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GastrointestinalandNutritionalIssuesinJointHypermobilitySyndrome/Ehlers-DanlosSyndrome,HypermobilityType

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 169C:54–75 (2015)

A R T I C L E

Gastrointestinal and Nutritional Issues inJoint Hypermobility Syndrome/Ehlers–DanlosSyndrome, Hypermobility TypeMARCO CASTORI, SILVIA MORLINO, GIULIA PASCOLINI, CARLO BLUNDO,AND PAOLA GRAMMATICO

Marco Castodegree with agenodermatosseveral book c

Silvia Morlinactivity of theconnective tiss

Giulia Pascoactivity of the D

Carlo BlundHospital in Romand behavioraneurology.

Paola GrammCamillo-Forlantesting and rapathology. She

Conflict of iFunding: No*Correspon

I-00152 RomeDOI 10.100Article first

� 2015 Wil

Gastrointestinal involvement is a well known complication of Ehlers–Danlos syndromes (EDSs), mainly in form ofabdominal emergencies due to intestinal/abdominal vessels rupture in vascular EDS. In the last decade, agrowing number of works investigated the relationship between a wide spectrum of chronic gastrointestinalcomplaints and various EDS forms, among which the hypermobility type (a.k.a. joint hypermobility syndrome;JHS/EDS-HT) was the most studied. The emerging findings depict a major role for gastrointestinal involvement inthe health status and, consequently, management of JHS/EDS-HT patients. Nevertheless, fragmentation ofknowledge limits its impact on practice within the boundaries of highly specialized clinics. In this paper, literaturereview on gastrointestinal manifestations in JHS/EDS-HT was carried out and identified papers categorized as (i)case-control/cohort studies associating (apparently non-syndromic) joint hypermobility and gastrointestinalinvolvement, (ii) case-control/cohort studies associating JHS/EDS-HT and gastrointestinal involvement, (iii) casereports/series on various gastrointestinal complications in (presumed) JHS/EDS-HT, and (iv) studies reportinggastrointestinal features in heterogeneous EDS patients’ cohorts. Gastrointestinal manifestations of JHS/EDS-HTwere organized and discussed in two categories, including structural anomalies (i.e., abdominal/diaphragmatichernias, internal organ/pelvic prolapses, intestinal intussusceptions) and functional features (i.e., dysphagia,gastro-esophageal reflux, dyspepsia, recurrent abdominal pain, constipation/diarrhea), with emphasis onpractice and future implications. In the second part of this paper, a summary of possible nutritional interventionsin JHS/EDS-HT was presented. Supplementation strategies were borrowed from data available for generalpopulationwithminormodifications in the light of recent discoveries in the pathogenesis of selected JHS/EDS-HTfeatures. © 2015 Wiley Periodicals, Inc.

KEYWORDS: abdominal pain; constipation; diet; Ehlers–Danlos syndrome; nutraceuticals

How to cite this article: Castori M,Morlino S, Pascolini G, Blundo C, Grammatico P. 2015. Gastrointestinaland nutritional issues in joint hypermobility syndrome/Ehlers–Danlos syndrome, hypermobility type.

Am J Med Genet Part C 169C:54–75.

ri is a medical geneticist enrolled as senior hospital-based clinician at the San Camillo-Forlanini Hospital in Rome. He obtained his PhDclinical and management study on Ehlers–Danlos syndrome(s). Major research topics include hereditary connective tissue disorders,es, clinical dysmorphology, and fetal pathology. He is author and co-author of more than 100 publications in international journals andhapters.o is a MD resident in Medical Genetics at the Sapienza University of Rome. She has a full-time involvement in the clinical and researchDivision of Medical Genetics at the San Camillo-Hospital in Rome. Her interests mostly include clinical dysmorphology and hereditaryue disorders.lini is aMD resident in Medical Genetics at the Sapienza University of Rome. She has a part-time involvement in the clinical and researchivision ofMedical Genetics at the San Camillo-Hospital in Rome. Her interests include clinical dysmorphology and intellectual disability.o is a senior neurologist and neuropsychologist, head of the Unit of Cognitive and Behavioral Neurology at the San Camillo-Forlaninie. He is actively involved in the diagnosis and management of various forms of dementia. Since 2011, he is also interested in cognitive

l aspects of Ehlers–Danlos syndrome and joint hypermobility syndrome. He is author of various books and book chapters in the field of

atico is an associate professor ofMedical Genetics at the SapienzaUniversity and director of the Division ofMedical Genetics at the Sanini Hospital in Rome. She has various responsibilities in the regional and national Healthcare system with focus on genetic laboratoryre diseases. Her major diagnostic and research interests include cutaneous melanoma, disorders of sex differentiation and fetalis author of more than 150 papers in international journals and various book chapters on medical genetics.

nterest: The authors have no conflict of interest to declare.funding was active on this project.

dence to: Marco Castori, M.D., PhD, Division of Medical Genetics, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87,, Italy. E-mail: m.castori@scf.gov.it.2/ajmg.c.31431published online in Wiley Online Library (wileyonlinelibrary.com).

ey Periodicals, Inc.

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 55

INTRODUCTION

Gastrointestinal (GI) involvement ofEDS is known since the late seventies[Beighton et al., 1969]. For many years,the attention of researchers and clini-cians was mostly attracted by the life-threatening complications of vascularEDS, which features spontaneous boweland abdominal vessel ruptures [Beightonet al., 1998]. However, literature alsoaccounts some papers pointing out awider spectrum of GI manifestations invarious forms of EDS [Burcharth andRosenberg, 2012]. The awareness onthe impact of GI manifestations to thehealth status of EDS patients rose in thelast decade, when Hakim and Grahame[2004] found a high rate of variousfunctional GI complaints in adults withjoint hypermobility syndrome (a.k.a.Ehlers–Danlos syndrome, hypermobil-ity type; JHS/EDS-HT). Accordingly,Levy [2012] listed functional boweldisorders as an “unofficial” minordiagnostic item in the 2004 version ofhis reference paper on JHS/EDS-HT.Since then, a growing number of workspresented data on the spectrum, rate andpossible pathogenesis of GI manifesta-tions in JHS/EDS-HT [see below].However, while actual knowledge ac-counts a number of studies highlightingthe impact of GI manifestations in JHS/EDS-HT, the emerging results stilldepict a fragmented picture which layson the heterogeneous and, occasionally,divergent perspectives of the involvedresearch groups.

In the first part of this paper, wecarried out a review of available datawith the aim of offering a comprehen-sive summary of GI involvement inJHS/EDS-HT.We also tried to present awider perspective by speculating onpathogenesis and actual managementapproach. As a side aspect of GIinvolvement in EDS, Mantle et al.[2005] proposed a set of nutritionalinterventions purportedly aimed atimproving selected disease manifesta-tions of this condition. The possibleapplications of this resource was re-inforced by Tinkle [2010]; who re-ported his experience on nutraceuticalsin his monograph on JHS/EDS-HT.

Research on nutritional interventions inEDS is still in its infancy. Nevertheless,data on the possible beneficial effects ofan increasing number of nutraceuticalsin many chronic complaints commonlyencountered in JHS/EDS-HT is nowavailable for the general population. Inthe second part of this paper, we presenta summary of actual knowledge andtheoretical applications of nutritionaltherapy in the management of somedisease aspects of JHS/EDS-HT.

METHODS

This study consisted in a PubMed searchwith the following research string:[“Ehlers–Danlos syndrome” OR EDSOR hypermobility] AND [abdominalOR anal OR bowel OR colonic ORconstipation OR diarrhea OR dyspha-gia OR esophagus OR gastric ORgastrointestinal OR gut OR liver ORprolapse OR rectal]. All relevant articlesdetected in this phase were furtherscrutinized for additional referencesnot appeared in this search. Review orhypothesis papers without novel datawere excluded from the Results section,while their contents were used forinterpretation of collected information.All papers clearly concerning EDSsubtypes other than JHS/EDS-HT(mainly, vascular and classic EDS) wereequally excluded. Case-control studiesrelating GI manifestations with non-syndromic/unclassified generalized jointhypermobility (gJHM), and case-controland case series works investigating GIinvolvement in patients with unclassifiedEDS or belonging to various EDSsubtypes were included, but their resultswere presented separately. Inclusion ofthese works was based on the following:(1) at the moment, apparently isolatedgJHM blurs within the increasingly widespectrum of JHS/EDS-HT and thedistinction between asymptomatic/”be-nign” gJHM and JHS/EDS-HT is oftendifficult especiallywithin the same family;(2) many studies investigating the associ-ation between gJHM and GI features donot declare a formal exclusion of JHS/EDS-HT in their cohorts; (3) with theexception, perhaps, of vascular manifes-tations and spontaneous rupture of thegut

which are typical of vascular EDS, allother GI manifestations seem shared bymost EDS subtypes; (4) JHS/EDS-HT isprobably the most common EDS sub-type. Single case reports were alsoselected. For these works, the likelihoodof the diagnosis of JHS/EDS-HT wasascertained by checking for a formalattribution of EDS subtype (i.e., JHS,EDS-HT, EDS type III) by the authorsthemselves, or by comparing the reportedextra-GI manifestations with the Ville-franche and Brighton criteria. Thepresence of spontaneous bowel ruptureand/or suspected vascular accidents leadto the attribution of vascular EDS and,then, to exclude the paper.

