrhea (47% vs 9%, p<0.001) are significantly higher in HSD/hEDS compared with non-HSD/hEDS individuals. Disorders of gut-brain interaction are also common, particularly functional dyspepsia. The pathophysiology of gut symptoms is poorly understood but may involve effects of connective tissue laxity and its functional consequences, and the influence of autonomic dysfunction, medication and comorbid mental health disorders. Awareness is the key to early diagnosis. Management is limited in evidence-base but ideally should include an integrated multidisciplinary approach. Conclusions: HSD/hEDS is a multisystemic disorder in which gastrointestinal symptoms, particularly related to disorders of gut-brain interaction are common. Deficiencies in knowledge regarding the pathophysiological processes limit evidence-based interventions and remain important areas for future research.

Beighton scoring system measures joint hypermobility on a 9-point scale. Joints assessed (left to right) include (a) passive dorsiflexion of fifth finger ≥ 90° (one point per side); (b) passive apposition of the thumb to ipsilateral forearm (one point per side); (c) hyperextension of the elbow ≥ 10° (one point per side); (d) hyperextension of the knee ≥ 10° (one point per side); and (e) spinal assessment (one point if both palms reach the floor when bending over with knees locked in extension and feet together). Redrawn from Malfait et al. (2017) with permission.

…

Overview of gastrointestinal symptoms observed in studies of patients with hypermobilility spectrum disorder/hypermobile Ehlers-Danlos Syndrome (HSD/hEDS) (excluding studies in gastroenterology specialist clinics)

…

Continued)

…

Checklist for a patient presenting with gastrointestinal symptoms potentially associated with HSD/hEDS

…

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REVIEW ARTICLE

Hypermobile Ehlers–Danlos syndrome and disorders of the

gastrointestinal tract: What the gastroenterologist needs to

know

Phoebe A Thwaites, Peter R Gibson and Rebecca E Burgell

*Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia

Key words

autonomic dysfunction, disorders of gut-brain

interaction, functional dyspepsia, hypermobile

Ehlers–Danlos syndrome, integrated care,

pelvic ﬂoor dysfunction.

Accepted for publication 14 June 2022.

Correspondence

Rebecca Burgell, Department of

Gastroenterology, Alfred Hospital, 99

Commercial Road, Melbourne, Vic. 3004,

Australia.

Email: rebecca.burgell@monash.edu

Declaration of conflict of interest: PAT: Has

received educational support from Pﬁzer and

Orphan Australia for conference attendance.

PRG: Consultant or advisory board member for

Anatara, Atmo Biosciences, Immunic Thera-

peutics, Novozymes, Novoviah and Comvita.

He has received research grants for

investigator-driven studies from Atmo Biosci-

ences. He holds shares in Atmo Biosciences.

His Department ﬁnancially beneﬁts from the

sales of a digital application, booklets and online

courses on the FODMAP diet. REB: Consultant

or advisory board member for Allergan, Atmo

Biosciences, Antara. She has received speaking

honoraria from Bayer.

Financial support: PAT is in receipt of a

Postgraduate Scholarship from the National

Health and Medical Research Council of

Australia. This work was supported by funding

from The Alfred Foundation.

Abstract

Background and Aim: Hypermobile Ehlers–Danlos syndrome (hEDS) and the hypermo-

bility spectrum disorders (HSD) can be challenging to diagnose and manage. Gastrointes-

tinal symptoms and disorders of gut-brain interaction are common in this cohort and

multifactorial in origin. The primary aim of this review is to arm the gastroenterologist with

a clinically useful understanding of HSD/hEDS, by exploring the association of gastroin-

testinal disorders with HSD/hEDS, highlighting current pathophysiological understanding

and providing a pragmatic approach to managing these patients.

Methods: Literature relevant to the gastrointestinal system and hypermobile

Ehlers–Danlos syndrome was systematically searched, critically appraised, and summa-

rized.

Results: Diagnosis is based upon clinical criteria and a genetic basis is yet to be deﬁned.

The prevalence of many gut symptoms, including abdominal pain (69% vs 27%,

P<0.0001), postprandial fullness (34% vs 16%, P= 0.01), constipation (73% vs 16%,

P<0.001), and diarrhea (47% vs 9%, P<0.001) are signiﬁcantly higher in HSD/hEDS

compared with non-HSD/hEDS individuals. Disorders of gut-brain interaction are also

common, particularly functional dyspepsia. The pathophysiology of gut symptoms is

poorly understood but may involve effects of connective tissue laxity and its functional

consequences, and the inﬂuence of autonomic dysfunction, medication and comorbid men-

tal health disorders. Awareness is the key to early diagnosis. Management is limited in

evidence-base but ideally should include an integrated multidisciplinary approach.

Conclusions: HSD/hEDS is a multisystemic disorder in which gastrointestinal symptoms,

particularly related to disorders of gut-brain interaction are common. Deﬁciencies in

knowledge regarding the pathophysiological processes limit evidence-based interventions

and remain important areas for future research.

Introduction

Ehlers–Danlos syndrome (EDS) was ﬁrst recognized in the time of

Hippocrates in the fourth century BC. Appreciation of its heteroge-

neity continues to evolve to this day. EDS is the most common

non-inﬂammatory connective tissue disorder featuring joint hyper-

mobility, with the hypermobile EDS (hEDS) subtype representing

80–90% of the burden of disease.

1,2

hEDS is now recognized as

part of the “hypermobility spectrum disorders”(HSD), which are

characterized by varying articular and extra-articular involvement

and impact on quality of life. The vast majority of those affected

are female, gastrointestinal symptoms are very common and

healthcare utilization is high.

3–5

Many patients meet diagnostic

criteria for disorders of gut-brain interaction (DGBI), but the path-

ophysiological link between DGBI and HSD/hEDS is yet to be es-

tablished beyond association. The primary aim of this review is to

arm the gastroenterologist with a clinically useful understanding of

HSD/hEDS, by exploring the association of gastrointestinal disor-

ders with HSD/hEDS, highlighting current pathophysiological un-

derstanding and providing a pragmatic approach to managing

these patients.

doi:10.1111/jgh.15927

1693Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,

provided the original work is properly cited, the use is non-commercial and no modiﬁcations or adaptations are made.

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Methodology

In order to perform this narrative review, the published literature

was systematically searched via PubMed, ProQuest and OVID

using key words that included hypermobile Ehlers–Danlos syn-

drome, hEDS, joint hypermobility syndrome, gastrointestinal dis-

orders, functional gut disorders, disorders gut-brain interaction,

functional dyspepsia, irritable bowel syndrome, constipation, diar-

rhea, rectal evacuatory dysfunction, autonomic function, and mo-

tility. Each subsection was additionally explored using targeted

searching, for example, “eating disorder”and hypermobile

Ehlers–Danlos Syndrome. Abstracts were appraised and relevant

articles were then reviewed and analyzed in full. Additional stud-

ies were located via cross-referencing. Studies in pediatric cohorts

were not included.

Terminology and diagnostic criteria

A major hindrance to the general understanding of EDS has been

its heterogeneity, in part related to the multiple classiﬁcation sys-

tems used over the years. The current nosology and diagnostic

criteria are deﬁned by the 2017 International Classiﬁcation of the

Ehlers–Danlos Syndromes in which 13 variants are recognized

(Table S1) although an additional subtype was added provisionally

in 2018 and is referred to as classical-like type 2 EDS.

6,7

Recog-

nized genetic mutations simplify the diagnosis for nearly all sub-

types. The exception is hEDS, where the genetic basis has not

been established.

As a result, the diagnosis of hEDS relies on

clinical features (Table 1). Central to the diagnosis of hEDS is

the Beighton score, which evaluates joint hypermobility using es-

tablished criteria (Fig. 1, Table 1).

Table 1 New diagnostic criteria for hypermobile Ehlers–Danlos syndrome (hEDS)

Criterion 1:

Must be met

The Beighton score for generalized joint

hypermobility

•Prepubertal children/adolescents: >6

•Men, women post puberty to age 50: >5

•Over age 50: >4

•If one point below diagnostic, score ≥2 in the 5-point questionnaire

indicates the presence of joint hypermobility (sensitivity 80–85%,

speciﬁcity 80–90%)

Criterion 2:

Two or more of the

following features

Feature A:

Systemic manifestations of a more

generalized connective tissue disorder

At least ﬁve of the following must be present:

•Unusually soft or velvety skin

•Mild skin hyperextensibility (skin stretch >1.5 cm distal forearm/

dorsum hand; >3 cm neck/elbow/knee; >1 cm palmar surface hand)

•Unexplained striae (without a history of signiﬁcant weight change)

•Bilateral piezogenic papules of heel (small, tender herniations of

adipose globules through fascia into dermis)

•Recurrent or multiple abdominal hernias

•Atrophic scarring involving at least two sites

•Pelvic ﬂoor, rectal and/or uterine prolapse in children, men or

nulliparous women without a history of morbid obesity or predisposing

medical condition

•Dental crowding and high or narrow palate

•Arachnodactyly

•Arm span-to-height ratio ≥1.05

•Mitral valve prolapse (based on strict echocardiographic criteria)

•Aortic root dilatation with z-score >+2 (i.e. >2 SD above the size and

gender speciﬁc population mean)

Feature B:

Positive family history

•≥1ﬁrst-degree relative with hEDS

Feature C: Musculoskeletal Complications One of the following:

•Musculoskeletal pain in ≥2 or more limbs, recurring daily for at least

3 months

•Chronic, widespread pain for ≥3 months

•Recurrent joint dislocations or frank joint instability, in the absence of

trauma

Criterion 3:

All must be met

•Absence of unusual skin fragility that should prompt consideration of

other types of EDS

•Exclusion of other heritable and acquired connective tissue disorders,

including autoimmune rheumatologic conditions

•In patients with an acquired/autoimmune connective tissue disorder,

must meet both Features A and B of Criterion 2. Feature C of Criterion

2 (chronic pain and/or instability) cannot be counted

•Exclusion of alternative diagnoses that may also include joint

hypermobility by means of hypotonia and/or connective tissue laxity

hEDS and gastrointestinal disorders PA Thwaites et al.

1694 Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

Various terms have been used historically to describe this group

of hypermobile patients, the most common being “joint hypermo-

bility syndrome”(JHS), which includes patients who meet the cur-

rent hEDS criteria, but also some who do not. To declutter the

confusing nomenclature, the term “hypermobility spectrum disor-

der”(HSD) is now used as an umbrella term (Fig. 2). hEDS is con-

sidered to sit on the more severe end of the spectrum as it is

associated with signiﬁcant somatic complaints related to musculo-

skeletal manifestations such ﬁbromyalgia (40%), chronic fatigue

(38%), and pain (almost 100%) (acute and chronic, nociceptive,

neuropathic, and nociplastic).

