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 in Joint Hypermobility Syndrome/Ehlers–Danlos Syndrome, Hypermobility Type MARCO CASTORI, SILVIA MORLINO, GIULIA PASCOLINI, CARLO BLUNDO, AND PAOLA GRAMMATICO Gastrointestinal involvement is a well known complication of Ehlers–Danlos syndromes (EDSs), mainly in form of abdominal emergencies due to intestinal/abdominal vessels rupture in vascular EDS. In the last decade, a growing number of works investigated the relationship between a wide spectrum of chronic gastrointestinal complaints 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 in the health status and, consequently, management of JHS/EDS-HT patients. Nevertheless, fragmentation of knowledge limits its impact on practice within the boundaries of highly specialized clinics. In this paper, literature review 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 gastrointestinal involvement, (ii) case-control/cohort studies associating JHS/EDS-HT and gastrointestinal involvement, (iii) case reports/series on various gastrointestinal complications in (presumed) JHS/EDS-HT, and (iv) studies reporting gastrointestinal features in heterogeneous EDS patients’ cohorts. Gastrointestinal manifestations of JHS/EDS-HT were organized and discussed in two categories, including structural anomalies (i.e., abdominal/diaphragmatic hernias, internal organ/pelvic prolapses, intestinal intussusceptions) and functional features (i.e., dysphagia, gastro-esophageal reflux, dyspepsia, recurrent abdominal pain, constipation/diarrhea), with emphasis on practice and future implications. In the second part of this paper, a summary of possible nutritional interventions in JHS/EDS-HT was presented. Supplementation strategies were borrowed from data available for general population with minor modifications in the light of recent discoveries in the pathogenesis of selected JHS/EDS-HT features. © 2015 Wiley Periodicals, Inc. KEY WORDS: abdominal pain; constipation; diet; Ehlers–Danlos syndrome; nutraceuticals How to cite this article: Castori M, Morlino S, Pascolini G, Blundo C, Grammatico P. 2015. Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers–Danlos syndrome, hypermobility type. Am J Med Genet Part C 169C:54–75. Marco Castori is a medical geneticist enrolled as senior hospital-based clinician at the San Camillo-Forlanini Hospital in Rome. He obtained his PhD degree with a clinical and management study on Ehlers–Danlos syndrome(s). Major research topics include hereditary connective tissue disorders, genodermatoses, clinical dysmorphology, and fetal pathology. He is author and co-author of more than 100 publications in international journals and several book chapters. Silvia Morlino is a MD resident in Medical Genetics at the Sapienza University of Rome. She has a full-time involvement in the clinical and research activity of the Division of Medical Genetics at the San Camillo-Hospital in Rome. Her interests mostly include clinical dysmorphology and hereditary connective tissue disorders. Giulia Pascolini is a MD resident in Medical Genetics at the Sapienza University of Rome. She has a part-time involvement in the clinical and research activity of the Division of Medical Genetics at the San Camillo-Hospital in Rome. Her interests include clinical dysmorphology and intellectual disability. Carlo Blundo is a senior neurologist and neuropsychologist, head of the Unit of Cognitive and Behavioral Neurology at the San Camillo-Forlanini Hospital in Rome. He is actively involved in the diagnosis and management of various forms of dementia. Since 2011, he is also interested in cognitive and behavioral aspects of Ehlers–Danlos syndrome and joint hypermobility syndrome. He is author of various books and book chapters in the field of neurology. Paola Grammatico is an associate professor of Medical Genetics at the Sapienza University and director of the Division of Medical Genetics at the San Camillo-Forlanini Hospital in Rome. She has various responsibilities in the regional and national Healthcare system with focus on genetic laboratory testing and rare diseases. Her major diagnostic and research interests include cutaneous melanoma, disorders of sex differentiation and fetal pathology. She is author of more than 150 papers in international journals and various book chapters on medical genetics. Conflict of interest: The authors have no conflict of interest to declare. Funding: No funding was active on this project. *Correspondence to: Marco Castori, M.D., PhD, Division of Medical Genetics, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87, I-00152 Rome, Italy. E-mail: [email protected]. DOI 10.1002/ajmg.c.31431 Article first published online in Wiley Online Library (wileyonlinelibrary.com). ß 2015 Wiley Periodicals, Inc.
