American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 175C:181–187 (2017) ARTICLE

Gastrointestinal Involvement in the Ehlers–Danlos Syndromes

ASMA FIKREE, GISELA CHELIMSKY, HEIDI COLLINS, KATCHA KOVACIC, AND QASIM AZIZ*

Current evidence suggests that an association exists between non-inflammatory hereditary disorders of connective tissue such as the Ehlers–Danlos syndromes (EDS) and gastrointestinal (GI) symptoms. Patients with EDS can present with both structural problems such as hiatus , visceroptosis, rectoceles, and as well as functional problems such as disordered gut motility. It has recently been demonstrated that patients with hypermobile EDS (hEDS) present with GI symptoms related to the fore and hind-gut and these patients frequently meet the criteria for functional gastrointestinal disorders such as functional dyspepsia and . Presence of GI symptoms in EDS patients influences their quality of life. Specific evidence based management guidelines for the management of GI symptoms in EDS patients do not exist and these patients are often treated symptomatically. There is, however, recognition that certain precautions need to be taken for those patients undergoing surgical treatment. Future studies are required to identify the mechanisms that lead to GI symptoms in patients with EDS and more specific treatment guidelines are required. © 2017 Wiley Periodicals, Inc.

KEY WORDS: Ehlers–Danlos syndrome; gut motility; abdominal pain; ; How to cite this article: Fikree A, Chelimsky G, Collins H, Kovacic K, Aziz Q. 2017. Gastrointestinal involvement in the Ehlers–Danlos syndromes. Am J Med Genet Part C Semin Med Genet 175C:181–187.

INTRODUCTION and each member should provide a list of and care guidelines for the management references relevant to specific areas. of EDS-related GI symptoms. GI The current information on the gastroin- The search terms used were “Ehlers– symptoms are normally managed on testinal manifestations of Ehlers–Danlos Danlos and gastrointestinal,”“Ehlers– empirical grounds using best practice syndrome (EDS) are summarized in this Danlos and GI,”“Joint-hypermobility models and evidence. review. Information about management and joint hypermobility syndrome (JHS) There are anecdotal reports of global principles based on current evidence is and gastrointestinal,”“Ehlers–Danlos hy- improvement of hypermobile type of provided together with suggestions for permobility (EDS-HT),”“Ehlers–Danlos Ehlers–Danlos syndrome (hEDS) related future research in the field. and perforation,”“Ehlers–Danlos vascu- symptoms following patient-led “trial lar,”“Ehlers–Danlos type IV and and error” diet-based interventions, as METHODS gastrointestinal.” well as through the use of enteral The gastrointestinal (GI) group had a nutrition via nasogastric feeding, percu- number of telephone conferences to taneous endoscopic gastrostomy/jeju- Management and Care Guidelines discuss the content of the literature nostomy feeding, and total parenteral review. It was agreed that a comprehen- There are currently no well validated nutrition. In 2005, a novel and theoreti- sive literature search should be conducted national or international management cal approach to symptom management in

Dr. Asma Fikree is a consultant gastroenterologist at the Royal London Hospital, London, UK. Her Ph.D. was on gut manifestations of hypermobile EDS. Dr. Gisela Chelimsky is a pediatric gastroenterologist in Milwaukee, Wisconsin, and is affiliated to Children's Hospital of Wisconsin and the Medical College of Wisconsin. Dr. Heidi Collins is a physical medicine and rehabilitation specialist. She is chair of the EDNF Professional Advisory Network and works at Beacon Medical Group, Memorial Hospital, South Bend, IN. Dr. Kovacic is assistant professor and a Pediatric Gastroenterologist. She is part of the nationally recognized GI motility program at the Children's Hospital of Wisconsin, Center for Pediatric Neurogastroenterology, Motility and Autonomic Disorders. Prof. Qasim Aziz is a professor of neurogastroenterology at Barts and The London School of Medicine and Dentistry, and specialists in disorders of gut function. *Correspondence to: Professor Qasim Aziz, The Wingate Institute of Neurogastroenterology, 26 Ashfield Street, London E1 2AJ. E-mail: [email protected] DOI 10.1002/ajmg.c.31546 Article first published online 10 February 2017 in Wiley Online Library (wileyonlinelibrary.com).

ß 2017 Wiley Periodicals, Inc. 182 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