2,5,11–13

In addition, various

non-musculoskeletal manifestations can be present including, neu-

rological (e.g. headaches), psychiatric and neurodevelopmental

(e.g. mood disorders, anxiety, and sleep disturbances), cardiorespi-

ratory (e.g. palpitations, chest pain, and dyspnea), autonomic (e.g.

syncope, postural instability, and thermoregulatory difﬁculties),

urogynecological (e.g. prolapse, urinary incontinence, and

dyspareunia), and gastroenterological.

2,5,12,14–18

Inﬂammatory

and systemic manifestations, postulated to relate to mast cell acti-

vation, are also reported.

Given the complexity of the historical

nomenclature and in order to incorporate published data that have

utilized previous terminology, the disorder will be referred to as

“HSD/hEDS”(unless speciﬁcally describing hEDS) for this re-

view. It is acknowledged that this will introduce some phenotypic

and genotypic heterogeneity. Using this deﬁnition, it is estimated

that the prevalence of HSD/hEDS is greater than 1:500.

Hypermobility spectrum

disorders/hypermobile Ehlers-Danlos

syndrome and the gastrointestinal

system

The association between gastrointestinal symptoms and

HSD/hEDS was ﬁrst described 15 years ago.

A vast array of

Figure 1 Beighton scoring system measures joint hypermobility on a 9-point scale. Joints assessed (left to right) include (a) passive dorsiﬂexion of

ﬁfth ﬁnger ≥90° (one point per side); (b) passive apposition of the thumb to ipsilateral forearm (one point per side); (c) hyperextension of the elbow

≥10° (one point per side); (d) hyperextension of the knee ≥10° (one point per side); and (e) spinal assessment (one point if both palms reach the ﬂoor

when bending over with knees locked in extension and feet together). Redrawn from Malfait et al. (2017) with permission.

Figure 2 Spectrum of joint hypermobility. The horizontal arrows depict the spectrum of joint disease, ranging from asymptomatic, non-syndromic

joint hypermobility, progressing through the newly recognized hypermobility spectrum disorder with various combinations of musculoskeletal and

non-musculoskeletal manifestations (insufﬁcient to meet the criteria for hEDS). Also depicted are the common manifestations contributing to the so-

matic complaints described. PoTS, postural orthostatic tachycardia syndrome.

PA Thwaites et al.hEDS and gastrointestinal disorders

1695Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

symptoms occur signiﬁcantly more often in HSD/hEDS compared

with non-HSD/hEDS patients (Fig. 3). Commonly, more than one

gastrointestinal symptom is present.

5,21,22

A greater severity and

extent of gastrointestinal involvement has been described in pa-

tients referred to gastroenterology clinics with a pre-existing diag-

nosis of HSD/hEDS, compared with patients with features of

HSD/hEDS but without a prior diagnosis, followed by those with-

out any features of HSD/hEDS.

Despite many studies, the true prevalence of gastrointestinal dis-

orders in this cohort is difﬁcult to assess due to varying nomencla-

ture and methodological biases, particularly selection bias, in the

studies published. Moreover, the reported prevalence of gastroin-

testinal symptoms varies widely depending on whether it is de-

rived from population-based studies, support groups,

non-gastroenterological specialist (genetics, cardiology and rheu-

matology) clinics (Table 2) and gastroenterology clinics

(Table 3).

4,14,23–28

Nevertheless, gastrointestinal symptoms have

been associated with impairment of quality of life in patients with

HSD/hEDS in each of the study settings.

3–5,22,27

Association with disorders of gut-brain interac-

tion. Criteria for DGBI are met frequently in patients with

HSD/hEDS, in both the community and hospital settings. For ex-

ample, 94% in HSD/hEDS survey respondents from the UK

EDS support group fulﬁlled criteria for DGBI compared with

47% of the control population (P<0.0001) and 91% in

rheumatology-referred HSD/hEDS patients compared with 48%

of non-HSD/hEDS patient referrals.

4,5

Moreover, patients seeking

gastroenterological review for DGBI were more likely to meet di-

agnostic criteria for HSD/hEDS than those presenting with organic

disorders (39% vs 28%, P= 0.002).

Dyspeptic symptoms are common and the diagnosis of func-

tional dyspepsia by both Rome III and IV criteria appears to be

more common in HSD/hEDS compared with controls in both gas-

troenterology (OR 2.08, CI 1.25–3.46 for functional gastroduode-

nal disorders, P= 0.005), and non-gastroenterology hospital

clinics (38% vs 9%, P= 0.029), support groups (57% vs 9%,

P<0.0001) and the general population (39% vs 23%,

P= 0.02).

5,21,22,27

There appears to be no difference in the type

or patterns of symptoms in patients with functional dyspepsia with

or without HSD/hEDS.

The prevalence of other DGBI in the HSD/hEDS population

have been inconsistently assessed (Tables 2and 3). Irritable bowel

syndrome (IBS) has a similar prevalence in HSD/hEDS patients

referred to gastroenterology clinics (OR 1.34, CI 0.90–2.00,

P= 0.15)

and in the general population examined for gut symp-

toms and hypermobility,

although studies conducted through

support groups and non-gastroenterology clinics have found IBS

to be generally more common than in the non-HSD/hEDS

Figure 3 Various gastrointestinal symptoms have been reported to occur signiﬁcantly more often in patients with HSD/hEDS compared with non-

HSD/hEDS controls. See Tables 2and 3.

hEDS and gastrointestinal disorders PA Thwaites et al.

1696 Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

Table 2 Overview of gastrointestinal symptoms observed in studies of patients with hypermobilility spectrum disorder/hypermobile Ehlers–Danlos

Syndrome (HSD/hEDS) (excluding studies in gastroenterology specialist clinics)

Author, year Classiﬁcation utilized Study type Study setting and number of patients Symptom prevalence

Castori

et al., 2010

Villefranche criteria +

Brighton criteria

Observational

cross-sectional

General genetics outpatients; Italy

n= 21 (18 female)

Reﬂux/heartburn (57%); dyspepsia

(67%); abdominal pain (62%);

constipation/diarrhea (33%); hernias

(abdominal) (5%)

Castori

et al., 2011

Villefranche criteria +

Brighton criteria

Observational

cross-sectional

Multidisciplinary joint hypermobility clinic;

Italy

Cumulative prevalence of symptoms

according to age reported—based on

patient recall

n= 50 (44 female)

By age ≥40 years: reﬂux/heartburn

(74%); abdominal pain (68%); chronic

gastritis (48%); alternating bowel habits

(72%); hernias (abdominal) (20%)

Mastoroudes

et al., 2013

Revised 1998 Brighton

criteria

Observational

case–control

Hypermobility clinic; UK

n= 60 HSD/hEDS; 60 age-matched

and sex-matched controls from

medical staff

Obstructive defecation symptoms:

23% vs 5% controls (P= 0.007);

straining: 62% (P<0.001); incomplete

evacuation: 63% (P<0.001); digitation:

33% (P= 0.001); constipation: 72%

(P<0.001)

Zeitoun

et al., 2013

Villefranche criteria Observational

cross-sectional

EDS patient support group; France

n= 134 (122 female); 108 HSD/hEDS

64% survey response rate

Nausea (71%); reﬂux/heartburn (69%);

dysphagia (63%); regurgitation (69%);

postprandial fullness (67%); belching

(71%); epigastric pain (71%);

constipation (36%); IBS-like symptoms

(48%)

Castori

et al., 2014

Villefranche criteria Observational

cross-sectional

Pedigrees were selected from two

Italian outpatient clinics for EDS

and inherited connective tissue

disorders. 23 families with

HSD/hEDS (n= 82)

Reﬂux/heartburn (34%); chronic

gastritis (23%); abdominal pain (20%);

constipation (28%)

Nelson

et al., 2015

Villefranche criteria +

Brighton criteria

Observational

retrospective

Medical Genetics Clinic (1994–2013)

687 EDS patients (n= 471 HSD/hEDS)

No control group included

HSD/hEDS vs other EDS: constipation:

42% vs 29% (P= 0.02); nausea: 44%

vs 37%; reﬂux/heartburn: 38% vs 36%;

vomiting: 25% vs 22%; waterbrash:

1% vs 2%; dysphagia: 11% vs 12%;

regurgitation: 4% vs 6%; postprandial

fullness: 7% vs 3%; bloating: 17% vs

10%; dyspepsia: 11% vs 7%;

abdominal pain: 56% vs 56%;

diarrhea: 23% vs 17%; fecal urgency:

1.5% vs 2.8%

Fikree

et al., 2017

Villefranche criteria +

Brighton criteria

Cross-sectional,

double-blinded,

case–control

University students (without prior

diagnosis of HSD/hEDS); UK

HSD/hEDS: n= 74 (48 female)

Controls: n=88

HSD/hEDS vs controls: postprandial

fullness: 34% vs 16% (P= 0.01); early

satiety: 32% vs 17% (P= 0.03);

bloating: 26% vs 23% (P= 0.59);

functional dyspepsia: 39% vs 23%

controls (P= 0.02);

No differences in lower gastrointestinal

symptoms (IBS, constipation, diarrhea,

alternating bowel habit, ≤4 bowel

motions/week).

Inayet

et al., 2018

Not speciﬁed Observational

cross-sectional,

case–control

Cardiology and rheumatology clinics; UK

45 Marfan syndrome and

45 HSD/hEDS (33 female)

90 age-matched and sex-matched

controls

HSD/hEDS vs controls: functional

abdominal pain: 69% vs 27%

(P<0.001); functional constipation:

73% vs 16% (P<0.001); functional

diarrhea: 47% vs 9% (P<0.001); IBS:

33% vs 7% (P= 0.0014); functional

heartburn: 47% vs 13% (P= 0.0011);

(Continues)

PA Thwaites et al.hEDS and gastrointestinal disorders

1697Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

population (54% vs 8%, P= 0.0001 in support group; 73% vs

16%, P= 0.001 in non-gastroenterology clinic setting).

5,27

Zweig

et al. reported a higher prevalence of joint hypermobility (but not

HSD/hEDS) in a cohort of constipation-predominant IBS com-

pared with diarrhea-predominant IBS (58% vs 35%, P= 0.008)

and found those with IBS and joint-hypermobility (not

HSD/hEDS) were more likely to have concomitant postprandial

distress (72% vs 49%, P= 0.007).

The data are even less clear

when considering other functional bowel disorders, including

functional constipation and functional diarrhea.

5,21,22,25

Similarly,

the prevalence of functional anorectal disorders is variably

reported

5,22,27,31

with, for example, no differences in patients re-

ferred to gastroenterology clinics with gastrointestinal symptoms

(OR 1.79, CI 0.97–3.30, P= 0.06)

through to a much greater

prevalence using Rome IV criteria in the UK support group

(53% vs 9%, P<0.0001).