Gastrointestinal and Nutritional Issues in Joint Hypermobility Syndrome/Ehlers–Danlos Syndrome, Hypermobility Type
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Gastrointestinal and nutritional issues in joint hypermobility syndrome/ehlers-danlos syndrome, hypermobility typeAmerican 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 in Joint Hypermobility Syndrome/Ehlers–Danlos Syndrome, Hypermobility Type MARCO CASTORI, SILVIA MORLINO, GIULIA PASCOLINI, CARLO BLUNDO, AND PAOLA GRAMMATICO
Marco Casto degree with a genodermatos several book c
Silvia Morlin activity of the connective tiss
Giulia Pasco activity of the D
Carlo Blund Hospital in Rom and behaviora neurology.
Paola Gramm Camillo-Forlan testing and ra pathology. She
Conflict of i Funding: No *Correspon
I-00152 Rome DOI 10.100 Article first
2015 Wil
Gastrointestinal involvement is a well known complication of Ehlers–Danlos syndromes (EDSs), mainly in form of abdominal emergencies due to intestinal/abdominal vessels rupture in vascular EDS. In the last decade, a growing number of works investigated the relationship between a wide spectrum of chronic gastrointestinal complaints 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 in the health status and, consequently, management of JHS/EDS-HT patients. Nevertheless, fragmentation of knowledge limits its impact on practice within the boundaries of highly specialized clinics. In this paper, literature review 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 gastrointestinal involvement, (ii) case-control/cohort studies associating JHS/EDS-HT and gastrointestinal involvement, (iii) case reports/series on various gastrointestinal complications in (presumed) JHS/EDS-HT, and (iv) studies reporting gastrointestinal features in heterogeneous EDS patients’ cohorts. Gastrointestinal manifestations of JHS/EDS-HT were organized and discussed in two categories, including structural anomalies (i.e., abdominal/diaphragmatic hernias, internal organ/pelvic prolapses, intestinal intussusceptions) and functional features (i.e., dysphagia, gastro-esophageal reflux, dyspepsia, recurrent abdominal pain, constipation/diarrhea), with emphasis on practice and future implications. In the second part of this paper, a summary of possible nutritional interventions in JHS/EDS-HT was presented. Supplementation strategies were borrowed from data available for general populationwithminormodifications in the light of recent discoveries in the pathogenesis of selected JHS/EDS-HT features. © 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. Gastrointestinal and 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 PhD clinical 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 and hapters. o is a MD resident in Medical Genetics at the Sapienza University of Rome. She has a full-time involvement in the clinical and research Division of Medical Genetics at the San Camillo-Hospital in Rome. Her interests mostly include clinical dysmorphology and hereditary ue disorders. lini is aMD resident in Medical Genetics at the Sapienza University of Rome. She has a part-time involvement in the clinical and research ivision 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-Forlanini e. 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 San ini Hospital in Rome. She has various responsibilities in the regional and national Healthcare system with focus on genetic laboratory re diseases. Her major diagnostic and research interests include cutaneous melanoma, disorders of sex differentiation and fetal is 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: [email protected]. 2/ajmg.c.31431 published 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 of EDS 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 vascular EDS, which features spontaneous bowel and abdominal vessel ruptures [Beighton et al., 1998]. However, literature also accounts some papers pointing out a wider spectrum of GI manifestations in various forms of EDS [Burcharth and Rosenberg, 2012]. The awareness on the impact of GI manifestations to the health status of EDS patients rose in the last decade, when Hakim and Grahame [2004] found a high rate of various functional GI complaints in adults with joint hypermobility syndrome (a.k.a. Ehlers–Danlos syndrome, hypermobil- ity type; JHS/EDS-HT). Accordingly, Levy [2012] listed functional bowel disorders as an “unofficial” minor diagnostic item in the 2004 version of his reference paper on JHS/EDS-HT. Since then, a growing number of works presented data on the spectrum, rate and possible pathogenesis of GI manifesta- tions in JHS/EDS-HT [see below]. However, while actual knowledge ac- counts a number of studies highlighting the impact of GI manifestations in JHS/ EDS-HT, the emerging results still depict a fragmented picture which lays on the heterogeneous and, occasionally, divergent perspectives of the involved research groups.