RESULTS

Studies Associating GeneralizedJoint Hypermobility WithGastrointestinal Complaints

A total of 16 papers, all published in thelast 18 years (1987–2014), were identi-fied. Fifteen studies compared the rate ofspecific GI features with gJHM in twopopulations. In one of these fifteenstudies [Arunkalaivanan et al., 2009],controls’ data were extracted by pre-viously published works [Nelson et al.,1995]. Twelve out of fifteen (80.0%)studies yielded positive results whichwere summarized in Table I. Theremaining three failed to demonstratean association between gJHM andspecific GI features, in particular pelvicprolapse [Brækken et al., 2009; Hafiziet al., 2013; Derpapas et al., 2014].Morespecifically, Brækken et al. [2009] didnot identify a relationship betweengJHM measured with the Beightonscore (with a cut-off of �4) and pelvicorgan prolapse comparing 49 womenwith 49 controls. Conversely, theyfound an association between pelvicorgan prolapse and other “soft”markers,such as easy bruising and varicose veins,of an underlying connective tissuedisorder (P¼ 0.001 and 0.005, respec-tively). Hafizi et al. [2013] comparedpositive Beighon score (with a cut-off of�4) with pelvic organ prolapse betweenpatients’ and controls’ groups eachcomposed of 60 adult females. Derpapas

TABLEI.

StudiesInvestigatingtheAssociationBetween(U

nclassified

/Nonsyndromic)Gen

eralized

JointHyp

ermobilityan

dGastrointestinal

Features

Reference

agJHM

assessing

strategy

No.

ofpatientsNo.

ofcontrols

Characteristicsof

patients

Characteristicsof

controls

Investigated

feature(s)

Ratein

patients

Ratein

controls

Pvalue

Summary

Marshman

etal.,1987

Measuring

fifth

fingerextension

with

aspecific

finger

goniom

eter

2525

4females

and

21males

(6–93

years)who

undergon

esurgeryfor

completerectal

prolapse

4females

and

21males

(mean67

years)

admitted

for

surgerybu

twith

outrectal

prolapse

Fifth

finger

extension

81�2.2

degrees

68�1.7

degrees

0.001

Fifth

fingerismore

extensible

inpatients

who

undergon

esurgery

repairforrectalprolapse

Norton

etal.,1995

2or

moreof

the

following:

1)passive

oppo

sitionof

thum

b(s)to

the

wrist,2)

passive

hyperextensio

nof

fifth

digit(s)to

greaterthan

55°,

3)active

hyperextensio

nof

elbow

(s)to

greaterthan

190°

3969

Females

(49–57

years)with

gJHM

Females

(51–

59years)

with

outgJHM

Rectocele

(any

grade)

84%

48%

0.0002

Rectocele

ismore

common

andsevere

infemales

with

gJHM

Rectocele

(grades2

and3)

34%

13%

0.009

Pulliam

and

Schu

ster,

1995

Opposition

ofthum

bto

wrist,

TMJdysfun

ction,

scoliosis

431566

39females

and

4males

(18–62

years)with

chronic

intestinal

pseudo

obstruction

Unselected

individu

alswith

GIsymptom

s

gJHM

46.5%

13.9%

<0.001

gJHM

ismorecommon

inpatientswith

chronic

intestinal

pseudo

obstruction

Al-Raw

iet

al.,2004

Beightonscore

(�4)

5050

28men

and22

wom

enwith

hiatus

herniaat

endo

scop

y

30men

and20

wom

enwith

norm

alendo

scopy

gJHM

22%

6%0.001

gJHM

ismorecommon

inadultswith

hiatus

hernia

Jha et

al.,2007

Beightonscore

(>4)

3030

Females

(20–58

years)with

gJHM

attend

ing

rheumatolog

ic

Females

(22–

56years)

with

outgJHM

attend

inga

Anal

incontinence

23%

0%0.01

Analincontinence

ismorecommon

infemales

with

gJHM

56 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

TABLEI.

(Continued)

Reference

agJHM

assessing

strategy

No.

ofpatientsNo.

ofcontrols

Characteristicsof

patients

Characteristicsof

controls

Investigated

feature(s)

Ratein

patients

Ratein

controls

Pvalue

Summary

clinic;

Caucasians,

Asian,

Afrocaribbean

rheumatolog

icclinic;

Caucasians,

Asian,

Afrocaribbean

Reilly etal.,2008

Beightonscore

(>4)

3941

13females

and

26males

(7–17

years)with

slow

transit

constip

ation

18females

and23

males

(7–17

years)

with

out

constip

ation

requ

iring

medical

treatm

ent

gJHM

(males)

38%

4%0.004

gJHM

isselectivelymore

common

inmales

with

slow

transit

constip

ation

Arunk

alaivanan

etal.,2009

Beightonscore

(>4)

148

NA

Adu

ltfemales

with

gJHM

mem

bersof

the

Hypermob

ility

Synd

rome

Associatio

n;Caucasians

(98%

)

Generaladult

popu

latio

n;previously

publish

eddatac

Faecal

incontinence

14.9%

2.2%

<0.05

Faecalincontinence

ismorecommon

infemales

with

gJHM

Vou

notrypidis

etal.,2009

Beightonscore;

Brightoncriteria

forJH

S

6967

32females

and

37males

(18–

50years)with

inflammatory

bowel

disease;

Greek

Caucasians

29females

and38

males

(18–50

years);

Greek

Caucasians

gJHM

b70.3%

(Crohn

disease)

25.4%

<0.0001

gJHM

ismorecommon

inpatientswith

Crohn

disease;

thechance

ofhaving

Crohn

disease

amon

gpatientswith

inflammatorybowel

diseaseandgJHM

istw

ofoldthan

ulcerative

colitis

Moh

ammed

etal.,2010

5-po

int

questio

nnaire

d65

135

63females

and

2males

(15–80

years)with

gJHM

and

intractableconstip

ation

116females

and19

males

(20–83

years)

with

intractable

constip

ation

andwith

out

Gender

(fem

ale/male)

96.9%/

3.1%

85.9%/

14.1%

0.02

Individu

alswith

gJHM

and

chronicconstip

ationare

morecommon

lyfemales

with

ahistoryof

surgery

forpelvic

prolapse

and

morecommon

lydisplay

Previous

surgeryfor

pelvic

organ

30.7%

17.0%

0.04

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 57

TABLEI.

(Continued)

Reference

agJHM

assessing

strategy

No.

ofpatientsNo.

ofcontrols

Characteristicsof

patients

Characteristicsof

controls

Investigated

feature(s)

Ratein

patients

Ratein

controls

Pvalue

Summary

gJHM

incompleterectal

evacuatio

n,functio

nal

rectoceleandextrinsic

compressio

nof

the

anterior

rectalwallat

anorectalph

ysiological

investigationthan

patientswith

outgJHM.

The

absenceof

aprecipitatin

geventfor

constip

ationismore

common

intheform

ergrou

p.

prolapse

Incomplete

rectal

evacuatio

n

80%

59%

0.004

Functio

nal

rectocele

58%

39%

0.01

Extrinsic

compressio

nof

the

anterior

rectalwall

111

0.006

Zarate

etal.,2010

Beightonscore

(>4)

6366

54females

and

9males

(16–71

years)with

gJHM

and

unexplainedGI

symptom

s

43females

and23

males

(18–78

years)

with

outgJHM

and

unexplainedGI

symptom

s

Kno

wn

etiology

19%

59%

<0.0001

Individu

alswith

gJHM

and

unexplainedGI

symptom

sareyoun

ger,

morefrequently

females,

andmorecommon

lydisplay

gastroesop

hagealreflu

xandbloatin

gthan

patientswith

outgJHM.

Etio

logy

ofsymptom

sin

gJHM

patientsismore

common

lyun

know

nthan

forindividu

alswith

out

gJHM.

Age

37years

(mean)

44years

(mean)

0.01

Gender

(fem

ale)

86%

65%

0.008

Gastroeso

phageal

reflu

x

56%

30%

0.005

Bloating

62%

46%

0.05

Lammers

etal.,2012

“Presence

ofa

luxatio

nor

spain

ofajoint”

110

100

Females

(51–89

years)with

gJHM

attend

ing

gynecologic

clinic

Females

(51–

95years)

with

outgJHM

attend

ing

gynecologic

clinic

Pelvic

organ

prolapse

19%

2%<0.01

Pelvic

organprolapse

ismorecommon

infemales

with

gJHM

Kajbafzadeh

etal.,2014

Beightonscore

(�4)

113

113

Children(5–14

years)with

voiding

dysfun

ction;

Health

yscho

olchildren

(5–14

years);

Iranians

gJHM

(total)

45%

17%

0.001

gJHM

ismorecommon

inchildrenwith

voiding

dysfun

ction.

Amon

gchildrenwith

gJHM,

gJHM

(fem

ales)

44%

23%

0.017

58 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

TABLEI.