Importantly, the presence of HSD/hEDS with DGBI appears to

be associated with greater overall impact in terms of healthcare

Table 2 (Continued)

Author, year Classiﬁcation utilized Study type Study setting and number of patients Symptom prevalence

functional dyspepsia: 38% vs 9%

control (P= 0.029); functional bloating/

distension: 31% vs 7% (P= 0.006)

Nee

et al., 2019

Not speciﬁed

(Villefranche and Berlin

nomenclature accepted)

Observational,

cross-sectional

Members of local and national

Marfan and EDS societies; US

EDS: n= 1804

HSD/hEDS, n= 1325);

MFS: n= 600);

94% female

HSD/hEDS vs other subtypes of EDS:

aerophagia: 24% vs 26% (P= 0.35);

bloating: 13% 12%; heartburn: 32% vs

37% (P= 0.04); dysphagia: 29% vs

28%; IBS: 58% vs 56%; functional

constipation: 8% vs 7%; diarrhea: 0.5%

vs 1.3%; functional dyspepsia: 55% vs

56%

Alomari

et al., 2020

2017 International

classiﬁcation of EDS

Observational

retrospective

Genetics clinic; US

n= 218 (198 female)

63% gastrointestinal symptoms at

hEDS diagnosis (63%); abdominal pain

(50%); nausea (50%); constipation

(45%); diarrhea (38%); heartburn

(36%); belching/bloating (27%);

vomiting (26%); IBS-like symptoms

(22%); dysphagia (14%); fecal

incontinence (6%)

Lam

et al., 2020

Not speciﬁed Case–control EDS support group; UK

HSD/hEDS: n= 603

Age-matched and sex-matched

controls: n= 1994

Mean age: 39 years, 96% female

20% survey response rate

HSD/hEDS vs control: functional

dyspepsia: 57% vs 9% (P<0.0001);

IBS: 54% vs 8% (P<0.001); functional

dysphagia: 42% vs 4% (P<0.001);

rumination: 31% vs 5% (P<0.001);

functional constipation: 12% vs 10%;

functional diarrhea: 5% vs 4.6%;

functional anorectal disorders: 53% vs

9% (P<0.001)

Tai

et al., 2020

Not speciﬁed Observational

cross-sectional,

case–control

EDS support group: UK

Established HSD/hEDS and

hypermobility spectrum

disorder: n= 616 (573 female);

mean age 39 years

PoTS n= 231

20% survey response

PoTS vs non-PoTS: functional

esophageal disorders: 66% vs 50%

(P<0.001); functional heartburn: 31%

vs 21% (P= 0.007); functional

dysphagia: 51% vs 37% (P= 0.001);

functional gastroduodenal disorders:

75% vs 67% (P= 0.04); functional

dyspepsia: 68% vs 50% (P<0.001);

postprandial distress syndrome: 63%

vs 42% (P<0.001); epigastric pain

syndrome: 40% vs 28% (P= 0.002);

functional bowel disorders: 89% vs

91% (P= 0.5); IBS: 59% vs 51%;

functional diarrhea: 3% vs 7%

(P= 0.01); functional anorectal

disorders: 60% vs 49% (P= 0.01)

†

Villefranche criteria.

hEDS and gastrointestinal disorders PA Thwaites et al.

1698 Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

Table 3 Overview of the key ﬁndings generated from studies based on patients attending gastroenterology clinics

Author Study type, clinic setting Patient cohort Assessment Key ﬁndings

Mohammed,

et al., 2010

Retrospective cohort

Gastroenterology clinic

Intractable constipation

and rectal evacuatory

dysfunction: n= 200 (joint

hypermobile n= 65; 179

female, median age

53 years)

•Questionnaires: 5PQ, Rome III

questionnaire for IBS,

comprehensive bowel symptom

questionnaire including

constipation score and fecal

incontinence score

•Anorectal physiology studies

Cases vs controls:

•Joint hypermobility: 33% (65/200)

vs 14% (P= 0.0005)

•Pelvic organ prolapse with or

without surgical repair: 31% (20/65)

vs 17% (23/135) (P= 0.04)

Hypermobile vs non-hypermobile

group:

•Abdominal pain: 75% vs 53%

(P= 0.003)

•Use of digital rectal evacuation:

69% vs 50% (P= 0.009)

•Laxative use: 55% vs 37%

(P= 0.03)

•Reduced squeeze increment

pressures: 32% vs 19% (P= 0.05)

•Incomplete rectal evacuation: 80%

vs 59% (P= 0.004)

•Anorectal anatomical abnormalities:

86% vs 64% (P= 0.001) including

large functional rectocele (28% vs

14%, P= 0.03); extrinsic

compression of anterior rectal wall

(11% vs 1%, P= 0.006); incomplete

rectal evacuation: 80% vs 59%

(P= 0.004)

Zarate et al.,

2010

Retrospective

neuro-gastroenterology

clinic

129 consecutive newly

referred patients stratiﬁed

by joint hypermobility

status; subset of 21

patients conﬁrmed with

HSD/hEDS

•Symptom assessment

•Joint hypermobility

49% (63/129) had generalized joint

hypermobility:

•Symptoms: abdominal pain (81%),

bloating (57%), nausea (57%),

reﬂux symptoms (48%), vomiting

(43%), diarrhea (14%)

•Compared with non-hypermobile

patients: younger; more often

female; more likely to have bloating

(62% vs 46%, P= 0.05), reﬂux

symptoms (56% vs 30%,

P= 0.005), unexplained

gastrointestinal symptoms (81% vs

41%, P<0.0001)

Fikree et al.,

2014

Prospective cross-sectional

General gastroenterology

clinic

Consecutive new referrals

(16–70 years) stratiﬁed by

HSD/hEDS status (Brighton

criteria) (Total n= 552;

HSD/hEDS = 372

Non-HSD/hEDS: n=80

HSD/hEDS patients

referred from

rheumatology clinic

(positive control): n=44

•Questionnaires: gut symptoms

(bowel disease questionnaire);

psychopathology (SCL-90);

autonomic symptoms

(COMPASS): quality of life (SF-

36)

•Examination

•Structured interview

Undiagnosed HSD/hEDS 33%

(n= 180/552):

•younger (41 years vs 44 years,

P= 0.003);

•more likely to be female (68% vs

55%, P= 0.002)

•greater prevalence of heartburn

(aOR 1.66, CI 1.1–2.5); waterbrash

(aOR 2.02, CI 1.3–3.1);

postprandial fullness (aOR 1.74, CI

1.2–2.6) adjusting for age and sex

(Continues)

PA Thwaites et al.hEDS and gastrointestinal disorders

1699Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

Table 3 (Continued)

Author Study type, clinic setting Patient cohort Assessment Key ﬁndings

Non-HSD/hEDS vs new HSD/hEDS vs

previously diagnosed HSD/hEDS:

•DGBI prevalence: 48% vs 58% vs

91% (P<0.001)

•Organic disorders: 44% vs 31% 8%

(P<0.001)

•Autonomic symptom scores:

urinary (0 vs 10 vs 30 (P<0.001);

orthostatic intolerance (25 vs 31.25

vs 68.75, (P<0.001); vasomotor (0

vs 0vs 56.7 (P<0.001)

Fikree et al.,

2015

Prospective case–control

(functional and organic

diagnosis)

Secondary gastroenterology

clinic

Consecutive referrals of

patients with

gastrointestinal symptoms,

no prior HSD/hEDS

diagnosis Total n= 641

(Organic disease controls

n= 306 vs DBI cases

n= 336; 378 female; mean

age 42 years)

•Questionnaires: bowel

disease questionnaire,

pscyhopathology SCL-90;

autonomic symptoms

(COMPASS), somatic

symptoms (PHQ-15) and

quality of life (SF-36);

•Structured interview and

examination for HSD/hEDS

(Brighton criteria) and

ﬁbromyalgia (1990 Wolfe

criteria)

DGBI vs organic disease controls:

•Female: 66% vs 52% (P<0.001)

•Mean age: 40 vs 44 years

(P= 0.001)

•HSD/hEDS prevalence: 39% vs

28% (P= 0.002)

Adjusted OR (age, gender) for HSD/

hEDS:

•Functional gastroduodenal

disorders (2.08, CI 1.25–3.46,

P= 0.005);

•Postprandial distress syndrome

(1.99 CI 1.0–3.76, P= 0.03)

•No association with lower

gastrointestinal symptoms,

including IBS

DGBI-HSD/hEDS vs non-HSD/EDS:

•Chronic pain: 23.2 vs 11.9

(P= 0.02),

•Fibromyalgia: 10.5 vs 3.1

(P= 0.01),Somatic sensitivity:

PHQ15 score 13 vs 10 (P<0.001)

•Anxiety: 0.5 vs 0.3 (P= 0.01);

•Poorer quality of life scores (in

domains of role-limiting emotional

and pain)

Fikree et al.,

2017

Retrospective, observational

Neuro-gastroenterology clinic

Consecutive HSD/hEDS

patients referred to

gastrointestinal physiology

unit for assessment of

reﬂux or dysphagia

HSD/hEDS: n= 30 (28

female; median age

30 years)—further stratiﬁed

by PoTS status;

non-HSD/hEDS dysphagia:

n= 98 (56 female)

Reﬂux controls: n= 108 (61

female)

•Questionnaires: reﬂux disease

questionnaire, hospital

odynophagia dysphagia

questionnaire, Hospital Anxiety

and Depression Scale (HADS)

•Medical and medication history

•High resolution manometry or

multichannel intraluminal

impedance testing

HSD/hEDS vs non-HSD/hEDS:

•Reﬂux hypersensitivity (21% vs

5%, P= 0.01).

•Esophageal hypomotility 40% in

HSD/hEDS vs 23% in (P= 0.09).

PoTS vs non-PoTS-HSD/hEDS:

•Reﬂux scores: 24.5 vs 16.5

(P= 0.05)

•Dysphagia scores: 21 vs 11.5

(P= 0.04)

(Continues)

hEDS and gastrointestinal disorders PA Thwaites et al.

1700 Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

utilization, quality of life, somatic symptoms and the extent of gas-

trointestinal involvement, compared with respondents meeting

criteria for DGBI alone.

5,22

Individuals with comorbid

HSD/hEDS and DGBI report more frequent experiences of pain

(23% vs 12%, P= 0.01), worse pain-related quality of life scores

(45 vs 63.5, P= 0.004), comorbid diagnosis of ﬁbromyalgia

(11% vs 3%, P= 0.01), higher somatization scores (13 vs 10,

P<0.001) and higher anxiety scores (0.50 vs 0.30, P= 0.01) com-

pared with non-HSD/hEDS DGBI patients.