In the first part of this paper, we carried out a review of available data with the aim of offering a comprehen- sive summary of GI involvement in JHS/EDS-HT.We also tried to present a wider perspective by speculating on pathogenesis and actual management approach. As a side aspect of GI involvement in EDS, Mantle et al. [2005] proposed a set of nutritional interventions purportedly aimed at improving selected disease manifesta- tions of this condition. The possible applications of this resource was re- inforced by Tinkle [2010]; who re- ported his experience on nutraceuticals in his monograph on JHS/EDS-HT.
Research on nutritional interventions in EDS is still in its infancy. Nevertheless, data on the possible beneficial effects of an increasing number of nutraceuticals in many chronic complaints commonly encountered in JHS/EDS-HT is now available for the general population. In the second part of this paper, we present a summary of actual knowledge and theoretical applications of nutritional therapy in the management of some disease aspects of JHS/EDS-HT.
METHODS
This study consisted in a PubMed search with the following research string: [“Ehlers–Danlos syndrome” OR EDS OR hypermobility] AND [abdominal OR anal OR bowel OR colonic OR constipation OR diarrhea OR dyspha- gia OR esophagus OR gastric OR gastrointestinal OR gut OR liver OR prolapse OR rectal]. All relevant articles detected in this phase were further scrutinized for additional references not appeared in this search. Review or hypothesis papers without novel data were excluded from the Results section, while their contents were used for interpretation of collected information. All papers clearly concerning EDS subtypes other than JHS/EDS-HT (mainly, vascular and classic EDS) were equally excluded. Case-control studies relating GI manifestations with non- syndromic/unclassified generalized joint hypermobility (gJHM), and case-control and case series works investigating GI involvement in patients with unclassified EDS or belonging to various EDS subtypes were included, but their results were presented separately. Inclusion of these works was based on the following: (1) at the moment, apparently isolated gJHM blurs within the increasingly wide spectrum of JHS/EDS-HT and the distinction between asymptomatic/”be- nign” gJHM and JHS/EDS-HT is often difficult especiallywithin the same family; (2) many studies investigating the associ- ation between gJHM and GI features do not declare a formal exclusion of JHS/ EDS-HT in their cohorts; (3) with the exception, perhaps, of vascular manifes- tations and spontaneous rupture of thegut
which are typical of vascular EDS, all other GI manifestations seem shared by most EDS subtypes; (4) JHS/EDS-HT is probably the most common EDS sub- type. Single case reports were also selected. For these works, the likelihood of the diagnosis of JHS/EDS-HT was ascertained by checking for a formal attribution of EDS subtype (i.e., JHS, EDS-HT, EDS type III) by the authors themselves, or by comparing the reported extra-GI manifestations with the Ville- franche and Brighton criteria. The presence of spontaneous bowel rupture and/or suspected vascular accidents lead to the attribution of vascular EDS and, then, to exclude the paper.
RESULTS
Studies Associating Generalized Joint Hypermobility With Gastrointestinal Complaints
A total of 16 papers, all published in the last 18 years (1987–2014), were identi- fied. Fifteen studies compared the rate of specific GI features with gJHM in two populations. In one of these fifteen studies [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 which were summarized in Table I. The remaining three failed to demonstrate an association between gJHM and specific GI features, in particular pelvic prolapse [Brækken et al., 2009; Hafizi et al., 2013; Derpapas et al., 2014].More specifically, Brækken et al. [2009] did not identify a relationship between gJHM measured with the Beighton score (with a cut-off of 4) and pelvic organ prolapse comparing 49 women with 49 controls. Conversely, they found an association between pelvic organ prolapse and other “soft”markers, such as easy bruising and varicose veins, of an underlying connective tissue disorder (P¼ 0.001 and 0.005, respec- tively). Hafizi et al. [2013] compared positive Beighon score (with a cut-off of 4) with pelvic organ prolapse between patients’ and controls’ groups each composed of 60 adult females. Derpapas
T A B L E I.