(Continued)

Reference

agJHM

assessing

strategy

No.

ofpatientsNo.

ofcontrols

Characteristicsof

patients

Characteristicsof

controls

Investigated

feature(s)

Ratein

patients

Ratein

controls

Pvalue

Summary

Iranians

urinarytractinfections

aremorecommon

infemales,while

constip

ationismore

common

inmales

gJHM

(males)

34%

5%0.04

GI,gastrointestinal;gJHM,g

eneralized

jointhyperm

obility;JH

S,jointhyperm

obility

synd

rome;

NA,no

tavailable;

TMJ,tempo

romandibu

larjoint.

a Onlyfeatures

with

statistically

significantdifferences

betw

eenpatients’andcontrols’

grou

psarerepo

rted

inthetable(i.

e.,P

value<0.05).

b 5ou

tof2

9individu

alsw

ithgJHM

andCrohn

diseaseand1ou

tof1

0individu

alsw

ithgJHM

andulcerativecolitisalso

metBrightoncriteriaforjointh

ypermob

ility

synd

romewith

acumulativeOR

of3.75.

c From

Nelsonet

al.[1995].

d The

5-po

intqu

estio

nnaire

isaself-repo

rted

questio

nnaire

investigatinghistoricalgJHM

[Hakim

andGrahame,2003].

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 59

et al. [2014] studied 270 women withurinary incontinence and pelvic organprolapse, who were screening for gJHMwith the self-reported 5-point ques-tionnaire by Hakim and Grahame[2003].

Of the 12 studies with positiveresults (Table I), four studied adultfemales only [Norton et al., 1995; Jhaet al., 2007; Arunkalaivanan et al., 2009;Lammers et al., 2012], five adult malesand females [Pulliam and Schuster, 1995;Al-Rawi et al., 2004; Reilly et al., 2008;Vounotrypidis et al., 2009; Zarate et al.,2010], two children and adolescents fromboth sexes [Mohammed et al., 2010;Kajbafzadeh et al., 2014], and onechildren, adolescents and adults fromboth sexes [Marshman et al., 1987].Theseworks differed also for the assessingmethod for gJHM, which was theBeighton score with a positive cut-offof>4 four times [Jha et al., 2007; Reillyet al., 2008; Arunkalaivanan et al., 2009;Zarate et al., 2010], Beighton score witha positive cut-off of �4 twice [Al-Rawiet al., 2004; Kajbafzadeh et al., 2014],Beighton score with an undefined pos-itive cut-off once [Vounotrypidis et al.,2009], the self-reported 5-point ques-tionnaire once [Mohammed et al., 2010],and a self-developed screening methodfour times [Marshman et al., 1987;Norton et al., 1995; Pulliam and Schus-ter, 1995; Lammers et al., 2012]. Asso-ciation between gJHM and chronicconstipation, alternatively termed aschronic intestinal pseudoobstruction[Pulliam and Schuster, 1995] or slowtransit constipation [Mohammed et al.,2010], appeared the most consistent,being observed four times in both sexesfromall ages [Pulliam andSchuster, 1995;Reilly et al., 2008; Mohammed et al.,2010; Kajbafzadeh et al., 2014]. Also thelink between gJHM with rectal/pelvicprolapse and anal/fecal incontinenceseemed strong in women [Marshmanet al., 1987;Norton et al., 1995; Jha et al.,2007; Arunkalaivanan et al., 2009;Lammers et al., 2012]. A study pointedout a relationship between constipationand a past history of pelvic prolapse infemales [Mohammed et al., 2010]. Threefurther works highlighted the associationbetween gJHM with some upper GI

TABLE II. Prevalence of Selected Gastrointestinal Features in Joint Hypermobility Syndrome/Ehlers–Danlos Syndrome,Hypermobility Type

FeatureCastori

et al., 2010Castori

et al., 2011aZarate

et al., 2010

No. of patients 21 50 21

0 – 10 years 11 –20 years 21 –30 years 31 –40 years >40 yearsDysphagia — — — — — — 14.3%Dyspepsia/chronic gastritis 66.7% 8% 28% 40% 44% 48% 14.3%Gastro-esophageal reflux 57.1% 20% 48% 60% 70% 74% 52.4%Bloating — — — — — — 57.1%Nausea — — — — — — 57.1%Vomiting — — — — — — 57.1%Recurrent abdominal pain 61.9% 26% 40% 54% 64% 68% 85.7%Constipation/diarrhea 33.3% 54% 60% 70% 70% 72% 76.2%Abdominal hernia(s) 4.8% 10% 14% 18% 18% 20% —

Abnormal esophageal manometry — — — — — — 33.3%a

Abnormal 24 h pH-metry — — — — — — 33.3%b

Delayed gastric emptying — — — — — — 80%c

Abnormal small bowel manometry — — — — — — 44.4%d

Abnormal colorectal transit — — — — — — 100%e

aFrom a total of 12 patients, and including hypotonic lower esophageal sphincter (#1), ineffective esophageal motility (#2), and poorperistalsis of the lower esophagus (#1).bFrom a total of 12 patients, and including mild reflux (#2) and pathologic reflux (#2).cFrom a total of 15 patients.dFrom a total of 9 patients, and including bursts of contractions (#2), loss of circadian cycles of motility (#2), absent nocturnal migratingmotor complex (#1), no postprandial changes (#1), poor amplitude contractions (#1), retroperistalsis in the phase III of the migratingmotor complex (#1), and lack of feeding pattern (#1).eFrom a total of 6 patients, and including delayed colonic transit (#3), rectal hypersensitivity (#1), rectocele (#1), poor evacuatory effort(#1), rectal evacuatory disorder (#1), and circumferential intussusceptions (#1).

60 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

complaints (i.e., gastro-esophageal refluxand bloating) [Zarate et al., 2010], hiatushernia [Al-Rawi et al., 2004], andCrohndisease [Vounotrypidis et al., 2009].“Functional” nature of constipation andupper GI complaints in individuals withgJHM was envisaged twice by the netprevalence of an absent precipitatingfactor for both features in these subjects[Mohammed et al., 2010; Zarate et al.,2010]. A further, not tabulated paperanalyzed the prevalence of specific anam-nestic features in 568womenat 12monthspostpartum after a high risk delivery (i.e.,instrumental delivery and/or high birth-weight infant), and found a relationshipbetween fecal incontinence and gJHMin the patients’ group [Chiarelli et al.,2003].

Studies InvestigatingGastrointestinal Manifestations inJHS/EDS-HT

Concerning GI manifestations in JHS/EDS-HT, identified articles were sub-divided in three groups: (1) worksshowing rough rates of selected GIfeatures in JHS/EDS-HT [Hakim andGrahame, 2004; Castori et al., 2010,2011a, 2012a; Zarate et al., 2010], (2)works comparing rates of selected GIfeatures between JHS/EDS-HT andgeneral population [Manning et al.,2003; Danese et al., 2011; Mastoroudeset al., 2013; Fikree et al., 2014], and (3)studies investigating the intra-pheno-typic variability and scrutinizing therelationship of GI features with other

manifestations/characteristics of JHS/EDS-HT [De Wandele et al., 2013;De Wandele et al., 2014; Pacey et al.,2014].

Group 1 consisted of five works.Hakim and Grahame [2004] first notedGI complaints in 37% of 170 womenaged from 18 to 65 years. In this study,the value was cumulative for nausea,stomach ache, diarrhea and constipa-tion, and separated rates were notavailable. By describing obstetric andgynecologic findings in 82 women withJHS/EDS-HT, we found GI complaintsin 71.9% and rectal prolapse in 11.1% ofcases [Castori et al., 2012a]. Threefurther works reported values by se-lected features and were summarized inTable II. While we described patient-

TABLEIII.

StudiesInvestigatingtheAssociationBetweenJointHyp

ermobilitySyn

drome/

Ehlers–Dan

losSyn

drome,

Hyp

ermobilityTyp

ean

dGastrointestinal

Features

Reference

a

JHS/EDS-HT

assessing

strategy

No.

ofpatients

No.

ofcontrols

Characteristics

ofpatients

Characteristics

ofcontrols

Investigated

GIfeature(s)

Ratein

patients

Ratein

controls

Pvalue

Summary

Manning

etal.,2003

Mod

ified

Brighton

criteria

404

397

Wom

enwith

LUTD

and

obstructed

defecatio

n

Wom

enwith

LUTD

and

with

out

obstructed

defecatio

n

JHS“features”

70.6%

50.0%

<0.0001

JHSseem

smorecommon

inwom

enwith

LUTD

and

obstructed

defecatio

nthan

inthosewith

outdefecatory

prob

lems;vice

versa,

defecatory

prob

lemsare

morecommon

inwom

enwith

LUTD

andJH

Sthan

inthosewith

LUTD

butwith

out

JHS

499

339

Wom

enwith

LUTD

and

JHS

Wom

enwith

LUTD

and

with

outJH

S

Childho

odconstip

ation

7.7%

3.2%

0.01

Frequent

loose

stoo

ls

29.5%

22.6%

0.03

Frequent

hard

stoo

ls

36.7%

25.0%

0.0005

Frequent

hard

andloose

stoo

ls

8.8%

4.9%

0.04

Danese

etal.,2011

Villefranche

andBrighton

criteria

31NA

25females

and6males

(years)with

JHS/EDS-HT

attend

ing

clinical

geneticsclinic

Italiangeneral

popu

latio

n;previously

publish

eddatab

Celiac

disease

(Marsh

classification)

16.1%

1.0%

0.002

Celiacdiseaseismore

common

inJH

S/EDS-HT

Mastoroud

eset

al.,2013

Brighton

criteria

6060

Females

(18–

60years)with

JHSattend

ing

hyperm

obility

clinic

Females

(18–

60years)

with

outJH

Srecruitedfrom

hospitalstaff

Vaginalbu

lge

interfering

defecatio

n

23.0%

5.0%

0.007

Defecatoryprob

lemsare

morecommon

infemales

with

JHS;

thereisa

significantcorrelation

betweendefecatory

prob

lemsandpo

sterior

compartmentprolapse

inJH

Sfemales

Strainingfor

defecatio

n61.7%

NA

<0.001

Incomplete

emptying

after

defecatio

n

63%

NA

0.001

Needof

digitatio

nfor

defecatio

n

33.3%

NA

<0.001

Fikree etal.,2014

Brighton

criteria

180

372

123females

and57

males

with

JHS

203females

and169males

with

outJH

S

Age

(mean)

40.6

years

44.2

years

0.003

JHSpatientswith

GI

symptom

sareyoun

gerand

morecommon

lyfemales

Gender

(fem

ale)

68.3%

54.6%

0.002

(Continued)

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 61

TABLEIII.