Organic gastrointestinal disease. There is a paucity of

studies exploring associations between HSD/hEDS with organic

Table 3 (Continued)

Author Study type, clinic setting Patient cohort Assessment Key ﬁndings

Menys et al.,

2017

Pilot feasibility

Tertiary

neuro-gastroenterology

clinic

HSD/hEDS with

Postprandial distress

(Rome III): n=9

Healthy controls: n=9

•MRI at baseline following

cessation of motility-inﬂuencing

medication

•Gastric emptying time, motility

and accommodation and

duodenal distension

and motility assessed

following ingestion of water.

HSD/hEDS vs control:

•Similar gastric emptying time: 12.5

vs 20 min (P= 0.15).

•Lower mean increase in gastric

motility: 11% vs 22% (P= 0.03).

•Similar gastric accommodation:

56% vs 67% (P= 0.19)

Zweig et al.,

2018

Retrospective review

of prospectively

collected data at

neuro-gastroenterology

clinic

228 IBS (Rome III) patients

(67% female); stratiﬁed by

joint hypermobility status

•Rome III criteria

•Beighton score and Brighton

criteria

•Psychological assessment:

visceral sensitivity index;

Hospital and Anxiety

Depression Scale

Joint hypermobility

•More common in female vs male:

83 (55%) vs 12 (16%) P<0.001

•Signiﬁcantly higher in IBS-C

compared with IBS-D (58% vs

35%, P= 0.008)

•IBS patients reported signiﬁcantly

more concomitant postprandial

distress: 72% vs 49%, P= 0.007

•Similar visceral sensitivity index 38

vs 37, P= 0.720

•No signiﬁcant association between

HSD/hEDS and IBS subtypes

Carbone et al.,

2021

Prospective case–control

University hospital clinic

Functional dyspepsia

(Rome III): n= 39 stratiﬁed

by HSD/hEDS status using

Brighton classiﬁcation

Healthy controls: n=15

•Questionnaire: dyspepsia

symptom severity score;

visual analogue scale

•Blinded nutrient drink i

nfusion via nasogastric

tube at 60 ml/min until

satiation or symptoms

•Intragastric pressure

measured by high

resolution manometry

HSD/hEDS vs controls

•Functional dyspepsia: 56% vs 7%

(P= 0.002)

•No differences in symptom pattern

Carbone, et al.

2022

Retrospective recruitment,

prospective evaluation

of joint hypermobility

Gastroenterology clinic

62 patients with

preexisting functional

dyspepsia

n= 62 (68% female, age

44 years, BMI 22 kg/m

)

•Interview and examination

for HSD/hEDS status

(Brighton criteria)

•Historic results for gastric

emptying (using

breath test); gastric barostat

assessment

55% HSD/hEDS criteria met vs 39%

no joint disease/syndrome vs 6%

“other”joint disorder

HSD/hEDS vs non-HSD/hEDS

•Female: 74% vs 63% (P= 0.02)

•Similar symptomatology:

postprandial fullness (76% vs 82%);

bloating (73% vs 77%); early satiety

(58% vs 41%); nausea (42% vs

36%); belching (42% vs 36%);

reﬂux (21% vs 5%)

•Similar rates of delayed gastric

emptying (32% vs 16%, P= 0.31)

•No differences in gastric

compliance, minimal distention

pressure and meal-induced proximal

stomach relaxation

PA Thwaites et al.hEDS and gastrointestinal disorders

1701Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

gastrointestinal conditions although potential links have been

identiﬁed.

Celiac disease. The potential association between celiac disease

and HSD/hEDS was initially proposed after 5 of 31 Italian patients

with HSD/hEDS (16%) had celiac disease, considerably more than

might be anticipated from the background prevalence of about

1%.

Subsequent interrogation of a large population-based Swed-

ish registry identiﬁed a signiﬁcant association of HSD/hEDS with

histologically proven celiac disease (14 vs 9 per 100 000

person-years with a hazard ratio of 1.49, 95% CI, 1.07–2.07,

P= 0.018).

Crohn’s disease. Joint hypermobility (using the Beighton score

alone) has been observed more frequently in patients with Crohn’s

disease with 29 of the 41 Crohn’s patients (71%) having joint hy-

permobility compared with 10 of the 28 patients (36%) with ulcer-

ative colitis (P= 0.006) and 17 of the 67 age-matched and

sex-matched healthy controls (25%) (P<0.0001).

Furthermore,

the prevalence of HSD/hEDS (using the Brighton criteria)

followed similar trends (12% in Crohn’s disease vs 4% in ulcera-

tive colitis [OR 3.75, 95% CI: 0.41–34.0]).

In another cohort,

HSD/hEDS was present in 8 of 25 patients with Crohn’s disease

(32%) and 8 of 38 patients (21%) with ulcerative colitis.

Other gastrointestinal diseases. There are no signals for an

increased risk of gastric or colorectal neoplasia or of complications

related to diverticular disease in patients with HSD/hEDS although

formal studies are lacking. The prevalence of diverticular disease,

similarly, has not been systematically assessed. In the only rele-

vant report, a study of issues associated with colonoscopy such

as safety and post procedure pain, 22 of 200 patients met criteria

for HSD and that sub-group had a similar prevalence of polyps

(27% vs 41%, respectively; P= 0.2) and diverticulosis (39% vs

36%, P= 0.7) as those without HSD.

Other studies have reported

rates of diverticular disease of 10–13% and rates of polyps of

8–23%. However, these data are drawn from retrospective chart

reviews of patients who were not systematically evaluated and so

the generalizability of these ﬁgures is uncertain.

14,36

Liver disease. While “at-risk”alcohol consumption has been re-

ported to occur more often in patients with joint hypermobility

(not hEDS speciﬁcally), there have been no data suggesting a

higher incidence of chronic liver disease in the HSD/hEDS

population.

37,38

One case–control study conducted from a rheu-

matology clinic reported an association between unconjugated

hyperbilirubinemia from Gilbert’s syndrome and hypermobile

joints.

However, the reason these patients were referred to the

rheumatology clinic in the ﬁrst instance was not examined and

the source of recruitment of the control group was not reported,

which may limit the generalizability of the conclusions.

Pathophysiological contributors to

gastrointestinal symptoms in HSD/hEDS

An understanding of the current status of the pathophysiological

basis for gastrointestinal and other symptoms in patients with

HSD/hEDS is valuable in counseling the patients. There are mul-

tiple hypotheses and potential explanations that largely fall into

three categories—the anatomical effects of connective tissue laxity

and weakness per se, their functional consequences, and the inﬂu-

ence of non-gastrointestinal issues that include autonomic dys-

function, medication effects or comorbid mental health disorders.

The current evidence base supporting these proposed hypotheses

remains limited.

Anatomical variation/abnormalities. A variety of ana-

tomical abnormalities related to increased connective tissue laxity

and weakness have been observed.

On ﬁrst principles, it seems

reasonable that such abnormalities might be associated with symp-

toms. Speciﬁc abnormalities include the following:

•Hiatus hernia:The prevalence of hiatus hernia in

HSD/hEDS has been variably reported, as high as 58%.

Other studies, however, have shown it to be similar to the

background population (8–26% in HSD/hEDS vs 2–22%

general population) suggesting hiatus hernia may not be the

main mechanism responsible for the commonly reported

symptom of reﬂux.

14,28,42–44

It has been postulated that there

is laxity of the gastro-hepatic and phreno-esophageal liga-

ments in patients with HSD/hEDS, providing a basis for

the reported association. This hypothesis is supported by

the observed depletion of elastic ﬁbers in those ligaments

of patients with gastroesophageal reﬂux disease and hiatus

hernia, although these patients were not assessed for underly-

ing HSD/hEDS.

•Visceroptosis: Abnormal connective tissue leading to altered

ﬁxation of viscera to the peritoneum has been implicated in

the development of visceroptosis (deﬁned as sinking of an

organ below its normal position) of various organs in case re-

ports of patients with HSD/hEDS.

46–49

The relationship be-

tween the structural change and clinical presentation has

not been well-deﬁned.

•Pelvic organ prolapse: This occurs about twice as often in

patients with HSD/hEDS compared with non-HSD/hEDS in-

dividuals. For example, in a case–control study of 60 fe-

males referred to a tertiary hypermobility clinic, 73% had

clinically-signiﬁcant prolapse compared with 35% of the

age-matched and sex-matched healthy controls

(P<0.001).

These individuals were also more likely to ex-

perience symptoms of obstructive defecation on questioning

(23% vs 5%, P= 0.007).

Likewise, more patients with rec-

tal evacuatory dysfunction reported a history of pelvic organ

prolapse (with or without surgery) in the HSD/hEDS cohort

compared with the non-HSD/hEDS group (31% vs 17%,

P= 0.04).

Objectively, anorectal anatomical abnormalities

seen on proctography were more common in the HSD/hEDS

group compared with the non-HSD/hEDS cohort (86% vs

64%, P= 0.001), speciﬁcally for large functional rectoceles

(28% vs 14%, P= 0.03) and extrinsic compression of the an-

terior rectal wall from an enterocele or the uterus (11% vs

1%, P= 0.006). Higher frequencies of reduced squeeze in-

crement pressures (32% vs 19%, P= 0.05) and incomplete

rectal evacuation (80% vs 59%, P= 0.004) compared with

the non-HSD/hEDS controls were also seen. No differences

in rectal sensation or frequency of reduced anal resting tone

hEDS and gastrointestinal disorders PA Thwaites et al.

1702 Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

were noted.

Fikree et al. also described a higher incidence

of organ prolapse in their study, which increased statistically

signiﬁcantly by HSD/hEDS status.

Despite this, the clinical

signiﬁcance of these ﬁndings is difﬁcult to interpret given

the lack of control data and the relatively common ﬁnding

of anatomical variations like prolapse in asymptomatic

subjects.

•Short-segment intussusception:This is postulated to arise

secondarily to altered tensile strength of hollow viscera lead-

ing to excessive visceral distension in combination with al-

tered ﬁxation of the viscera to the peritoneum in patients

with HSD/hEDS. However, the prevalence of intussuscep-

tion in both the HSD/hEDS and general populations remains

unknown and the mechanistic relationship of short-segment

intussusception to gastrointestinal symptoms, such as ab-

dominal pain and bloating, is poorly understood. There was

no observed difference in the prevalence of rectal intussus-

ception, which presumably has similar pathophysiological

mechanisms, in the study of rectal evacuatory dysfunction

in patients with and without HSD/hEDS (41% vs 39%,

P= 0.76).

•Dolichocolon (elongation or redundancy of the colon):

Such an anatomical variant may predispose patients to vol-

vulus, abdominal pain or constipation. To date this has not

been substantiated by evidence as a potential mechanism in

HSD/hEDS.