S tu d ie s In ve st ig at in g th e A ss o ci at io n B et w ee n (U
n cl as si fi ed
/N o n sy n d ro m ic ) G en
er al iz ed
er m o b il it y an
d G as tr o in te st in al
F ea tu re s
R ef er en ce
a gJ H M
st ra te gy
of co nt ro ls
C ha ra ct er ist ic s of
pa tie nt s
co nt ro ls
fe at ur e( s)
R at e in
pa tie nt s
R at e in
co nt ro ls
P va lu e
et al ., 19 87
fif th
w ith
fin ge r
go ni om
an d
un de rg on
co m pl et e re ct al
pr ol ap se
an d
t w ith
pr ol ap se
81 2. 2
ex te ns ib le
in pa tie nt s
w ho
e su rg er y
re pa ir fo r re ct al pr ol ap se
N or to n
et al ., 19 95
op po
n of
fif th
gr ea te r th an
55 °,
n of
19 0°
39 69
gJ H M
(a ny
is m or e
co m m on
w ith
an d 3)
of th um
ct io n,
an d
ch ro ni c
ps eu do
in di vi du
al s w ith
s
in pa tie nt s w ith
ch ro ni c
ps eu do
A l- R aw
( 4)
in ad ul ts w ith
hi at us
he rn ia
Jh a et
al ., 20 07
(> 4)
gJ H M
at te nd
ic
at te nd
in g a
A na l
23 %
is m or e co m m on
in fe m al es
w ith
gJ H M
56 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
T A B L E I.
(C on tin ue d)
R ef er en ce
a gJ H M
st ra te gy
of co nt ro ls
C ha ra ct er ist ic s of
pa tie nt s
co nt ro ls
fe at ur e( s)
R at e in
pa tie nt s
R at e in
co nt ro ls
P va lu e
cl in ic ;
A sia n,
rh eu m at ol og
ic cl in ic ;
A sia n,
B ei gh to n sc or e
(> 4)
an d
slo w
an d 23
m al es
is se le ct iv el y m or e
co m m on
in m al es
et al ., 20 09
(> 4)
w ith
ili ty
Sy nd
n; C au ca sia ns
(9 8%
po pu
la tio
pu bl ish
14 .9 %
2. 2%
< 0. 05
is m or e co m m on
in fe m al es
w ith
et al ., 20 09
B ri gh to n cr ite ri a
fo r JH
an d
in fla m m at or y
bo w el
an d 38
m al es
(1 8– 50
ye ar s) ;
G re ek
gJ H M
b 70 .3 %
(C ro hn
in pa tie nt s w ith
C ro hn
of ha vi ng
in fla m m at or y bo w el
di se as e an d gJ H M
is tw
co lit is
an d
gJ H M
at io n
an d 19
m al es
(2 0– 83
ye ar s)
co ns tip
at io n
96 .9 % /
3. 1%
85 .9 % /
14 .1 %
0. 02
at io n ar e
m or e co m m on
ly fe m al es
w ith
su rg er y
pr ol ap se
ly di sp la y
Pr ev io us
pe lv ic
or ga n
30 .7 %
17 .0 %
0. 04
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 57
T A B L E I.
(C on tin ue d)
R ef er en ce
a gJ H M
st ra te gy
of co nt ro ls
C ha ra ct er ist ic s of
pa tie nt s
co nt ro ls
fe at ur e( s)
R at e in
pa tie nt s
R at e in
co nt ro ls
P va lu e
gJ H M
ev ac ua tio
n, fu nc tio
na l
re ct oc el e an d ex tr in sic
co m pr es sio
n of
th e
an or ec ta l ph
ys io lo gi ca l
in ve st ig at io n th an
pa tie nt s w ith
ou t gJ H M .
T he
a pr ec ip ita tin
g ev en t fo r
co ns tip
co m m on
er gr ou
re ct al
58 %
39 %
n of
th e
11 1
(> 4)
an d
gJ H M
sy m pt om
an d 23
m al es
(1 8– 78
ye ar s)
an d
sy m pt om
sy m pt om
ge r,
fe m al es ,
ly di sp la y
ga st ro es op
ha ge al re flu
x an d bl oa tin
g th an
ou t gJ H M .
E tio
lo gy
s in
co m m on
al s w ith
ph ag ea l
62 %
46 %
et al ., 20 12
“ Pr es en ce
11 0
10 0
gJ H M
at te nd
cl in ic
at te nd
cl in ic
Pe lv ic
or ga n
is m or e co m m on
in fe m al es
w ith
et al ., 20 14
( 4)
ye ar s) w ith
vo id in g
(5 – 14
in ch ild re n w ith
vo id in g
gJ H M ,
gJ H M
0. 01 7
58 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
T A B L E I.