(Continued)

Reference

a

JHS/EDS-HT

assessing

strategy

No.

ofpatients

No.

ofcontrols

Characteristics

ofpatients

Characteristics

ofcontrols

Investigated

GIfeature(s)

Ratein

patients

Ratein

controls

Pvalue

Summary

attend

ing

gastroenterologic

clinic

attend

ing

gastroenterologic

clinic

than

non-JH

Spatients;

hearthbu

rn,water

brashand

post-prand

ialfullnessare

morecommon

inJH

Spatients;JH

Spatientswith

GIsymptom

shave

more

common

lyextra-GI

autono

mic

symptom

s,fib

romyalgiaandchronic

pain

than

non-JH

Spatients;

JHSpatientsattend

ing

rheumatolog

icclinic

feel

worse

than

JHSpatients

attend

inggastroenterologic

clinic.

Heartbu

rn33.0%

23.5%

0.01

Water

brash

30.9%

18.5%

0.001

Postprandial

fullness

41.4%

27.1%

0.006

EDS-HT,

Ehlers–Danlossynd

rome,hyperm

obility

type;GI,gastrointestinal;JH

S,jointhyperm

obility

synd

rome;LU

TD,low

erurinarytractdisfun

ction;

NA,n

otavailable.

a Onlyfeatures

with

statistically

significantdifferences

betweenpatients’andcontrols’

grou

psarerepo

rted

inthetable(i.

e.,P

value<0.05).

bFrom

Menardo

etal.[2006]andDub

éet

al.[2005].

62 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

reported symptoms only [Castori et al.,2010, 2011a], Zarate et al. [2010]offered details on a series of GIphysiology investigations includingesophageal manometry, 24 hr pH-me-try, gastric emptying study, small bowelmanometry, and colorectal physiologystudy. In addition to the high rate ofmost GI complaints, the last workdemonstrated a widespread dysfunctionof the gut from the lower esophagus tothe anus.

Group 2 comprised four workssummarized in Table III. In the paperby Manning et al. [2003], women withlower urinary tract dysfunction wereinvestigated for clustering of specificfeatures and a clear relationship betweenJHS/EDS-HT and defecatory problemsemerged in this patients’ subgroup.Danese et al. [2011] reported a smallstudy suggesting a relationship betweenceliac disease and JHS/EDS-HT com-paring data between 31 JHS/EDS-HTpatients of both sexes and with variousages, to previously published data on rateof celiac disease in the general popula-tion [Dubé et al., 2005; Menardo et al.,2006]. Mastoroudes et al. [2013] dem-onstrated a significant excess of variousdefecatory problems in 60 JHS/EDS-HT women compared to highlymatched controls. The largest study isthat by Fikree et al. [2014] on 187 JHS/EDS-HT adults compared to 372 con-trols, all attending a gastroenterologicclinics. In this work, JHS/EDS-HTpatients resulted more commonly fe-males and younger than controls andtended to display more commonlyseveral upper GI complaints. An associ-ation of extra-GI autonomic com-plaints, fibromyalgia, and chronicpain with JHS/EDS-HT was alsoconfirmed.

Group 3 included three papers. Inone paper, De Wandele et al. [2013]carried out a multiple questionnairestudy on 78 JHS/EDS-HT adults (70women and 8 men) screened for theVillefranche criteria, with the aim ofinvestigating feature clustering. Threeclusters were identified and GI com-plaints resulted more common in cluster2, which showed the highest rate offatigue, sleeping disorders, orthostatic

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 63

intolerance, thermoregulatory prob-lems, inflammatory signs and cardiovas-cular symptoms, as well as the largestfunctional impairment and the mostsevere pain. In a further work, the sameresearch group from Ghent (Belgium)compared the rate and impact on qualityof life of selected “autonomic” com-plaints in 80 adults with JHS/EDS-HTin comparison with 11 individuals withclassic EDS, 7 with vascular EDS, 38with fibromyalgia and 43 controls.Among the EDS groups, JHS/EDS-HT patients showed the highest rate ofautonomic features, and the burden washigher than other EDS patients andcomparable with the fibromyalgiagroup. In this study, selected GI com-plaints included gastroparesis (registeredin 58 JHS/EDS-HT patients), consti-pation (53 patients) and diarrhea (51patients) [De Wandele et al., 2014].Pacey et al. [2014] presented the resultsof a questionnaire study in 89 childrenwith the Brighton criteria for JHS.Analysis of data identified five clustersand one of them (called “systemic JHS”)was characterized by the unique symp-toms of skin involvement and urinarystress incontinence, as well as a high rateof recurrent joint instability and GIinvolvement. GI involvement was de-fined by the presence of recurrentconstipation, diarrhea or abdominalpain, or the diagnosis of slow transitconstipation or irritable bowel syn-drome. No further detail was offeredon these features.

Surgical Reports in JHS/EDS-HT

Fifteen case reports describe surgicaltechniques (and their outcomes) forvarious GI problems in JHS/EDS-HT(Table IV). A definite diagnosis of JHSaccording to Brighton criteria or EDS-HT according to Villefranche criteriawas declared in seven instances [deWeerd et al., 2012; Reinstein et al.,2012; Dordoni et al., 2013; Fogel, 2013;Sardeli et al., 2013; Plackett et al., 2014].In six patients, the diagnosis of EDSremained unclassified in the originalreport, but JHS/EDS-HT was consid-ered, retrospectively, the most likelybased on the description of extra-GI

features [Douglas and Douglas, 1973;Shaikh and Turner, 1988; Leung, 1989;Defuentes et al., 2004; Levine andAdler, 2005; Chen and Jao, 2007]. Intwo additional cases, the authors pro-posed the diagnosis of classic EDS butapplied criteria did not satisfy availablerecommendations [Mayer et al., 2013].In these cases, JHS/EDS-HTwas con-sidered more appropriate in the light ofthe described picture [Phadke, 1978;Pelizzo et al., 2013]. Summarizing datafrom available literature is difficult dueto the extreme heterogeneity in clinicalpresentation, accuracy of EDS subtypedefinition and details on the long-termoutcome. In JHS/EDS-HT, surgeryappeared repeatedly successful for treat-ing diaphragmatic defects leading to avariety of clinical presentations [Phadke,1978; Shaikh and Turner, 1988; Leung,1989; Levine and Adler, 2005]. In turn,surgery was uneffective multiple timesfor the correction of visceroptosis andpelvic organ prolapse [de Weerd et al.,2012; Dordoni et al., 2013; Pelizzo et al.,2013]. Laparoscopic subtotal colectomyfor bowel ptosis had positive results inone instance [Reinstein et al., 2012], aswell as the repair of a recto-vaginal fasciawith porcine small intestinal submucosamesh in a woman with pelvic organdiscomfort for multiple prolapses [Sar-deli et al., 2013]. The injection of 5mlof 5% phenol in almond oil resultedeffective in treating recurrent rectalprolapse in a 2-year-old infant [Douglasand Douglas, 1973].

Studies InvestigatingGastrointestinal Manifestations inPatients’ Cohorts WithUnclassified EDS Subtypes

A handful of papers report large data onvarious GI aspects in EDS, but infor-mation cannot be extrapolated byclinical subtype. As JHS/EDS-HT ispresumed to represent a proportion ofEDS patients, except those presentingwith acute symptoms due to sponta-neous vessel or bowel rupture, in moststudies, the main results of these workswere equally summarized. An earlywork by Beighton et al. [1969] reporteda retrospective study on GI complica-

tions in 125 EDS patients. Stratificationwas not available and vascular compli-cations are likely related to the vascularsubtype. However, in this work, theauthors pointed out a not stochasticassociation between EDS and a series ofGI and abdominal features, includingdiverticula at different points of the gut,rectal prolapse, and various abdominaland diaphragmatic hernias. A morerecent study found swallowing difficul-ties in 39% of 411 EDS patients affectedby the types I, II, III, IV, and VI (formerclassification) [Hunter et al., 1998].Carley and Schaffer [2000], by reportingdata on urinary incontinence and pelvicorgan prolapse in 12 Marfan and 8 EDSwomen, described rectal prolapse in 2(25%) EDS patients. More recently,Zeitoun et al. [2013] reported the resultsof a questionnaire study on 134 patientswith various EDS subtypes (with apresumably high prevalence of JHS/EDS-HT) and found a high rate ofsymptoms of dyspepsia and gastroeso-phageal reflux, irritable bowel syn-drome, and functional constipation.The Gastrointestinal Quality of Lifeindex was significantly lower in theEDS cohort compared to controls.Based on their experience, the authorsconsidered endoscopy of the upper gutrelatively safe, while they were moresensitive in performing colonoscopy dueto organ fragility in vascular EDS and therisk of mucosal bleeding in most EDSsubtypes. Abonia et al. [2013] describeda 8-fold risk of eosinophilic esophagitisin patients with hereditary connectivetissue disorders compared to the generalpopulation. The genetic background ofthe connective tissue disorder groupseemed heterogeneous with patientswith EDS, Marfan and Loeys–Dietzsyndromes. A peculiar facies in patientswith the combination of connectivetissue disorder and eosinophic esoph-agitis was also proposed.