40,52

Altered gastrointestinal tract function. There are sev-

eral interrelated aspects to potential alteration of gastrointestinal

function:

•Altered compliance of the gastrointestinal tract wall and

changes in mechanoreceptor function: Increased elasticity

(compliance) of the gastrointestinal wall will manifest as in-

creased distension from a given intraluminal force. Thus,

theoretically, a given amount of luminal gas in a patient with

altered connective tissue arising from HSD/hEDS may yield

greater intestinal distension and subsequent mechanorecep-

tor stimulation than a person without HSD/hEDS. Because

luminal wall stretch is a major stimulus to inducing pain

and bloating, it might be anticipated that patients with

HSD/hEDS will be more susceptible to symptom induction

following gaseous distension.

Neither colonic compliance

nor gut mechanoreceptor function in the hEDS population

have been measured to test this hypothesis although no

changes in gastric accommodation have been observed in

HSD/hEDS studies of functional dyspepsia using MRI or in-

tragastric barostat measures, arguing against this

hypothesis.

54,55

•Dysmotility: Following on from the aforementioned hypoth-

esis, altered wall compliance/elasticity and mechanoreceptor

function also inﬂuences gastrointestinal motility. Studies in

murine and guinea pig models show that enteric neurons

are activated or inhibited by luminal stretch with resultant

motility changes.

This hypothesis is supported by studies

in the IBS population following luminal gas infusion, in

which objective abdominal distension and subjective

reporting of abdominal symptoms appear to be more related

to an altered motility response (poor gas transit) than to in-

creased gas volume.

57,58

It is possible a similar process pre-

dominates in hEDS. In support of this, gastric MRI

revealed altered motility in response to water ingestion in

HSD/hEDS patients with functional dyspepsia compared

with healthy controls.

Other studies of gastric sensorimotor

function, compliance and emptying in small cohorts of pa-

tients with HSD/hEDS have otherwise revealed few speciﬁc

abnormalities.

14,26,29,36,43,54,55

Similarly, colonic transit stud-

ies have also revealed no speciﬁc abnormalities in

HSD/hEDS patients.

14,26,36,50

•Visceral hypersensitivity:Direct alterations in neuronal

function leading to visceral hypersensitivity have also been

proposed as a contributor for symptoms in hEDS. A number

of hypotheses have been proposed. First, tenascin-X, a gly-

coprotein component of extracellular matrix for which a

genetically-driven deﬁciency, has been rarely linked with

HSD/hEDS, plays a role in the neural control of colonic sen-

sory and motor function. This has also recently been shown

to play a role in upper gastrointestinal function.

59,60

TNX de-

ﬁciency in mice has been shown to correlate with increased

sensitivity of vagal afferent nerves to gastric distension and

associated with accelerated gastric emptying.

Nevertheless,

the correlation between gastric emptying and symptoms in

functional dyspepsia has not been borne out in studies in

non-HSD/hEDS cohorts, which limits the conclusions that

can be drawn.

Secondly, α-2 adrenergic activity plays a

role in visceral sensitivity in healthy volunteers and could

potentially play a role in connective tissue disorders, al-

though this has not been speciﬁcally studied in the

HSD/hEDS population.

Thirdly, central sensitization, as

seen with generalized, chronic widespread pain, will second-

arily promote visceral hypersensitivity.

This hypothesis is

supported by a greater prevalence of reﬂux hypersensitivity

(high-resolution manometry and pH manometry) in patients

with upper gastrointestinal symptoms in those with and with-

out HSD/hEDS (21% vs 5%, P= 0.01).

•Altered vascular compliance:Venous pooling in the lower

limbs has been described in HSD/hEDS related to altered

connective tissue of blood vessels and has been proposed

to contribute to cardiovascular and autonomic symptoms

present in HSD/hEDS patients. Alterations in splanchnic cir-

culation may also be expected and could contribute to the

gastrointestinal symptoms experienced.

Non-gastrointestinal mechanisms. HSD/hEDS is char-

acterized by a number of non-musculoskeletal manifestations

(Figs 2and 3) which can contribute to the patient’s presentation

to a gastroenterologist. Three important factors are proposed to

contribute: autonomic dysfunction, effects of medications, and

mental health disorders, including eating disorders.

•Autonomic dysfunction:The autonomic nervous system

plays a key role in maintaining homeostasis in the body, with

roles in ﬂuid balance, temperature regulation and blood pres-

sure. Symptoms of autonomic dysfunction can include

presyncope, orthostatic intolerance, chest pain, palpitations,

thermoregulatory difﬁculties, and gastrointestinal complaints

PA Thwaites et al.hEDS and gastrointestinal disorders

1703Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

and are commonly reported in patients with

HSD/hEDS.

63–65

For example, they are almost three times

more likely than healthy controls to experience presyncopal

symptoms (41% vs 15%) and experience orthostatic

intolerance frequently (94% of HSD/hEDS in one

study).

15,63,65

Cardiovascular autonomic dysfunction can include ortho-

static hypotension, orthostatic intolerance,

neurally-mediated hypotension and postural orthostatic

tachycardia syndrome (PoTS), the latter of which is com-

monly associated with HSD/hEDS.

PoTS is a heteroge-

neous syndrome that is manifested by a rapid increase in

heart rate (>30 bpm in adults) within 10 minutes of chang-

ing from recumbent to upright position without orthostatic

hypotension.

Multisystemic involvement is common, with

gastrointestinal symptoms (including nausea, irregular bowel

movements, abdominal pain, bloating and constipation) the

most frequent non-cardiovascular symptoms reported.

68,69

The cause for these symptoms is likely to be multifactorial,

but may be related to changes in splanchnic circulation, pres-

ence of small ﬁber neuropathy or altered vascular compli-

ance related to the generalized tissue laxity in hEDS.

68,69

The prevalence of PoTS in HSD/hEDS cohorts ranges from

15% to 41%.

36,63,64,70–72

The prevalence of hEDS also ap-

pears to be higher in PoTS cohorts compared with the gen-

eral population, with 31% of PoTS patients meeting the

2017 diagnositc criteria for hEDS.

The clinical association between HSD/hEDS and PoTS is

noted, but their relationship remains unclear. There is some

evidence that the copresence of the two disorders may repre-

sent a more severe disease phenotype.

36,43,70,71

For example,

studies have shown that symptoms of gastroesophageal re-

ﬂux and dysphagia are worse, esophageal hypomotility more

marked and pathological gastroesophageal reﬂux disease

more severe in those with comorbid HSD/hEDS and PoTS

compared with HSD/hEDS alone.

Abnormal gastrointesti-

nal motility is also more than ﬁve times likely,

and the bur-

den of DGBI is greater.

Cohorts of patients with comorbid

PoTS and HSD/hEDS appear to be younger than either

alone, suggesting that the symptoms become apparent at an

earlier age or perhaps present more severely leading to ear-

lier diagnosis.

67,71

•Medication effects:Patients with HSD/hEDS report high

regular medication use, with opiates being potentially the

most troublesome from a gastrointestinal perspective. Up to

92% of HSD/hEDS respondents in one study reported regu-

lar medication use of which analgesics were the most

common.

Polypharmacy is also prevalent, with an average

of three medications per patient reported and chronic opiate

use seen in over one third of HSD/hEDS patients.

While

Fikree et al.’s studies did not ﬁnd any association between

gastrointestinal symptoms or esophageal dysmotility and

opiate use, the widespread actions of opiates on multiple as-

pects of gastrointestinal function and their established side

effect proﬁle including constipation, nausea, vomiting and

pain sensitization means they cannot be ignored.

4,43,73

Other

potential pharmaceutical contributors such as antidepres-

sants, are used by 15–27% of HSD/hEDS patients. These

medications also have vasoactive properties, effects on

autonomic function and a range of gastrointestinal side

effects.

4,65,74

•Mental health contributors:There is a recognized increased

prevalence of mental health disorders in patients with

HSD/hEDS, including anxiety and depression.

38,75–77

In a

retrospective survey of 391 patients with a diagnosis of

mostly HSD (80%) or EDS (notably no hEDS), almost half

of the respondents were affected by a psychiatric disorder

and almost 30% described two or more simultaneous psychi-

atric diagnoses.

Signiﬁcant associations were noted be-

tween gastrointestinal dysfunction and mood disorders (OR

2.07, 95% CI 1.33–3.25, P= 0.001), depression (OR 1.68,

95% CI 1.07–2.66, P= 0.026), somatoform disorders (OR

2.61, 95% CI 1.62–4.19, P<0.001) and anxiety (OR

2.26, 95% CI 1.39–3.67, P <0.001). In a long term popula-

tion cohort study with 15 years of follow up, those patients

with HSD/hEDS deﬁned by Brighton criteria performed at

the time of recruitment (29 of the 137 subjects) had a relative

risk of panic disorder or agoraphobia 22 times greater than

that of the non-HSD/hEDS patients.

There is also increas-

ing interest in the association between HSD and

neurodevelopmental disorders, including attention-deﬁcit/

hyperactivity-disorder and autism spectrum disorder.

•Disordered eating and HSD/hEDS:There are multiple rea-

sons patients with HSD/hEDS might modify their eating pat-

terns. Oral mucosal fragility, temporomandibular

dysfunction, masticatory muscular problems and dental is-

sues, such as poor dentition or overcrowding of the teeth

may lead to altered oral intake.

2,78,79

Patients with hEDS

may also experience enhanced interoception (heightened

awareness of bodily information and stimuli), somatosensory

ampliﬁcation and have underlying chemosensory disorders

(involving smell and taste changes), inﬂuencing oral intake

and the development of food aversions.

Finally, and unre-

lated to HSD/hEDS itself, is that modiﬁcation of diet is com-

mon in patients with DGBI, where food type and quantity is

altered by perceived food intolerances as a strategy to mini-

mize symptoms such as bloating.

Differentiating a primary eating disorder from disordered

eating patterns related to the aforementioned factors can be

challenging in patients with HSD/hEDS.

A weak associa-

tion of eating disorders with EDS, based upon theory and

case reports, is noted but formal studies are limited.

Aware-

ness of such diagnostic challenges is critical to managing

these patients who are often young females, with anorexia,

low body weight and signiﬁcant gastrointestinal symptoms.

The consequences of weight loss and poor nutrition should

also not been overlooked as these may worsen the natural

history of hEDS by contributing to physical deconditioning,

reduced bone mass, fatigue, and poor quality of life.

79,82

Management considerations

There is a general lack of evidence to guide therapeutic approaches

for patients with HSD/hEDS. Indeed there is also no single ap-

proach that will ﬁt all HSD/hEDS patients, given the various com-

binations of manifestations that may be present. Management is

largely supportive in nature and symptom-focused, and often

hEDS and gastrointestinal disorders PA Thwaites et al.

1704 Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

Table 4 Checklist for a patient presenting with gastrointestinal symptoms potentially associated with HSD/hEDS

Actions Notes

Screen patients for hEDS with 5-point questionnaire •5-point questionnaire

1.Can you now (or could you ever) place your hands flat on the floor without bending your

knees?