(C on tin ue d)
R ef er en ce
a gJ H M
st ra te gy
of co nt ro ls
C ha ra ct er ist ic s of
pa tie nt s
co nt ro ls
fe at ur e( s)
R at e in
pa tie nt s
R at e in
co nt ro ls
P va lu e
Ir an ia ns
ur in ar y tr ac t in fe ct io ns
ar e m or e co m m on
in fe m al es , w hi le
co ns tip
co m m on
in m al es
5% 0. 04
G I, ga st ro in te st in al ; gJ H M ,g
en er al iz ed
jo in t hy pe rm
ob ili ty ; JH
ob ili ty
ro m an di bu
la r jo in t.
a O nl y fe at ur es
w ith
sig ni fic an t di ffe re nc es
be tw
ee n pa tie nt s’ an d co nt ro ls’
gr ou
rt ed
e. ,P
b 5 ou
al sw
di se as e an d 1 ou
to f1
al sw
ith gJ H M
an d ul ce ra tiv e co lit is al so
m et B ri gh to n cr ite ri a fo r jo in th
yp er m ob
a cu m ul at iv e O R
of 3. 75 .
al .[ 19 95 ].
d T he
rt ed
qu es tio
nn ai re
in ve st ig at in g hi st or ic al gJ H M
[H ak im
an d G ra ha m e, 20 03 ].
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 59
et al. [2014] studied 270 women with urinary incontinence and pelvic organ prolapse, who were screening for gJHM with the self-reported 5-point ques- tionnaire by Hakim and Grahame [2003].
Of the 12 studies with positive results (Table I), four studied adult females only [Norton et al., 1995; Jha et al., 2007; Arunkalaivanan et al., 2009; Lammers et al., 2012], five adult males and 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 from both sexes [Mohammed et al., 2010; Kajbafzadeh et al., 2014], and one children, adolescents and adults from both sexes [Marshman et al., 1987]. Theseworks differed also for the assessing method for gJHM, which was the Beighton score with a positive cut-off of>4 four times [Jha et al., 2007; Reilly et al., 2008; Arunkalaivanan et al., 2009; Zarate et al., 2010], Beighton score with a positive cut-off of 4 twice [Al-Rawi et 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 method four times [Marshman et al., 1987; Norton et al., 1995; Pulliam and…
A R T I C L E
Gastrointestinal and Nutritional Issues in Joint Hypermobility Syndrome/Ehlers–Danlos Syndrome, Hypermobility Type MARCO CASTORI, SILVIA MORLINO, GIULIA PASCOLINI, CARLO BLUNDO, AND PAOLA GRAMMATICO
Marco Casto degree with a genodermatos several book c
Silvia Morlin activity of the connective tiss
Giulia Pasco activity of the D
Carlo Blund Hospital in Rom and behaviora neurology.
Paola Gramm Camillo-Forlan testing and ra pathology. She
Conflict of i Funding: No *Correspon
I-00152 Rome DOI 10.100 Article first
2015 Wil
Gastrointestinal involvement is a well known complication of Ehlers–Danlos syndromes (EDSs), mainly in form of abdominal emergencies due to intestinal/abdominal vessels rupture in vascular EDS. In the last decade, a growing number of works investigated the relationship between a wide spectrum of chronic gastrointestinal complaints 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 in the health status and, consequently, management of JHS/EDS-HT patients. Nevertheless, fragmentation of knowledge limits its impact on practice within the boundaries of highly specialized clinics. In this paper, literature review 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 gastrointestinal involvement, (ii) case-control/cohort studies associating JHS/EDS-HT and gastrointestinal involvement, (iii) case reports/series on various gastrointestinal complications in (presumed) JHS/EDS-HT, and (iv) studies reporting gastrointestinal features in heterogeneous EDS patients’ cohorts. Gastrointestinal manifestations of JHS/EDS-HT were organized and discussed in two categories, including structural anomalies (i.e., abdominal/diaphragmatic hernias, internal organ/pelvic prolapses, intestinal intussusceptions) and functional features (i.e., dysphagia, gastro-esophageal reflux, dyspepsia, recurrent abdominal pain, constipation/diarrhea), with emphasis on practice and future implications. In the second part of this paper, a summary of possible nutritional interventions in JHS/EDS-HT was presented. Supplementation strategies were borrowed from data available for general populationwithminormodifications in the light of recent discoveries in the pathogenesis of selected JHS/EDS-HT features. © 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. Gastrointestinal and 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 PhD clinical 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 and hapters. o is a MD resident in Medical Genetics at the Sapienza University of Rome. She has a full-time involvement in the clinical and research Division of Medical Genetics at the San Camillo-Hospital in Rome. Her interests mostly include clinical dysmorphology and hereditary ue disorders. lini is aMD resident in Medical Genetics at the Sapienza University of Rome. She has a part-time involvement in the clinical and research ivision 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-Forlanini e. 