DISCUSSION

In this review, we confirmed a strongrelationship between a variety of GIdisorders and JHS/EDS-HT. Given therelatively high frequency of this con-dition compared to other heritable

TABLEIV

.CaseRep

ortsofJointHyp

ermobilitySyn

drome/

Ehlers–Dan

losSyn

drome,

Hyp

ermobilityTyp

eWithSurgical

FeaturesInvo

lvingtheGut

Reference

EDS

subtype

Age

Sex

Ascertainment

Mainclinical

feature(s)

GI

symptom

(s)

Anatomical

finding/feature(s)

Surgery

Dou

glas

and

Dou

glas,

1973

Presum

edEDS-HT

2 years

Unk

nown

Rectal

prolapse

gJHM,“inelastic”skin

Recurrent

rectalprolapse

Rectal

prolapse

Effectivetreatm

entwith

theinjectionof

5mlof

5%ph

enol

inalmon

doil

Phadke,

1978

Presum

edEDS-HTa

71 years

Female

Prolon

ged

emesis

gJHM,osteoarthritis,

kyph

oscolio

sis,skin

hyperextensib

ility,

poor

wou

ndhealing,

subcutaneous

spheroids

Recurrent

emesis

Eventratio

nof

left

diaphragm

andtorsion

ofstom

ach

Effectiverepairof

the

diaphragmatic

defect

Shaikh

and

Turner,

1988

Presum

edEDS-HT

17 years

Female

Acute

GI

complaints

gJHM,

dislo

catio

ns,

scoliosis

Epigastric

pain,em

esis

andan

history

ofgeneralized

abdo

minalpain

Strangulationand

infarctio

nof

the

stom

achthroughthe

diaphragm

Effectivegastrectom

ywith

pyloroplastic

Leun

g,1989

Presum

edEDS-HT

22 years

Male

Acute

GI

complaints

NA

Epigastric

pain,em

esis

Strangulationof

the

stom

ach

Effectiverepairof

the

diaphragmatic

defect

Defuentes

etal.,2004

Presum

edEDS-HT

25 years

Female

GIcomplaints

gJHM,skin

hyperextensib

ility,

absent

lingualand

hypo

plastic

labialfrenula

Abdom

inal

pain

with

fever

Multip

lediverticulaof

descendent

and

trasversecolon

Non

e

Levine

and

Adler,2005

Presum

edEDS-HT

22 years

Female

Dyspn

ea,

chestpain,

emesis

gJHM,dislo

catio

ns,

fractures,po

orwou

ndhealing,

positivefamily

history

Emesisafter

pharmacolog

ictherapy

foradislo

catio

n

Rup

ture

ofdiaphragm,

paraesop

hagealhernia

Effectiverepairof

the

diaphragmatic

defect

andNissen

fund

oplication

Chenand

Jao,

2007

Presum

edEDS-HT

20 years

Male

Defecation

prob

lems

gJHM,skin

hyperextensib

ility,

easy

bruisin

g,large

rectalprolapse

Defecation

prob

lems

Rectalprolapse

Effectiveconservative

treatm

ent

Reinstein

etal.,2012

EDS-HT

28 years

Female

GIcomplaints

gJHM,dislo

catio

ns,soft

skin,easy

bruisin

g,arachn

odactyly,myopia

Disabling

abdo

minal

distensio

nand

bloatin

g

Prolapse

ofthesm

all

bowel

andtransverse

colon,

increasedbowel

mob

ility

underdirect

manipulation

Effectivelaparoscop

icsubtotalcolectom

y

64 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

TABLEIV

.(Continued)

Reference

EDS

subtype

Age

Sex

Ascertainment

Mainclinical

feature(s)

GI

symptom

(s)

Anatomical

finding/feature(s)

Surgery

deWeerd

etal.,2012

EDS-HT

47 years

Female

Defecation

prob

lems

NA

Incomplete

evacuatio

n,constip

ation,

pelvic

pain

and

discom

fort

Hiatalhernia,anal

mucosalprolapse,

recto-anal

intussusception,

small

rectoceleandlarge

enterocele

Abdom

inalplastic

surgery,previous

unsuccessful

operation

foranalprolapse

and

recto-analintus-

susceptio

n,Nissen

fund

oplication,

hysterectomy

Dordo

niet

al.,2013

JHS

38 years

Female

GIcomplaints

Beightonscore4/9,

jointpain,skin

hyperextensib

ility,

striaedistensae,

delayedwou

ndhealing,

blue

sclerae,

myopia

Dyspepsiaand

constip

ation

Prolapse

ofstom

ach,

liver,sm

allandlarge

bowel,leftkidn

ey,

ovaries

Recurrenceafter

repeated

gastropexy

and

neph

ropexy

JHS

70 years

Male

Family

stud

ySkin

hyperextensib

ility,

multip

ledislo

catio

ns,

blue

sclerae,

obstructivelung

disease

Irritable

bowel

synd

rome

Mild

prolapse

ofthe

smallbowel,inguinal

hernia

Non

e

Fogel,2013

EDS-HT

35 years

Female

Retrospective

surgerystud

yMultip

lekn

eedislo

catio

nswhich

needed

wheelchair,

positivefamily

history

NA

Multip

lesepsiswith

microperforations

ofthecolon,

smallbowel

obstruction

Cho

lecystectomy,

append

ectomy,total

abdo

minalcolectom

yandileostomy,lysis

ofadhesio

nsPelizzo

etal.,2013

Presum

edEDS-HTa

14 years

Female

Shockwith

abdo

minal

distensio

nand

dehydration

NA

Chron

icintestinal

pseudo

-ob

struction

symptom

s

Dilatatio

nof

the

ascend

ingcolonand

term

inalileum

Recurrenceafter

repeated

ileostomy

Sardeli

etal.,2013

EDS-HT

57 years

Female

Recurrenceof

defecatio

ndysfun

ction

Jointandlim

bpain,

patellarluxatio

ns,

easy

bruisin

g

Inability

toevacuate,

constip

ation

andmass

sensationin

thevagina

Rectocele

Successful

correctio

nof

thedefect

intherecto-

vaginalfasciawith

porcinesm

allintestinal

subm

ucosamesh

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 65

TABLEIV

.(Continued)

Reference

EDS

subtype

Age

Sex

Ascertainment

Mainclinical

feature(s)

GI

symptom

(s)

Anatomical

finding/feature(s)

Surgery

Plackett

etal.,2014

EDS-HT

34 years

Female

Bleeding

hemorrhoids

gJHM,dislo

catio

ns,

back

pain,skin

hyperextensib

ility,

easy

bruisin

g

Rectal

bleeding

Hem

orrhoids

Con

servativetreatm

ent

(outcomeno

tavailable)

GI,gastrointestinal;EDS-HT,

Ehlers–Danlossynd

rome-

hyperm

obility

type;gJHM,g

eneralized

jointhyperm

obility;JH

S,jointhyperm

obility

synd

rome.

a Inthesecases,thediagno

sisofclassic

EDSwasprop

osed

bytheauthorsw

iththesolepresence

ofsubcutaneous

calcified

spheroidsinPh

adnk

e[1978]andun

repo

rted

“hallm

arksofdisturbed

fibrillogenesis”atskin

biop

syin

Pelizzo

etal.[2013].

66 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

connective tissue disorders, JHS/EDS-HTemerges as a model for studying thepathophysiologic basis of such an asso-ciation and, reasonably, identifyingmore tailored management and treat-ment approaches. A great proportion ofthe reviewed studies investigated the linkbetween apparently, non-syndromicgJHM and various GI manifestations.At the moment, whether their findingscan be generalized to JHS/EDS-HT ornot remains to be determined.However,these studies emphasize the relevance ofraising the scientific interest in this field.In fact, accumulated evidence on thenon-casual association between gJHMand many potentially disabling GI dis-orders opens us a novel approach forinterpreting highly prevalent complaintsin humans. Based on results of thisreview, the spectrum of GI manifesta-tions in JHS/EDS-HT may be simplis-tically organized in structural andfunctional features. Available evidenceconcerning these two groups is sum-marized as follows.

Structural features:(1) Abdominal hernias occur in up

to one fifth of the patients, the chance ofoccurrence increases with age, and theirsurgical treatment seems effective understandard procedures.

(2) Rectal prolapse is observed inmore than one tenth of women. It canoccur in nulliparous women but its rate ishighest in those who underwent episiot-omy. As the chance of fecal incontinenceas symptomatic surrogate of pelvic dys-function associates with high-risk deliv-eries also in the general population, inJHS/EDS-HT pregnant women, it seemsreasonable to recommendCesarean as thefirst-choice delivery modality in order toprevent long-term disabilities in an af-fectedmother. Treatment of symptomaticpelvic prolapse remains problematic inJHS/EDS-HT and surgery is generallynot effective. There is a single report ofrectal prolapse in a 2-year-old infant withpresumed JHS/EDS-HT [Douglas andDouglas, 1973].The rate of rectal prolapsein men and children with JHS/EDS-HTremains unknown.