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

3.As a child, did you amuse your friends by contorting your body into strange shapes, or

could you do the splits?

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

5.Do you consider yourself double-jointed?

•Consider new diagnosis of hEDS in patients with multisystemic symptoms and DGBI

•Early referral to multi-disciplinary teams if available

Exclusion of organic gastrointestinal conditions •Screening for celiac disease (e.g. celiac-speciﬁc serology if consuming gluten) and

inﬂammatory bowel disease (e.g. fecal calprotectin, colonoscopy if high suspicion) as

recommended in any patient with chronic gastrointestinal symptoms

•In patients with Crohn’s disease, consider HSD/hEDS overlap with spondyloarthropathy

•Judicious use of investigations and procedures to minimize duplication of care and iatrogenic

risk from low yield procedures. Endoscopic procedures should be performed on their clinical

merits. No evidence of increased procedural risks (perforation, post-procedural pain in HSD;

possible increased risk of bleeding in hEDS patients with minor bleeding disorder)

Institute integrated management for DGBI symptoms Evidence for management speciﬁcally in HSD/hEDS lacking–attention to:

•Integrated care and behavioral therapies

•Dietary management: FODMAP diet efﬁcacious in HSD/hEDS-related DGBI

•Pelvic ﬂoor dysfunction: consider early referral for anorectal physiological assessment and

biofeedback/pelvic ﬂoor physiotherapy

•Psychology input to address psychological comorbidity

Consider nutritional and dietary issues •Assess nutritional status as undernutrition is common and multifactorial

•Optimization of bone health: vitamin D and calcium supplementation as required

•Screen for weight loss and disordered eating patterns (dietitian)

•Consider the following

○Underlying eating disorder, in particular avoidant/restrictive food intake disorder (ARFID)

○Dental and oral mucosal health, temporomandibular joint (dys)function

○Presence of underlying chemosensory disorder (altered taste and smell)

○Alteration of diet due to presence of DGBI symptoms

○Consider the impact of eating disorder itself on gastrointestinal function (e.g. generation of

IBS-like symptoms, constipation, postprandial fullness, bloating, and early satiety)

Address extra-intestinal manifestations—consider referral

to appropriate healthcare professional

•Increased risk of psychiatric comorbidities

•Increased risk of ‘at risk’substance use (alcohol, tobacco)

•Musculoskeletal involvement often widespread, affecting joints beyond those listed in

diagnostic criteria

•Chronic pain syndromes common—individualized pain management appropriate, awareness

of opiate use

•Chronic fatigue symptoms common—multidisciplinary approach

•Consider contribution of autonomic nervous system-related symptoms

•Consider physical deconditioning, which may exacerbate autonomic dysfunction and

musculoskeletal symptoms, fatigue and pain

•Consider referral to cardiologist for surveillance in those with positive family history of

cardiac/aortic disease or abnormal cardiovascular clinical examination ﬁndings on

auscultation; no clear guideline regarding routine/baseline echocardiographic surveillance

2,90

Pharmacological considerations •Consider the effects of medication on symptoms (e.g. fatigue, sleep quality, and

gastrointestinal dysfunction)

•Caution with opiates, particularly in those with gastrointestinal symptoms

Support •Referral to support group/local hEDS organization

•Providing patients with pathways to obtain further information about the condition and allow

family members to consider this diagnosis where appropriate

Professional education and training •Further healthcare professional training is available through EDS Society (EDS ECHO),

established 2019 with evidence for improved outcomes and physician conﬁdence

PA Thwaites et al.hEDS and gastrointestinal disorders

1705Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

recommended on the basis of prior clinical experience or using

strategies adapted from management of “similar”patient groups.

We have proposed a suggested “hEDS checklist”that could be

followed in deﬁning therapeutic strategies in patients with hEDS

who are presenting with gastrointestinal symptoms (Table 4).

Awareness of the multiple pathways by which such symptoms

can arise is important in order to provide the best individualized

treatment. If standard therapies fail, alternative etiologies for the

symptoms should be considered.

Awareness of HSD/hEDS. The presentation of HSD/hEDS

varies greatly between individuals and thus the diagnosis is often

delayed, referred to as the “diagnostic odyssey.”

Greater aware-

ness of HSD/hEDS among physicians may enable an earlier diag-

nosis and more timely uptake of integrated, multidisciplinary care

providing holistic and expert support for the various systems po-

tentially affected. This process is particularly important given that

few centers offer multi-specialty HSD/hEDS clinics. Additional

beneﬁts of this approach might include reduced healthcare utiliza-

tion and costs associated with numerous medical consultations, in-

vestigations, unnecessary surgeries and other interventions,

treatment regimens and time off work. It is also important to avoid

the incorrect use of the label “hEDS.”Clear diagnostic criteria

should be used and patient education facilitated by a sound work-

ing knowledge of the hypermobility spectrum disorders and their

diagnostic limitations.

Integrated care. While evidence for timely, collaborative

care is limited in the HSD/hEDS population, integrated care of pa-

tients with irritable bowel syndrome and other DGBI have been

shown to improve health-related quality of life, patient psycholog-

ical wellbeing and other outcomes.

84,85

Given the complexity of

the multisystemic issues that often present in patients with

HSD/hEDS, care of highly symptomatic patients may require col-

laborative input from various health professionals including (but

not limited to) general practitioners, physicians (e.g. gastroenterol-

ogy, cardiology, and rheumatology), psychiatrists and psycholo-

gists, chronic pain specialists, dietitians, physiotherapists/exercise

physiologists, and dentists.

Safety with surgery and endoscopy. Patients and doc-

tors alike may express concern regarding the safety of endoscopic

and surgical procedures in patients with connective tissue and au-

tonomic problems. Indeed orthopedic complications are known to

be higher in HSD/hEDS. However, in general, the risks of severe

adverse procedural outcomes are low in HSD/hEDS.

General

considerations, however, may include: anesthetic risks (including

circulatory management in patients with autonomic dysfunction,

temporomandibular joint subluxation/dislocation or cervical spine

instability); history of bruising and tissue fragility;

hyperextension/force on joints at risk of dislocation or subluxation

when the patient is being mobilized; and the procedural risks

themselves.

40,86

Symptoms will dictate the need for a colonoscopy and/or upper

gastrointestinal endsocopy in many patients. The risk of perfora-

tion does not appear to be increased. This is in contrast to patients

with vascular EDS in whom vascular and visceral perforation risk

is high.

Procedural difﬁculty has been theorized to be more chal-

lenging due to the presence of hernias and increased laxity of the

colon, but has not been veriﬁed in studies.

Indeed

endoscopist-reported difﬁculty and cecal intubation rates are not

dissimilar between HSD and non-HSD cohorts.

There does not

appear to be a signiﬁcantly greater rate of post-procedural pain.

Increased risk of bleeding in association with colonoscopy has

not been reported but should be assessed in the context of the pa-

tient’s personal history of bleeding (which may be increased) and

the planned procedure, particularly in those with mast cell activa-

tion syndrome.

Laboratory results are usually within normal

range.

Familial screening. There are currently no formal guidelines

on familial screening. However, family history is a component of

the new diagnostic criteria and the syndrome is believed to be

inherited in an autosomal dominant manner with incomplete pen-

etrance, which makes screening family members a relevant consid-

eration. The spectrum of the disorder means that family members

may present with their own unique manifestations and remain un-

diagnosed despite meeting the criteria. As there is no diagnostic

molecular marker known, referrals to genetics clinics are likely

to be managed variably according to local practices and based on

waitlists and availability. Recommendations regarding familial

echocardiographic screening are best determined by the treating

cardiologist as the understanding of the natural history of cardio-

vascular abnormalities in HSD/hEDS continues to evolve.

Future research directions. The key impediment to prog-

ress in improving the diagnosis and understanding of the clinical

manifestations of this spectrum of disorders is the identiﬁcation

of the genetic basis (es) to HSD/hEDS. In the absence of such ob-

jective markers, evaluation of the more stringent 2017 Interna-

tional Classiﬁcation of the EDS is needed in order to clarify the

many areas of imprecision and to minimize inaccurate and some-

what emotive attribution of many illnesses to the underlying con-

nective tissue disorder. The same applies to how gastrointestinal

anatomy and physiology are altered in hEDS, and how (and if)

these relate to the intestinal and extra-intestinal manifestations ob-

served in hEDS. Consideration of the complex interaction between

the gut, brain, other organs and the environment (including medi-

cation), and how these may alter the susceptibility of a patient to

the development of abdominal symptoms, also needs further con-

sideration. Greater understanding of pathophysiological processes

will then allow more targeted treatment strategies with integrated

care to be studied and implemented.

Conclusions

All general gastroenterologists will encounter patients with (diag-

nosed or undiagnosed) HSD/hEDS. Recognition of such patients

and a general understanding of the implication of such a disorder

will provide the opportunity for timely and reassuring explanation,

for arranging multidisciplinary care as required, and minimizing

inappropriate investigations and therapies. In this way, gastroenter-

ologists have the opportunity to improve the long term outcomes

of these patients.

hEDS and gastrointestinal disorders PA Thwaites et al.

1706 Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

Acknowledgment

Open access publishing facilitated by Monash University, as part

of the Wiley - Monash University agreement via the Council of

Australian University Librarians.

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Supporting information

Additional supporting information may be found online in the

Supporting Information section at the end of the article.

Table S1 2017 International classiﬁcation of the Ehlers-Danlos

syndromes including key clinical features, prevalence, genetic ba-

sis and gastrointestinal involvement.

7,91

PA Thwaites et al.hEDS and gastrointestinal disorders

1709Journal of Gastroenterology and Hepatology 37 (2022) 1693–1709

Esophageal Striae as a Possible Gastrointestinal Manifestation of Hypermobile Ehlers-Danlos Syndrome

Article

Full-text available

Jun 2024

Clinical-Genomic Analysis of 1261 Patients with Ehlers–Danlos Syndrome Outlines an Articulo-Autonomic Gene Network (Entome)

Article

Full-text available

Mar 2024
CURR ISSUES MOL BIOL

Systematic evaluation of 80 history and 40 history findings diagnosed 1261 patients with Ehlers–Danlos syndrome (EDS) by direct or online interaction, and 60 key findings were selected for their relation to clinical mechanisms and/or management. Genomic testing results in 566 of these patients supported EDS relevance by their differences from those in 82 developmental disability patients and by their association with general rather than type-specific EDS findings. The 437 nuclear and 79 mitochondrial DNA changes included 71 impacting joint matrix (49 COL5), 39 bone (30 COL1/2/9/11), 22 vessel (12 COL3/8VWF), 43 vessel–heart (17FBN1/11TGFB/BR), 59 muscle (28 COL6/12), 56 neural (16 SCN9A/10A/11A), and 74 autonomic (13 POLG/25porphyria related). These genes were distributed over all chromosomes but the Y, a network analogized to an ‘entome’ where DNA change disrupts truncal mechanisms (skin constraint, neuromuscular support, joint vessel flexibility) and produces a mirroring cascade of articular and autonomic symptoms. The implied sequences of genes from nodal proteins to hypermobility to branching tissue laxity or dysautonomia symptoms would be ideal for large language/artificial intelligence analyses.