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 San ini Hospital in Rome. She has various responsibilities in the regional and national Healthcare system with focus on genetic laboratory re diseases. Her major diagnostic and research interests include cutaneous melanoma, disorders of sex differentiation and fetal is 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: [email protected]. 2/ajmg.c.31431 published 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 of EDS 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 vascular EDS, which features spontaneous bowel and abdominal vessel ruptures [Beighton et al., 1998]. However, literature also accounts some papers pointing out a wider spectrum of GI manifestations in various forms of EDS [Burcharth and Rosenberg, 2012]. The awareness on the impact of GI manifestations to the health status of EDS patients rose in the last decade, when Hakim and Grahame [2004] found a high rate of various functional GI complaints in adults with joint hypermobility syndrome (a.k.a. Ehlers–Danlos syndrome, hypermobil- ity type; JHS/EDS-HT). Accordingly, Levy [2012] listed functional bowel disorders as an “unofficial” minor diagnostic item in the 2004 version of his reference paper on JHS/EDS-HT. Since then, a growing number of works presented data on the spectrum, rate and possible pathogenesis of GI manifesta- tions in JHS/EDS-HT [see below]. However, while actual knowledge ac- counts a number of studies highlighting the impact of GI manifestations in JHS/ EDS-HT, the emerging results still depict a fragmented picture which lays on the heterogeneous and, occasionally, divergent perspectives of the involved research groups.
In the first part of this paper, we carried out a review of available data with the aim of offering a comprehen- sive summary of GI involvement in JHS/EDS-HT.We also tried to present a wider perspective by speculating on pathogenesis and actual management approach. As a side aspect of GI involvement in EDS, Mantle et al. [2005] proposed a set of nutritional interventions purportedly aimed at improving selected disease manifesta- tions of this condition. The possible applications of this resource was re- inforced by Tinkle [2010]; who re- ported his experience on nutraceuticals in his monograph on JHS/EDS-HT.
Research on nutritional interventions in EDS is still in its infancy. Nevertheless, data on the possible beneficial effects of an increasing number of nutraceuticals in many chronic complaints commonly encountered in JHS/EDS-HT is now available for the general population. In the second part of this paper, we present a summary of actual knowledge and theoretical applications of nutritional therapy in the management of some disease aspects of JHS/EDS-HT.
METHODS
This study consisted in a PubMed search with the following research string: [“Ehlers–Danlos syndrome” OR EDS OR hypermobility] AND [abdominal OR anal OR bowel OR colonic OR constipation OR diarrhea OR dyspha- gia OR esophagus OR gastric OR gastrointestinal OR gut OR liver OR prolapse OR rectal]. All relevant articles detected in this phase were further scrutinized for additional references not appeared in this search. Review or hypothesis papers without novel data were excluded from the Results section, while their contents were used for interpretation of collected information. All papers clearly concerning EDS subtypes other than JHS/EDS-HT (mainly, vascular and classic EDS) were equally excluded. Case-control studies relating GI manifestations with non- syndromic/unclassified generalized joint hypermobility (gJHM), and case-control and case series works investigating GI involvement in patients with unclassified EDS or belonging to various EDS subtypes were included, but their results were presented separately. Inclusion of these works was based on the following: (1) at the moment, apparently isolated gJHM blurs within the increasingly wide spectrum of JHS/EDS-HT and the distinction between asymptomatic/”be- nign” gJHM and JHS/EDS-HT is often difficult especiallywithin the same family; (2) many studies investigating the associ- ation between gJHM and GI features do not declare a formal exclusion of JHS/ EDS-HT in their cohorts; (3) with the exception, perhaps, of vascular manifes- tations and spontaneous rupture of thegut
which are typical of vascular EDS, all other GI manifestations seem shared by most EDS subtypes; (4) JHS/EDS-HT is probably the most common EDS sub- type. Single case reports were also selected. For these works, the likelihood of the diagnosis of JHS/EDS-HT was ascertained by checking for a formal attribution of EDS subtype (i.e., JHS, EDS-HT, EDS type III) by the authors themselves, or by comparing the reported extra-GI manifestations with the Ville- franche and Brighton criteria. The presence of spontaneous bowel rupture and/or suspected vascular accidents lead to the attribution of vascular EDS and, then, to exclude the paper.