(3) Ptosis of internal organs (Figs. 1and 2), such as stomach, transverse colonand kidney is described in few clinical

reports. Although apparently rare, renal,colonic, and gastric ptosis may be under-estimated in JHS/EDS-HT and theirmanifestations may be influenced byposition and gravity. Treatment byorgano-pexis is generally unsuccessful and the linkbetween such an anatomic feature and thepresumably associated symptoms remainsunclear in JHS/EDS-HT. Colonic reduc-tion by laparoscopy resulted effective once.

(4) Diaphragmatic (e.g., hiatus)hernias and intestinal intussusceptionsare likely additional structural manifes-tations of GI involvement in JHS/EDS-HT, but available data are too prelimi-nary to affirm a non-casual relationship.

Functional manifestations:(1) Collectively, the rate of func-

tional GI symptoms is high, increaseswith age and ranges from�1/3 to�3/4of the patients. Although GI manifes-tations are still not included in theavailable clinical criteria for JHS/EDS-HT, their frequency and related impacton quality of life suggest consideration ofGI involvement as a major feature of thiscondition.

2) In JHS/EDS-HT, functional GIfeatures span from mouth to anus andmainly includes dysphagia, gastroeso-phageal reflux, dyspepsia, irritablebowel disease, and chronic constipation.The typical adult patient presents withmultiple, variably combined symptoms,while (isolated) chronic constipation isthe most common manifestation inchildren.

3) Functional tests, includingesophageal manometry, 24 hr pH-me-try, gastric emptying study, small bowelmanometry, and colorectal transitystudy, often lead to positive results butshould be considered second-line inves-tigations and performed in highlyspecialized settings, preferably by pro-fessionals with experience on JHS/EDS-HT. Swallowing studies could bealso considered in patients with upperGI complaints but evidence is stilllacking.

4) First-line investigations, such asupper GI endoscopy, could be per-formed safely, but usually lead tonegative or inconsistent results. Colo-noscopy should be performed with caredue to a possibly increased risk of

Figure 1. Ptosis of the gut in JHS/EDS-HT.Gastroptosis in awomanwith JHS/EDS-HTwho also displayed delayed gastric emptyingat gastric emptying study (A). The same patient also showing dislocation of the small bowel in the pelvis (B). Different degrees of largebowel ptosis in orthostatism in adults with JHS/EDS-HT (C, D).

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 67

mucosal bleeding. Colonic redundancy,ptosis and/or hypermobility may befurther limitations to colonoscopy.

5) Treatment of functional GIcomplaints in JHS/EDS-HT is prob-lematic due to the absence of tailoredstrategies and an apparent resistance topharmacologic treatments at standarddosages/regimens. The exclusion ofcommon co-morbidities, such as celiacdisease, lactose intolerance, and Helico-bacter pylori infection, is reasonable at firstexamination.

6) Due to the lack of efficacioustreatments and the absence of knownprecipitating triggers (perhaps, exceptfor inadequate surgical treatment ofinternal and pelvic organ prolapse(s) as

well as traumatic deliveries), patients’education, also comprising diet andnutritional advice, seems at the momentthe most effective management tool.

Pathogenesis of GI manifestationsin JHS/EDS-HT is still largely un-known and the existence of specificfactors remains speculative. Recently,particular attention has been posed ondysautonomia as a major contributor toonset and/or progression of a widespectrum of functional GI complaints inJHS/EDS-HT [Zarate et al., 2010;Castori et al., 2013b; De Wandeleet al., 2013, 2014; Farmer et al.,2014]. The strength of this hypothesis,though promising, is actually hamperedby the descriptive nature of published

works and the objective difficultiesencountered in investigating its under-lying pathophysiology. Furthermore, inJHS/EDS-HT, the influence of dysau-tonomia is reasonably weaker for otherGI manifestations, such as internal organprolapse and mucosal bleeding.

More widely, connective tissue isstrongly represented in various compo-nents of the GI apparatus, such asperitoneal ligaments, gut wall andsplanchnic vessels. Peritoneal ligamen-tous laxity leading to hypermobility ofthe intra-abdominal viscera is consid-ered a predisposing factor to abdominaltwists and torsions [Timpone et al.,2011], and could facilitate visceralprolapse or hernias under the additive

Figure 2. Contrast abdominal radiograph in an adult with JHS/EDS-HT. Comparison between the supine (A) and erect position (B).There is an overt downward dislocation of the entire colon, sigmoid, and rectum in orthostatism compared to clinostatism.

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effect of orthostatism and other factorsincreasing intra-abdominal pressure(such as, pregnancy and chronic con-stipation). Accordingly, Curci et al.[2008] found subtle alterations of theelastic fibers in the supporting ligamentsof the gastro-esophageal junction inpatients with gastro-esophageal refluxand hiatus hernia.

An abnormal connective tissuecontent within the gut wall may affectits functions by increasing the compli-ance of hollow viscera with excessivedistension, as well as by directly inter-fering with gut mechano-receptorsembedded in the connective tissue-rich muscularis externa [Grundy andSchemann, 2006]. Summative effectsof this process may include influences onpain thresholds and gut motility, bothknown contributors to various func-tional GI complaints, such as gastro-esophageal reflux, abdominal pain,bloating, diarrhea and constipation[Farmer and Aziz, 2014]. Furthermore,a defect of the extracellular matrix in thelamina propria and secondary alterationsof luminal microbiota may affect per-meability of gut mucosa, a mechanismwhich may explain, in part, the associ-ations with celiac disease [Danese et al.,2011], Crohn disease [Vounotrypidis

et al., 2009] and eosinophilic esophagitis[Abonia et al., 2013].

Capillary fragility is a well-knowncutaneous and oral manifestation ofJHS/EDS-HT [Castori et al., 2015].Although accurate data are lacking, anextension of this feature to the entireGI mucosa is reasonable and mayexplain a presumed propensity tominor hemorrhages. A reduced capil-lary and small vessels resilience may alsocontribute to peripheral blood steal,which may exacerbate various auto-nomic manifestations, such as nauseaand bloating. Finally, reduced vascularresilience to external forces may ex-acerbate the transitory effects of mes-enteric tractions and compressions onperipheral blood supply, which, inturn, is related to peritoneal ligamen-tous hypermobility.

Finally, literature review empha-sized the role of GI complaints onquality of life of JHS/EDS-HT patients.Comparably tomusculoskeletal pain andfatigue [Voermans and Knoop, 2011],GI manifestations should be consideredmajor contributors to disability in JHS/EDS-HT. However, the scarce knowl-edge of their pathophysiologic basisexplains why surgery and standardpharmacologic treatments are usually

of minor effect at the long-term, withgreat frustration for patients and practi-tioners. Hence, in the ensuing years,clinical research should be focused on:(1) identifying reliable and standardizedprocedures for assessing the role of thevarious pathogenic contributors to theresulting GI disability in any givenpatient; (2) moving towards a multi-disciplinarymanagement of GI disabilityin JHS/EDS-HT with a more activeinvolvement of nutritionists, physio-therapists, pelvic floor specialists, andnon-traditional medicine practitioners;(3) making up prevention programs tobe applied in order to counteract thedownward spiral of GI disability, andbased on tailored lifestyle interventionsand diet education. Concerning thelatter, the following section is dedicatedto reasonable nutriceutical interventionsin JHS/EDS-HT.

NUTRITIONAL ASPECTS

Background

The role of nutritional therapy in EDSand, in particular, in JHS/EDS-HT is, atthe moment, purely speculative. In2005, Mantle et al. listed a series ofdietary supplements and nutraceuticals

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potentially beneficial for improvingsome EDS features. Among thesesupplementations, there are carnitine,co-enzymeQ10, vitamin C, and variouschondral protectors, which could beeasily prescribed for both preventive andtherapeutic issues. Accordingly, Tinkle[2010] reported his experience withselected nutraceuticals in JHS/EDS-HT.

The role of diet in symptom onsetand progression in JHS/EDS-HT mayextend much beyond the biochemicalcounteract of single pathogenic proc-esses in the postnatal life. The under-standing of epigenetic effects of dietarysupplementations in both health anddisease in humans is in its infancy.Nevertheless, a couple of papers in thefield of gJHM put the basis for possiblefuture studies. In particular, Hasija andet al. [2008] demonstrate a directrelationship between degree of gener-alized gJHM and nutritional status inIndian children. This study envisagesthat a healthy and balanced diet mayimprove the range of joint motion alsoin the symptomatic pediatric patient,with or without a pre-existing diagnosisof EDS. De Felice et al. [2007] focusedon 77 children born with intrauterinegrowth retardation and identified asubgroup of patients characterized byhigher head circumference and anincreased rate of bilaterally nonfunc-tional posterior communicating arteries,peculiar external ear morphology andotoacustic emissions, soft skin andgJHM. Follow-up observations showthat some of these features, including earmorphology, otoacustic emission pat-tern and bilaterally nonfunctional pos-terior communicating arteries, are alsopresent in the patients’ mothers, andthat this subgroup of children associateswith a lower rate of maternal inducedhypertension/pre-eclampsia duringpregnancy.