Integrative medicine for hypermobility spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS): a feasibility study

Article

Full-text available

Feb 2024
DISABIL REHABIL

Purpose: Hypermobility spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS) are multisystem conditions marked by dysfunctional connective tissue. This feasibility study evaluated a 9-week integrative medicine program in this population. Methods: Using a single-arm study design, adults with HSD or EDS were given recommendations for an anti-inflammatory Mediterranean diet and self-management with additional behavioral and psychosocial support. Preliminary data on feasibility based on recruitment and retention, adherence to the diet, mobile app tracking, changes to perceived well-being via health outcomes, and satisfaction with care were obtained. Results: Thirteen participants were enrolled within a 4-month timeframe. Eight participants completed the study. Three participants met dietary tracking requirement in at least 4 of 8 intervention weeks and met the macronutrient requirements in at least half of the weeks tracked. No decreases in VAS pain scores after 5 and 9 weeks were noted; however, 62.5% (n = 5) of participants had decreased pain at 9 weeks, compared to baseline. There were significant improvements (p<.05) in six of twelve measurements of satisfaction with care at the end of the intervention. Conclusion: This study provides a foundation for future research on patient experience and introduces a novel treatment paradigm focused on nutrition and self-management. Supplementary material available at: https://doi.org/10.6084/m9.figshare.c.6486154.v3

Hypermobility, Trauma, and the Roads That Lead to Rome

Article

Dec 2023

Nitin K. Ahuja

Looking back and beyond the 2017 diagnostic criteria for hypermobile Ehlers‐Danlos syndrome: A retrospective cross‐sectional study from an Italian reference center

Article

Full-text available

Sep 2023

The most common conditions with symptomatic joint hypermobility are hypermobile Ehlers‐Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). Diagnosing these overlapping connective tissue disorders remains challenging due to the lack of established causes and reliable diagnostic tests. hEDS is diagnosed applying the 2017 diagnostic criteria, and patients with symptomatic joint hypermobility but not fulfilling these criteria are labeled as HSD, which is not officially recognized by all healthcare systems. The 2017 criteria were introduced to improve diagnostic specificity but have faced criticism for being too stringent and failing to adequately capture the multisystemic involvement of hEDS. Herein, we retrospectively evaluated 327 patients from 213 families with a prior diagnosis of hypermobility type EDS or joint hypermobility syndrome based on Villefranche and Brighton criteria, to assess the effectiveness of the 2017 criteria in distinguishing between hEDS and HSD and document the frequencies of extra‐articular manifestations. Based on our findings, we propose that the 2017 criteria should be made less stringent to include a greater number of patients who are currently encompassed within the HSD category. This will lead to improved diagnostic accuracy and enhanced patient care by properly capturing the diverse range of symptoms and manifestations present within the hEDS/HSD spectrum.

Connective tissue disorders and the gut

Article

May 2024

Asma Fikree

A ramble through the small bowel

Article

Apr 2024
CURR OPIN GASTROEN

Reena Sidhu

Mast cell activation and nutritional disorders in patients with hypermobility

Article

Feb 2024
CURR OPIN GASTROEN

Purpose of review Individuals with joint hypermobility disorders are increasingly referred to gastroenterology services for support with the investigation and management of gastrointestinal complaints. Individuals can present with a myriad of complex coexisting diagnoses, the inter-relationship of which is unclear. This review discusses the proposed association between hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) with disorders of mast cell activation and provides an overview of gastrointestinal symptoms and nutritional outcomes in this patient cohort. Recent findings It is unclear whether a true association between hEDS/HSD and mast cell activation disorders exists. There is a high prevalence of nonspecific gastrointestinal symptoms in individuals with hEDS/HSD and patients may be at risk of macro-nutrient and micro-nutrient deficiencies, although the current evidence base is limited. Summary We advocate a pragmatic approach to the investigation and management of gastrointestinal symptoms in patients with hEDS/HSD. This centres on excluding organic pathology, discussing the overlap with disorders of gut-brain interactions, trialling evidence-based therapies targeting individual symptoms, and supporting nutritional deficiencies where present via the least invasive approach. Engagement with a broad multidisciplinary team is also important to support the holistic needs of this patient cohort.

Cardiovascular Symptoms, Dysautonomia, and Quality of Life in Adult and Pediatric Patients with Hypermobile Ehlers-Danlos Syndrome: A Brief Review

Article

Jan 2024
Curr Cardiol Rev

Background: Hypermobile Ehlers-Danlos Syndrome (hEDS) is a connective tissue disorder characterized by joint hypermobility and other systemic manifestations, such as cardiovascular symptoms, musculoskeletal pain, and joint instability. Cardiovascular symptoms, such as lightheadedness and palpitations, and types of dysautonomia, including postural orthostatic tachycardia syndrome (POTS), are frequently reported in adults with hEDS and have been shown to negatively impact quality of life (QoL). Objective: This brief review will be an overview of co-occurring symptoms in POTS and hEDS to inform potential cardiovascular screening procedures. Results: While many patients with hEDS report cardiovascular symptoms, few have structural abnormalities, suggesting that dysautonomia is likely responsible for these symptoms. One validated screening measure for dysautonomia symptom burden is the Composite Autonomic Symptom Scale (COMPASS-31). Studies have found that adults with POTS, hEDS, and both POTS and hEDS have higher COMPASS-31 scores than the general population, suggesting a high symptom burden due to dysautonomia, which leads to impaired QoL. Conclusion: While studies have examined cardiovascular symptoms and the impact of dysautonomia in adults with and without hEDS, there is scant literature on dysautonomia in pediatric patients with hEDS. Therefore, more studies on cardiovascular symptoms and dysautonomia, as they relate to the quality of life in pediatric patients with hEDS, are needed. This brief review summarizes the current literature on dysautonomia and cardiovascular symptoms in pediatric and adult populations with hEDS.

EXPRESS: The Spectrum of Gastrointestinal Functional Bowel Disorders in Joint Hypermobility Syndrome and in an Academic Referral Center

Article

Oct 2023
J INVEST MED

Joint hypermobility syndrome (JHS) is a non-inflammatory hereditary disorder of connective tissue with varied clinical presentations, including frequent joint dislocations, hyperextensible skin, easy bruising, and abnormal paper-thin scar formation. Many of these patients have unexplained gastrointestinal (GI) symptoms. Our aim was to evaluate the prevalence of JHS in a tertiary gastroenterology motility clinic and the spectrum of functional bowel disorders in JHS patients. In this retrospective cohort study, we screened the medical records of 277 patients seen over four years at an academic GI Motility Center. The patients who met the criteria for JHS by Beighton hypermobility score were evaluated for the presence of functional gastrointestinal disorders by Rome IV criteria. Also patient underwent gastric emptying study (GES) and glucose breath testing for small intestinal bacterial overgrowth. The prevalence of JHS in the study population was 9.7 %. The mean age was 27 years, and 92.5% were female. The symptoms experienced by these patients include nausea/vomiting (89%), abdominal pain (70%), constipation (48%), and bloating (18.5%). The disorders associated with JHS include gastroparesis (52%), irritable bowel syndrome (55.5%), and gastroesophageal reflux disease (30%). Also, 10 patients (37%) were diagnosed with postural hypotension tachycardia syndrome (POTS) secondary to autonomic dysfunction. Essentially, 10% of patients referred for a suspected functional bowel disorder had hypermobility syndrome. GI practitioners should become familiar with all criteria for JHS as well as how to elicit the specific physical exam findings. There should be high suspicion of JHS in patients with idiopathic gastroparesis.

Association of mast-cell-related conditions with hypermobile syndromes: a review of the literature

Article

Full-text available

Aug 2022

Ehlers–Danlos syndrome (EDS) is a group of related connective tissue disorders consisting of 13 subtypes, each with its own unique phenotypic and genetic variation. The overlap of symptoms and multitude of EDS variations makes it difficult for patients to achieve a diagnosis early in the course of their disease. The most common form, hypermobile type EDS (hEDS) and its variant, hypermobile spectrum disorder (HSD), are correlated with rheumatologic and inflammatory conditions. Evidence is still needed to determine the pathophysiology of hEDS; however, the association among these conditions and their prevalence in hEDS/HSD may be explained through consideration of persistent chronic inflammation contributing to a disruption of the connective tissue. Aberrant mast cell activation has been shown to play a role in disruption of connective tissue integrity through activity of its mediators including histamine and tryptase which affects multiple organ systems resulting in mast cell activation disorders (MCAD). The overlap of findings associated with MCAD and the immune-mediated and rheumatologic conditions in patients with hEDS/HSD may provide an explanation for the relationship among these conditions and the presence of chronic inflammatory processes in these patients. It is clear that a multidisciplinary approach is required for the treatment of patients with EDS. However, it is also important for clinicians to consider the summarized symptoms and MCAD-associated characteristics in patients with multiple complaints as possible manifestations of connective tissue disorders, in order to potentially aid in establishing an early diagnosis of EDS.

Ehlers-Danlos Syndrome in the Field of Psychiatry: A Review

Article

Full-text available

Jan 2022

Ehlers-Danlos syndrome (EDS) comprises a series of rare hereditary connective tissue diseases characterized by joint hypermobility, joint dislocation, and hyperextensibility of the skin, as well as cardiovascular involvement. EDS is often associated with chronic widespread physical pain, which can lead to psychological pain. Poor awareness and limited diagnosis of EDS and related symptoms result in decreased self-esteem and confusion regarding physical sensation. Furthermore, EDS imposes substantial psychological burden on patients due to exercise restriction, scars, keloids, and subcutaneous fat accumulation on the extremities, which leads to parental overprotection and bullying experiences from other children at school age. Recent large-scale studies have suggested that patients with EDS have a higher risk of mood disorders than the general population. Other cohort studies indicated high prevalence of anorexia nervosa, addiction, obsessive compulsive disorder, and anxiety disorder were found in patients with EDS. Case reports instead indicated that some psychiatric disorders were secondary symptoms due to physical problems from EDS. Therefore, psychiatrists must be more knowledgeable and proactive about EDS in their practice. We review the previous case reports and literature for patients with EDS, along with our own case of complicated psychiatric problems, which are strongly related to early stressful situations through childhood and adolescence. This is to aid general psychiatrists in the discussion of appropriate medical management in such infrequent, yet challenging conditions.