RESULTS
Studies Associating Generalized Joint Hypermobility With Gastrointestinal Complaints
A total of 16 papers, all published in the last 18 years (1987–2014), were identi- fied. Fifteen studies compared the rate of specific GI features with gJHM in two populations. In one of these fifteen studies [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 which were summarized in Table I. The remaining three failed to demonstrate an association between gJHM and specific GI features, in particular pelvic prolapse [Brækken et al., 2009; Hafizi et al., 2013; Derpapas et al., 2014].More specifically, Brækken et al. [2009] did not identify a relationship between gJHM measured with the Beighton score (with a cut-off of 4) and pelvic organ prolapse comparing 49 women with 49 controls. Conversely, they found an association between pelvic organ prolapse and other “soft”markers, such as easy bruising and varicose veins, of an underlying connective tissue disorder (P¼ 0.001 and 0.005, respec- tively). Hafizi et al. [2013] compared positive Beighon score (with a cut-off of 4) with pelvic organ prolapse between patients’ and controls’ groups each composed of 60 adult females. Derpapas
T A B L E I.
S tu d ie s In ve st ig at in g th e A ss o ci at io n B et w ee n (U
n cl as si fi ed
/N o n sy n d ro m ic ) G en
er al iz ed
er m o b il it y an
d G as tr o in te st in al
F ea tu re s
R ef er en ce
a gJ H M
st ra te gy
of co nt ro ls
C ha ra ct er ist ic s of
pa tie nt s
co nt ro ls
fe at ur e( s)
R at e in
pa tie nt s
R at e in
co nt ro ls
P va lu e
et al ., 19 87
fif th
w ith
fin ge r
go ni om
an d
un de rg on
co m pl et e re ct al
pr ol ap se
an d
t w ith
pr ol ap se
81 2. 2
ex te ns ib le
in pa tie nt s
w ho
e su rg er y
re pa ir fo r re ct al pr ol ap se
N or to n
et al ., 19 95
op po
n of
fif th
gr ea te r th an
55 °,
n of
19 0°
39 69
gJ H M
(a ny
is m or e
co m m on
w ith
an d 3)
of th um
ct io n,
an d
ch ro ni c
ps eu do
in di vi du
al s w ith
s
in pa tie nt s w ith
ch ro ni c
ps eu do
A l- R aw
( 4)
in ad ul ts w ith
hi at us
he rn ia
Jh a et
al ., 20 07
(> 4)
gJ H M
at te nd
ic
at te nd
in g a
A na l
23 %
is m or e co m m on
in fe m al es
w ith
gJ H M
56 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
T A B L E I.
(C on tin ue d)
R ef er en ce
a gJ H M
st ra te gy
of co nt ro ls
C ha ra ct er ist ic s of
pa tie nt s
co nt ro ls
fe at ur e( s)
R at e in
pa tie nt s
R at e in
co nt ro ls
P va lu e
cl in ic ;
A sia n,
rh eu m at ol og
ic cl in ic ;
A sia n,
B ei gh to n sc or e
(> 4)
an d
slo w
an d 23
m al es
is se le ct iv el y m or e
co m m on
in m al es
et al ., 20 09
(> 4)
w ith
ili ty
Sy nd
n; C au ca sia ns
(9 8%
po pu
la tio
pu bl ish
14 .9 %
2. 2%
< 0. 05
is m or e co m m on
in fe m al es
w ith
et al ., 20 09
B ri gh to n cr ite ri a
fo r JH
an d
in fla m m at or y
bo w el
an d 38
m al es
(1 8– 50
ye ar s) ;
G re ek
gJ H M
b 70 .3 %
(C ro hn
in pa tie nt s w ith
C ro hn
of ha vi ng
in fla m m at or y bo w el
di se as e an d gJ H M
is tw
co lit is
an d
gJ H M
at io n
an d 19
m al es
(2 0– 83
ye ar s)
co ns tip
at io n
96 .9 % /
3. 1%
85 .9 % /
14 .1 %
0. 02
at io n ar e
m or e co m m on
ly fe m al es
w ith
su rg er y
pr ol ap se
ly di sp la y
Pr ev io us
pe lv ic
or ga n
30 .7 %
17 .0 %
0. 04
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 57
T A B L E I.