These findings introduce the con-cept that, in selected subjects/families,generalized gJHM could associate or bea consequence of a “primary” form ofintrauterine growth restriction and thata series of apparently unrelated featurescan be traced along the maternal side.The link between growth restriction

and gJHM remains unexplained, but if itexists it probably lies on the adequacy ofintrauterine nourishment to the em-bryo/fetus. On this perspective, gJHMand, possibly, various associated featuresseem to be strongly influenced by dietand, then, it is reasonable that they areefficiently managed/improved by ad hocnutritional supplementations.

Given such a unsolved gap ofknowledge, we simplistically fragmentedthe disability of JHS/EDS-HT in fivedomains, including osteoarticular man-ifestations, musculoskeletal pain, poorsleep quality and fatigue, skin andmucosal features, and GI manifestations,in order to discuss the possible applica-tion of nutritional supplementations inthe long-term management of thiscondition. All the following consider-ations should be considered low-levelrecommendations exclusively based onthe authors’ experience and speculations.This sectionof paper is inspired bya bookchapter recently published by the authorson the same topic [Castori et al., 2014].

Osteoarticular Features

Whether gJHM predisposes to or ratherprotects from premature osteoarthritis isstill a matter of debate [Jónsson et al.,2009]. Most publications are focusedon unselected individuals ascertainedfor the presence/absence of gJHM.With this approach, personalization ofdata by phenotypic subgroup (e.g.,JHS/EDS-HT) is lost. Nevertheless,while in the general population thelink between congenital laxity of jointsand premature joint damage is unclear,in subjects with JHS/EDS-HT thisassociation seem likely [Castori et al.,2013a]. Recurrent joint macro- andmicrotraumatisms are more commonin patients with JHS/EDS-HT. Theensuing early and polyarticular chon-dral damage is probably one of the veryfirst steps acting in the evolution ofmusculoskeletal pain in JHS/EDS-HT.Improved joint stability may be at-tained by regular physical activityaimed at improving muscle tone andproprioception. However, the prevent-ing and, hopefully, therapeutic effect ofthis general recommendation could be

amplified by specific nutritional inter-ventions. An extensive review is avail-able describing actual nutritionalresources for osteoarthritis in generalpopulation [Lopez, 2012ab]. Amongthose accounting data in support tosafeness and beneficial effects on osteo-arthritis, there are: eicosapentaenoicþdecosahexaenoic acid (polyunsaturatedfatty acids - PUFA) 2–4 g/day, g-linolenic acid 0.5–2 g/day, glucosamine2mg/kg/day, chondroitin 1.2 g/die,hyaluronan 50–100mg/day, avocado-saybean saponifiable fraction (ASU)300–600mg/day, S-adenosylmethio-nine 400–600mg twice/day, MSM(an organic sulfur donor nutrient) 1–3 g twice/day, phytoflavonoids/poly-phenols 150–1,000mg twice/day, pro-biotics/prebiotics 1–6 billion CFU/day, vitamin C 250mg twice/day,vitamin E 200 IU/day, vitamin D31,000–4,000 IU/day, vitamin K2 0.5–1mg/day, selenium 200–400mg/day,manganese 5–10mg/day, boron 6–8mg/day and zinc 25–50mg/day, aswell as undenatured type II collagen(40mg/day) [Lugo et al., 2013].

Reduced bone mass is a furtherosteoarticular feature which is com-monly encountered in JHS/EDS-HT[Dolan et al., 1998; Gulbahar et al.,2003]. Therefore, in JHS/EDS-HTpatients a preventive therapy withvitamin D3 is envisaged. In the absenceof ad hoc prescriptions, the JHS/EDS-HT patient should follow the scheduleof the recommended dietary allowanceof vitamin D (e.g., 400 IU/day up forthe first year of life, 600 IU/day up to70 years and 800 IU/day over 70 years).Higher dosages of vitamin D3 (e.g.,880 IU/day for adults) are recom-mended in case of demonstrated re-duced bone mass. As JHS/EDS-HTpatients could suffer of various forms ofGI dysfuction, dosage of serum vitaminD3 and calcium levels may be usefulparticularly at the beginning of dietarysupplementation.

Musculoskeletal Pain

Pain is a major disability contributor inJHS/EDS-HT [Voermans and Knoop,2011]. Its pathogenesis remains not

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well understood. Nevertheless, obser-vational data on large patients’ sampleshelp in tracing the natural history ofpain in JHS/EDS-HT [Castori et al.,2010, 2011a, 2013a]. In light of theserecent advances, it is presumed thatdifferent pathogenic mechanisms con-tribute to the perceived pain at differ-ent disease phases. In the first phase,pain is likely related to joint damage.Hence, delay in the onset of preco-cious osteoarthritis could result in adelay in recurrent/chronic painfulperceptions.

In more advanced disease phase,pain tends to chronification and thischange is usually marked/accompaniedby neuropathic symptoms. Again, manyof the previously cited nutraceuticals,such as PUFAs and phytoflavonoids/polyphenols, with beneficial effects onjoint health may mitigate painful sensa-tions via a contra-inflammatory effect.With the onset of neuropathic pain[Camerota et al., 2010], the repertoire ofnutriceutical supplementations may beexpanded to other supplementationsrecently tested in common painfulconditions also frequently reported inJHS/EDS-HT. In particular, magne-sium therapy, consisting in a 2-weekdaily intravenous administration ofmagnesium solphate 1 g followed by a4-week oral administration of magne-sium oxide 400mg and magnesiumgluconate 100mg, has been recentlydemonstrated effective in a double-blinded randomized controlled studyin chronic back pain with a neuropathiccomponent [Yousef and Al-deeb, 2013].Vitamins B are further dietary supple-mentations with potential usefulness incontrolling chronic pain [Sesti et al.,2011]. For example, a recent workhighlights the improvement of theanalgesic effect of diclofenac by supple-mentations with thiamine (vitamin B1)100mg, pyridoxine (vitamin B6)100mg and cyanocobalamin (vitaminB12) 5mg in patients with osteoarthritis[Magaña-Villa et al., 2013]. Such astrategy may be considered in JHS/EDS-HT, especially in presence of earlyosteoarthritis.

Palmitoylethanolamide (PEA) is anendogenous fatty acid amide which,

through modulation of mast cells andspinal glial cells activation on peripheraland central nervous system neurons, hasbeen demonstrated effective on thedifferent inflammatory mechanismsthat develop and maintain both neuro-genic and neurophatic pain [KeppelHesselink, 2012]. Clinical practice isexperiencing an increasing body ofevidence supporting the successfulnessof its application [Keppel Hesselink andHekker, 2012]. PEA is classified as afood for medical purposes or as a dietsupplement in various countries ofEurope. With a standard dose of600mg twice/day (with possibility ofreduction to 300mg twice/day), it maybe used as a dietary supplementationwith potentially beneficial effects onpain, especially of neuropathic origin.As data on the effects of a long-lastingdietary supplementation by PEA arestill lacking, prudence suggests parsi-monious use limited to periods ofexacerbation of symptoms in JHS/EDS-HT.

Poor Sleep Quality and Fatigue

Quality of sleep is generally poor inEDSs [Verbraecken et al., 2001; Voer-mans et al., 2010a] and possible causesinclude periodic limb movements andnocturnal musculoskeletal pain [Ver-braecken et al., 2001; Voermans et al.,2010b]. Although true sleep apneaseems relatively rare in EDSs [Ver-braecken et al., 2001], a recent paperreporting results of polysomnography in34 EDS patients demonstrates flowlimitation, apneas and hypopneas witha decrease in flow limitation and anincrease of apnea and hypopnea eventswith age [Guilleminault et al., 2013].Treatment of the prevalent symptom/mechanism, if any, is indicated alongwith adherence to standard recommen-dations of sleep hygiene (consultable at:yoursleep.aasmnet.org/Hygiene.aspx).In addition to dietary supplementationspossibly beneficial for musculoskeletalpain, melatonine is commonly pre-scribed in JHS/EDS-HT at standarddosage [Tinkle, 2010].

Mechanisms leading to chronicfatigue in JHS/EDS-HT, are obscure

and specific treatments are lacking.Possible major contributors includepoor postural control, nocturnal painand cardiovascular dysautonomia [Cas-tori et al., 2013a]. Various papers high-light the common co-morbidity withchronic fatigue syndrome and fibro-myalgia [Oflouglu et al., 2006; Castoriet al., 2011b]. These association studiespoint out the possibility of a commonpathogenesis which could lay in asecondary mitochondrial dysfunction[Smits et al., 2011]. Accordingly, theJHS/EDS-HT-associated fatiguemay bemanaged with dietary supplementationsused in various mitochondrial dysfunc-tions [Nicolson, 2013]. A combinationof oral supplements, which resultedefficacious in treating chronic fatiguein patients with a variety of diagnoses,includes membrane phospholipids2,000mg/day, co-enzyme Q10 35mg/day, microencapsulated reduced nicoti-namide adenine dinucleotide (NADH)35mg/day, L-carnitin 160mg/day, anda-ketoglutaric acid 180mg/day [Nic-olson et al., 2012a,b]. In the previousreview on nutritional supplementationsin EDS,Mantle et al. suggested a 100mgdaily dose of coenzyme Q10 and a250mg daily dose of carnitin. Recentspeculations indicate a higher efficacy ofthe acetyl-L-carnitin derivative in treat-ing symptoms of central origin [Mala-guarnera, 2012], such as fatigue.