Pain in the Ehlers–Danlos syndromes: Mechanisms, models, and challenges

Article

Full-text available

Nov 2021

Chronic pain is one of the most common, yet poorly studied, complaints in people suffering from Ehlers–Danlos syndromes (EDS). This heterogeneous group of heritable connective tissue disorders is typically characterized by skin hyperextensibility, joint hypermobility, and generalized connective tissue fragility. Most EDS types are caused by genetic defects that affect connective tissue biosynthesis, thereby compromising collagen biosynthesis or fibrillogenesis and resulting in a disorganized extracellular matrix. Even though chronic pain is a major source of disability, functional impairment, and psychosocial suffering in EDS, currently used analgesics and other treatment strategies provide inadequate pain relief and thus represents an important unmet medical need. An important contributor to this is the lack of knowledge about the underlying mechanisms. In this narrative review, we summarize the current understanding of pain and the associated mechanisms in EDS based on clinical studies focusing on questionnaires and experimental pain testing as well as studies in animal models of EDS. In addition, we highlight the challenges, gaps, and opportunities in EDS-pain research.

Is the Pain Just Physical? The Role of Psychological Distress, Quality of Life, and Autistic Traits in Ehlers–Danlos Syndrome, an Internet-Based Survey in Italy

Article

Full-text available

Oct 2021

Background: Ehlers-Danlos syndromes (EDS) have been associated with psychological distress, comorbid psychiatric disorders, and worsening in quality of life (QoL). Among the neurodevelopmental disorders, autism spectrum disorders (ASD) have shown the highest rates of co-occurrence with EDS. The reasons for these associations are unknown and a possible role of pain in increasing the risk of psychiatric disorders in EDS has been suggested. However, a detailed picture of an Italian EDS sample is still lacking. Methods: We conducted a web-based survey in a third level center for the diagnosis of EDS in northern Italy, to investigate psychological distress, QoL, and the presence of autistic traits. Furthermore, we correlated the psychometric data with some clinical variables. Results: We observed a high rate of psychological distress with 91% of the responders at high risk of common mental disorders, low QoL, and high prevalence of autistic traits in EDS patients. Specifically, patients lacking a specific genetic test, diagnosed as suspects of EDS appeared to be at greater risk and reported worse psychological QoL. Pain was significantly associated with both psychological distress and worse QoL. Conclusions: Our findings support the need of further research and of a multi-disciplinary approach to EDS including psychological and psychiatric liaison.

Patients with Ehlers–Danlos syndrome on the diagnostic odyssey: Rethinking complexity and difficulty as a hero's journey

Article

Full-text available

Sep 2021

Patients with hypermobile Ehlers–Danlos syndrome, an hereditary disorder of the connective tissue, often face a long and difficult diagnostic odyssey in pursuit of a name for their condition. Clinicians may dismiss subjective symptoms of chronic pain, thus prolonging patients' odysseys and worsening their care and satisfaction and creating antagonisms in the patient–provider relationship. A greater understanding of patient experiences is necessary in order to decrease burdens of this relationship and to improve care. To that end, we conducted 22 in‐depth, semistructured interviews with individuals who had undergone this diagnostic odyssey. We focused on the impact that the odyssey had on their lives, both inside and outside the clinic. Through narrative analysis, we found a sort of “hero's journey” in the description of their cases, highlighting issues of uncertainty and integration as well as honoring their struggles. Interviewees had encountered difficulties in working with clinicians, in multiplying symptoms, and in negative psychosocial consequences. Attention to patients' lived experience may help to build empathy and understanding for the difficult and complex clinical situation presented by Ehlers–Danlos syndrome. Using the hero's journey as a lens onto this experience allows for a more patient‐centered approach to this understanding and has potential value for comprehension of other complex diseases and invisible illnesses.

Are patients with hypermobile Ehlers–Danlos syndrome or hypermobility spectrum disorder so different?

Article

Full-text available

Oct 2021
RHEUMATOL INT

Diagnosing hypermobile Ehlers–Danlos syndrome (hEDS) remains challenging, despite new 2017 criteria. Patients not fulfilling these criteria are considered to have hypermobile spectrum disorder (HSD). Our first aim was to evaluate whether patients hEDS were more severely affected and had higher prevalence of extra-articular manifestations than HSD. Second aim was to compare their outcome after coordinated physical therapy. Patients fulfilling hEDS/HSD criteria were included in this real-life prospective cohort (November 2017/April 2019). They completed a 16-item Clinical Severity Score (CSS-16). We recorded bone involvement, neuropathic pain (DN4) and symptoms of mast cell disorders (MCAS) as extra-articular manifestations. After a standardized initial evaluation (T0), all patients were offered the same coordinated physical therapy, were followed-up at 6 months (T1) and at least 1 year later (T2), and were asked whether or not their condition had subjectively improved at T2. We included 97 patients (61 hEDS, 36 HSD). Median age was 40 (range 18–73); 92.7% were females. Three items from CSS-16 (pain, motricity problems, and bleeding) were significantly more severe with hEDS than HSD. Bone fragility, neuropathic pain and MCAS were equally prevalent. At T2 (20 months [range 18–26]) 54% of patients reported improvement (no difference between groups). On multivariable analysis, only family history of hypermobility predicted (favorable) outcome ( p = 0.01). hEDS and HDS patients showed similar disease severity score except for pain, motricity problems and bleeding, and similar spectrum of extra-articular manifestations. Long-term improvement was observed in > 50% of patients in both groups. These results add weight to a clinical pragmatic proposition to consider hEDS/HSD as a single entity that requires the same treatments.

A review of respiratory manifestations and their management in Ehlers-Danlos syndromes and hypermobility spectrum disorders

Article

Full-text available

Jul 2021
Chron Respir Dis

Background: Ehlers-Danlos Syndromes (EDS) and Hypermobility Spectrum Disorders (HSD) are a heterogeneous group of heritable genetic connective tissue disorders with multiple characteristics including joint hypermobility, tissue fragility, and multiple organ dysfunction. Respiratory manifestations have been described in EDS patients, but have not been systematically characterized. A narrative review was undertaken to describe the respiratory presentations and management strategies of individuals with EDS and HSD. Methods: A broad literature search of Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane CENTRAL was undertaken from inception to November 2020 of all study types, evaluating EDS/ HSD and pulmonary conditions. This narrative review was limited to adult patients and publications in English. Results: Respiratory manifestations have generally been described in hypermobile EDS (hEDS), classical and vascular EDS subtypes. Depending on EDS subtype, they may include but are not limited to dyspnea, dysphonia, asthma, sleep apnea, and reduced respiratory muscle function, with hemothorax and pneumothorax often observed with vascular EDS. Respiratory manifestations in HSD have been less frequently characterized in the literature, but exertional dyspnea is the more common symptom described. Respiratory symptoms in EDS can have an adverse impact on quality of life. The respiratory management of EDS patients has followed standard approaches with thoracotomy tubes and pleurodesis for pleural manifestations, vocal cord strengthening exercises, continuous positive pressure support for sleep apnea, and exercise training. Reduced respiratory muscle function in hEDS patients responds to inspiratory muscle training. Conclusion: Respiratory symptoms and manifestations are described in EDS and HSD, and have generally been managed using conservative non-surgical strategies. Research into the prevalence, incidence and specific respiratory management strategies in EDS and HSD is needed to mitigate some of the associated morbidity.

Hypermobile Ehlers–Danlos syndrome: A review and a critical appraisal of published genetic research to date

Article

Full-text available

Jul 2021
CLIN GENET

The Ehlers–Danlos syndromes (EDS) are a collection of rare hereditary connective tissue disorders with heterogeneous phenotypes, usually diagnosed following clinical examination and confirmatory genetic testing. Diagnosis of the commonest subtype, hypermobile Ehlers–Danlos Syndrome (hEDS), relies solely on a clinical diagnosis since its molecular aetiology remains unknown. We performed an up‐to‐date literature search and selected 11 out of 304 publications according to a set of established criteria. Studies reporting variants affecting collagen proteins were found to be hindered by cohort misclassification and subsequent lack of reproducibility of these genetic findings. The role of the described variants affecting Tenascin‐X and LZTS1 is yet to be demonstrated in the majority of hEDS cases, while the functional implication of associated signaling pathways and genes requires further elucidation. The available literature on the genetics of hEDS is scant, dispersed and conflicting due to out‐dated nosology terminology. Recent literature has suggested the role of several promising candidate mechanisms which may be linked to the underlying molecular aetiology. Knowledge of the molecular genetic basis of hEDS is expected to increase in the near future through the mainstream use of high‐throughput sequencing combined with the updated classification of EDS, and the upcoming Hypermobile Ehlers–Danlos Genetic Evaluation (HEDGE) study.

Cardiovascular manifestations of hypermobile Ehlers–Danlos syndrome and hypermobility spectrum disorders

Article

Jan 2022

Introduction: Mitral valve prolapse and aortic root dilatation are reported in association with hypermobile Ehlers–Danlos syndrome (hEDS), but the full phenotypic spectrum of cardiovascular complications in this condition has not been studied in the aftermath of updated nosology and diagnostic criteria. Methods: We performed a retrospective review of 258 patients (> 94% adults) referred to a multidisciplinary clinic for evaluation of joint hypermobility between January 2017 and December 2020 and diagnosed with hEDS or a hypermobility spectrum disorder (HSD) to determine the incidence and spectrum of cardiovascular involvement. Results: Mitral valve prolapse was present in 7.5% and thoracic aortic dilatation in 15.2%. Aortic dilatation was more frequent in individuals with hEDS (20.7%) than with HSD (7.7%) and similarly prevalent between males and females, although was mild in > 90% of females and moderate-to-severe in 50% of males. Five individuals (1.9%) with hEDS/HSD had extra-aortic arterial involvement, including cervical artery dissection (CeAD, n = 2), spontaneous coronary artery dissection (SCAD, n = 2), and SCAD plus celiac artery pseudoaneurysm ( n = 1). This is the first series to report the prevalence of CeAD and SCAD in hEDS/HSD. Conclusions: Cardiovascular manifestations in adults with hEDS/HSD, especially females, are typically mild and readily assessed by echocardiography. Since the risk of progression has not yet been defined, adults with hEDS/HSD who are found to have aortic dilatation at baseline should continue ongoing surveillance to monitor for progressive dilatation. Cardiovascular medicine specialists, neurologists, and neurosurgeons should consider hEDS/HSD on the differential for patients with CeAD or SCAD who also have joint hypermobility.

Ehlers–Danlos syndromes, hypermobility spectrum disorders, and associated co‐morbidities : Reports from EDS ECHO

Article

Nov 2021

Hypermobile Ehlers‐Danlos Syndrome and disorders of the gastrointestinal tract. What the Gastroenterologist needs to know

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