(C on tin ue d)
R ef er en ce
a gJ H M
st ra te gy
of co nt ro ls
C ha ra ct er ist ic s of
pa tie nt s
co nt ro ls
fe at ur e( s)
R at e in
pa tie nt s
R at e in
co nt ro ls
P va lu e
gJ H M
ev ac ua tio
n, fu nc tio
na l
re ct oc el e an d ex tr in sic
co m pr es sio
n of
th e
an or ec ta l ph
ys io lo gi ca l
in ve st ig at io n th an
pa tie nt s w ith
ou t gJ H M .
T he
a pr ec ip ita tin
g ev en t fo r
co ns tip
co m m on
er gr ou
re ct al
58 %
39 %
n of
th e
11 1
(> 4)
an d
gJ H M
sy m pt om
an d 23
m al es
(1 8– 78
ye ar s)
an d
sy m pt om
sy m pt om
ge r,
fe m al es ,
ly di sp la y
ga st ro es op
ha ge al re flu
x an d bl oa tin
g th an
ou t gJ H M .
E tio
lo gy
s in
co m m on
al s w ith
ph ag ea l
62 %
46 %
et al ., 20 12
“ Pr es en ce
11 0
10 0
gJ H M
at te nd
cl in ic
at te nd
cl in ic
Pe lv ic
or ga n
is m or e co m m on
in fe m al es
w ith
et al ., 20 14
( 4)
ye ar s) w ith
vo id in g
(5 – 14
in ch ild re n w ith
vo id in g
gJ H M ,
gJ H M
0. 01 7
58 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
T A B L E I.
(C on tin ue d)
R ef er en ce
a gJ H M
st ra te gy
of co nt ro ls
C ha ra ct er ist ic s of
pa tie nt s
co nt ro ls
fe at ur e( s)
R at e in
pa tie nt s
R at e in
co nt ro ls
P va lu e
Ir an ia ns
ur in ar y tr ac t in fe ct io ns
ar e m or e co m m on
in fe m al es , w hi le
co ns tip
co m m on
in m al es
5% 0. 04
G I, ga st ro in te st in al ; gJ H M ,g
en er al iz ed
jo in t hy pe rm
ob ili ty ; JH
ob ili ty
ro m an di bu
la r jo in t.
a O nl y fe at ur es
w ith
sig ni fic an t di ffe re nc es
be tw
ee n pa tie nt s’ an d co nt ro ls’
gr ou
rt ed
e. ,P
b 5 ou
al sw
di se as e an d 1 ou
to f1
al sw
ith gJ H M
an d ul ce ra tiv e co lit is al so
m et B ri gh to n cr ite ri a fo r jo in th
yp er m ob
a cu m ul at iv e O R
of 3. 75 .
al .[ 19 95 ].
d T he
rt ed
qu es tio
nn ai re
in ve st ig at in g hi st or ic al gJ H M
[H ak im
an d G ra ha m e, 20 03 ].
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 59
et al. [2014] studied 270 women with urinary incontinence and pelvic organ prolapse, who were screening for gJHM with the self-reported 5-point ques- tionnaire by Hakim and Grahame [2003].
Of the 12 studies with positive results (Table I), four studied adult females only [Norton et al., 1995; Jha et al., 2007; Arunkalaivanan et al., 2009; Lammers et al., 2012], five adult males and 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 from both sexes [Mohammed et al., 2010; Kajbafzadeh et al., 2014], and one children, adolescents and adults from both sexes [Marshman et al., 1987]. Theseworks differed also for the assessing method for gJHM, which was the Beighton score with a positive cut-off of>4 four times [Jha et al., 2007; Reilly et al., 2008; Arunkalaivanan et al., 2009; Zarate et al., 2010], Beighton score with a positive cut-off of 4 twice [Al-Rawi et 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 method four times [Marshman et al., 1987; Norton et al., 1995; Pulliam and…
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