Skin and Mucosal Manifestations

Skin and mucosal fragility is a feature ofJHS/EDS-HT. Easy bruising, delayedwound healing, recurrent gingival hem-orrhages after tooth brushing andproneness to gingival retractions are allcommonly reported. It is well estab-lished that vitamin C is necessary forwound healing, as naturally demon-strated by the adverse effects of vitaminC deficiency in selective malnutrition(“scurvy”). In fact, vitamin C is acofactor of lysyl- and prolyl-hydroxy-lases, which stabilize the triple-helicalstructure of collagen and, if mutated, cancause various heritable connective tissuedisorders, such as kyphoscoliotic type ofEDS. A dose of 500–3,000mg/day maybe prescribed in JHS/EDS-HT.

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Although literature is not clear,many JHS/EDS-HT patients refer awide range of cutaneous features possiblyrelated to impaired epithelial integrity,such as keratosis pilaris, xerosis, itching,eczema-like changes, and various skinallergies. As many of these findings areequally observed in scurvy, an adequateintake of vitamin C in JHS/EDS-HTcould improve also these satellite features.Skin health may be improved by regularintake of many other dietary supplemen-tations, including but not limited tovitamin E, polyphenols, coenzymeQ10,prebiotics/probiotics, and polyunsatu-rated fatty acids (vitamin F) [Schagenet al., 2012].Regular assumption of thesedietary supplementations by JHS/EDS-HT patients is supported by theirsimultaneous beneficial effect on jointprotection (see previous section). Vita-min A is a further antioxidant withpotential beneficial effect on skin healthand integrity. Nevertheless, as it is aknown teratogen and many JHS/EDS-HT patients, at the time of first evalua-tion, are young women, the use ofvitamin A should not be recommendedoutside specific conditions, such as adultmales and older women (i.e., vitamin A0.8–1mg/day¼ 2,400–3000 IU/day).

Mucosal dryness is a feature of JHS/EDS-HT and it causes various disablingfeatures, such as xerophthalmia withpositive Schirmer test [Gharbiya et al.,2012], xerostomia, and dyspaurenia andrecurrent vaginal infectionsdue tovaginaldryness. Adequate daily hydration (2–2.5 lt/day for adults) is a harmless dietaryhabit which may contribute in reducingsymptom intensity. Beneficial effect ontear composition and dry eye may be alsoobtained by regular carnitin intake, aspreviously reported for fatigue [Flanaganet al., 2010], as well as vitamin A.

Gastrointestinal Manifestations

The first part of this paper highlights thatGI functional complaints are extremelycommon in JHS/EDS-HT. Despitetheir high prevalence, disease-orientedtreatment strategies are still lacking andavailable therapies have little impact onthe long-term quality of life of affectedindividuals. In addition, common GI

affections such as lactose intolerance,celiac disease, non-celiac glucose intol-erance and opioid-drug overuse, notnecessarily related to the underlyingdisorder may concur with JHS/EDS-HT. Therefore, adherence to appropri-ate dietary habits (appropriate number/fragmentation of meals, regular fiberintake, avoiding specific foods stimulat-ing gastric secretion, and/or gut mo-tility, etc) should be consideredmandatory.

Among the various dietary supple-mentations with potential effects, pro-biotics and prebiotics are the sole forwhich experimental studies have beenpublished, mostly in irritable bowelsyndrome. Recent reviews of the liter-ature [e.g., Whelan, 2011; Whelan andQuigley, 2013] indicate that, in irritablebowel syndrome, probiotics result ef-fective in not all studies and that itseffectiveness is mostly related to singlesymptoms rather than the entire GIphenotype. In addition, variability in theoutcome is influenced by many factors,including microbiological characteris-tics of probiotics and “quality” of theindustrial product used in the study.Therefore, the level of evidence for theefficacy of probiotics in functional GIdisorders is still low and needs furtherrefinement. In consideration of thepresumed beneficial effect of probioticson joint health (see above), after carefulassessment of the GI status—Especiallyin symptomatic patients -, regular intakeof prebiotics and probiotics (e.g., 1–6 billion CFU/day) may be consideredin JHS/EDS-HT.

CONCLUSIONS

Previous sections illustrate the potentialapplications of nutritional supplementa-tions in JHS/EDS-HT. Although all theabove listed recommendations are basedon low-level evidence data, they may beorganized in a holistic schedule ofadministration in the JHS/EDS-HTpatient (Table V). Some dietary supple-ments are optimal for prevention ofosteoarthritis and a few additionalfeatures, while others are best suitablefor treatment of specific complaints,mostly including pain, fatigue and

epithelial/vascular fragility. Listed dos-ages and recommendations may be usedin the practice, but their applicationsneed caution. All reported dosages areextracted from previous experimentalworks carried out within a discrete timewindow or from expert reviews. There-fore, all prescriptions should be alwayspersonalized considering patient’s ageand co-morbidities, and their efficacy(and possible side-effects) should beperiodically monitored by close fol-low-ups. Our experience on JHS/EDS-HT envisages the urgent need of moreefficacious treatment strategies, whichshould be planned and tested with aholistic approach. In this perspective,nutritional supplementations, togetherwith other lifestyle interventions, arelikely to become a centerpiece of thefuture prevention and, perhaps, treat-ment approach to JHS/EDS-HT.

FINAL REMARKS

In this paper, pertinent literature wasreviewed in order to stress two issues: (i)GI manifestations are diverse and com-mon in JHS/EDS-HT, and often repre-sent a major contributor to the overalldisability of the affected individual; (ii)nutrient deficiencies may participate inthe onset orworseningof selected clinicalmanifestations of JHS/EDS-HT (e.g.,pain, fatigue, osteoarthritis, reducedbone mass, and skin and mucosalfeatures), and that tailored nutritionalsupplementations may improve patients’quality of life. Investigating the linkbetween these two apparently separatedconcepts could be one of the future aimsof clinical research in JHS/EDS-HT. Inthe first part of this paper, the dyadicnature of GI involvement in JHS/EDS-HT has been emphasized with a widerange of functional and structural man-ifestations. Both could directly (e.g.,altered gut structure) or indirectly (e.g.,dysmotility leading to altered micro-biota) influence gut permeability tomicronutrients. In addition, there is aweak support of an increased rate ofbowel inflammatory conditions (i.e.,celiac disease, Crohn disease and eosi-nophilic esophagitis) in gJHM and JHS/EDS-HT. If supported by more robust

TABLE V. Proposed Nutritional Supplementation in Joint Hypermobility Syndrome/Ehlers–Danlos Syndrome,Hypermobility Type

Supplementation Quantity per dose No. of doses/day Note

PreventionEicosapentaenoic and

decosahexaenoic acid3 g 1 Prevention of osteoarthritis and epithelial

fragilityGlucosamine/chodroitin/hyaluronan 2mg(/kg)/1.2mg/75mg 1 Prevention of osteoarthritisPhytoflavonoids/polyphenols 750mg 2 Prevention of osteoarthritis and epithelial

fragilityS-adenosylmethionine 500mg 1 Prevention of osteoarthritisSelenium/manganese/boron/zinc 300mg/10mg/8mg/50 mg 1 Prevention of osteoarthritisUndenatured collagen II 40mg 1 Prevention of osteoarthritisVitamin C 250mg 2 Prevention of osteoarthritis, and capillary

and epithelial fragilityVitamin D3 400–800 IU 1 Prevention of osteoarthritis and reduced

bone massVitamin E 200 IU 1 Prevention of osteoarthritis and epithelial

fragilityVitamin K2 1mg 1 Prevention of osteoarthritisg-linolenic acid 1 g 1 Prevention of osteoarthritisTreatmentAcetyl-L-carnitin 250mg 1 Treatment of chronic fatigue; treatment of

xerophthalmiaCo-enzyme Q10 100–400mg 1 Treatment of chronic fatigueIsotonic liquids 2–2.5 L — Treatment of fatigue; treatment of

xerophthalmiaMagnesium oxide/gluconate 400mg/100mg 1 Treatment of

chronic/neurogenic/neuropathic painMelatonin 3–5mg 1

(bedtime)Sleep regularization

Membrane phospholipids 2,000mg 1 Treatment of chronic fatigueNADH 35mg 1 Treatment of chronic fatiguePalmitoylethanolamide 300–600mg 2 Treatment of chronic/neuropathic painProbiotics 1–6 billion CFU 1 Treatment of irritable bowel syndrome

(optimal pros vs. cons evaluation)Thiamine/pyridoxine/cyanocobalamin 100mg/100mg/5mg 1 Treatment of chronic/neuropathic pain (i.e.,

improvement of analgesic effect ofpainkillers)

Vitamin A 0.8mg 1 Treatment of dry eye (after careful clinicalinvestigations, and exclusion of pregnancy

status and planning)Vitamin C 500–3,000mg 1 Treatment of skin/capillary/mucosal

fragilityVitamin D3 880 IU 1 Treatment of reduced bone massa-ketoglucaric acid 180mg 1 Treatment of chronic fatigue

72 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

data in adequately selected samples,the link between gut mucosal integrityand immune dysregulation, and JHS/EDS-HT may open a new era ofinvestigative studies aimed at under-standing the pathologic bases of manyJHS/EDS-HT-associated complaints

and, hopefully, at identifying morespecific therapies.

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