EDS was described by Mantle et al. GI complications such as bleeding or poorer pain-related quality of life com- [2005]. The authors suggested that perforation has been described in the pared to those without the overlap. attention to nutrient intake, by use of literature. These approaches range from Thus, it is likely that management of supplements, may impact on symptom refrain from intervention with conser- FGID patients with and without EDS severity in EDS. Tinkle [2009] has also vative non-surgical management of overlap may differ. For instance, those reported his experience with similar intestinal perforation [Casey et al., with overlap may require earlier identi- selected nutraceuticals in hEDS. In a 2014] to more conventional surgical fication and holistic multidisciplinary 2015 review of gastrointestinal and management with resections of appro- management involving for instance nutritional issues in hEDS, Castori priate segments of the gut. It has been rheumatologists, autonomic neurolo- et al. [2015] suggested that there is a suggested that during surgery, all organs gists, and pain specialists. theoretical basis which suggests that must be treated gently due to tissue Chronic musculoskeletal and vis- lifestyle and nutrients may be beneficial fragility [Omori et al., 2011]. A system- ceral pain is common in patients with in hEDS. Consequently, it is reasonable atic review of GI surgery and related EDS. It is, therefore, likely that opioids to postulate that these features may be complications in EDS [Burcharth and will be considered in the management of managed or improved by nutritional Rosenberg, 2012] suggests that surgery these patients, which can significantly supplementation and lifestyle modifica- in patients with EDS is associated with a influence GI function and lead to tions. In the author’s own clinical high risk of complications, which is why deterioration in symptoms. Hence, practice, low FODMAP (Fructose, Oli- preoperative indications should be care- avoidance of opioids should be a con- gosaccharides, Disaccharides, Mono- fully considered. Furthermore, optimal sideration in those with GI involvement. amines, and Polyols) diet is frequently therapy for these patients includes the used to good effect for abdominal awareness that EDS is a systemic disease bloating, pain, and diarrhea, these fea- involving fragility, bleeding, and spon- tures often overlap with irritable bowel taneous perforations from almost all Chronic musculoskeletal and syndrome (IBS) where the efficacy of this systems. The authors suggested diet is now well established. Given that that a nonsurgical approach can be the visceral pain is common in approximately 37% of patients with a best choice for these patients, depending patients with EDS. It is, diagnosis of IBS meet the criteria of on the condition. hEDS [Fikree et al., 2015], it is not Desmopressin has been used in a therefore, likely that opioids surprising that efficacyof this diet is being preliminary study of hEDS associated will be considered in the seen. However, further controlled studies bleeding symptoms such as easy bruis- management of these patients, are required to determine efficacy of the ing, epistaxis, menorrhagia, and gum diet based interventions in patients with bleeding [Mast et al., 2009]. In these which can significantly GI symptoms associated with hEDS. patients, desmopressin was given intra- influence GI function and lead nasally or intravenously and led to significantly reduced bleeding time. In to deterioration in symptoms. In the author’s own clinical the same study, desmopressin was also Hence, avoidance of opioids given to patient’s pre-surgery (non-GI practice, low FODMAP surgery) and none of these patients should be a consideration in (Fructose, Oligosaccharides, suffered from any post-surgical bleeding those with GI involvement. complications, in contrast, 30% of the Disaccharides, Monoamines, patients who did not receive desmo- and Polyols) diet is frequently pressin developed post-operative bleed- Recognition that anatomical ab- used to good effect for ing complications. This suggests that normalities such as , rec- desmopressin may have a role in the toceles, and prolapse can occur in abdominal bloating, pain, and management of GI peri-surgical bleed- patients with EDS may help to plan diarrhea, these features often ing complications in EDS patients but investigation and treatment in patients further studies are required to test this with GI symptoms. For instance, con- overlap with irritable bowel hypothesis. stipation is common in patients with syndrome (IBS) where the Recently, Fikree et al. [2015] have hEDS [Fikree et al., 2014], and recog- demonstrated that a significant propor- nition that symptoms may at least partly efficacy of this diet is now tion of patients with Functional Gastro- be due to rectal evacuatory dysfunction well established. intestinal Disorders (FGID) meet the due to the anatomic abnormalities such criteria for hEDS. Patients with this as rectocele and or prolapse may help to overlap have a different phenotype with guide the management toward nurse led Surgical management of patients more chronic pain, somatization, auto- therapy aimed at improving defecatory with vascular EDS who develop acute nomic symptoms and anxiety, and dynamics or in some severe cased ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 183 surgical correction of the anatomic Case reports of patients with hEDS by which this may occur [Gazit et al., abnormality. describe further anatomical abnormali- 2003; Hakim and Grahame, 2004], and ties in small numbers of patients. since then it has been shown that Diverticular disease has been described Postural Tachycardia Syndrome (PoTS) GI Connective Tissue in association with EDS [Lindor and is associated with GI symptoms such as Abnormalities in Disease Bristow, 2005]. Visceroptosis of the nausea, reflux, bloating, constipation, Localized abnormalities in connective bowel has been described in two patients and diarrhea [Mathias et al., 2011]. tissue have been described in association with hEDS [Reinstein et al., 2012]. This Thus, it would appear that hEDS, with GI pathology. In diverticular refers to the downward displacement of autonomic symptoms, and GI symp- disease, there is increased elastin deposi- abdominal organs below their natural toms are indeed linked, though the tion in the taenia of the colon, and position. It is rare and its aetiology is exact mechanism for the association is structural changes in the collagen of the unknown. It can cause kinking of thin unknown. smooth muscle [Whiteway and Morson, walled structures such as blood vessels 1985]. Patients with hiatus hernias have and nerves and thereby cause symptoms, fragmentation and distortion of elastin which can be severe. In the case in their gastro-hepatic and phreno- described, the patient presented with a The association between esophageal ligaments [Curci et al., 4 year history of abdominal distension hEDS and GI symptoms was 2008]. Children with have and bloating that interfered with her atrophy of collagen in the tendinous eating and activities of daily living. first described 12 years ago by connective tissue membrane of the Hakim and Grahame. They myenteric plexus and muscularis prop- EDS and Abnormal GI Physiology ria, referred to as “atrophic desmosis” found that hEDS patients [Meier-Ruge, 1998]. Evidence also Results of gastrointestinal physiological attending a hypermobility exists for the association between GI studies were reported in a retrospective clinic had significantly more pathology and both inflammatory and observational study from the Mayo non-inflammatory connective tissue clinic in EDS patients of whom the GI symptoms compared to age disorders [Braun and Sieper, 1999]. A vast majority had hEDS (71.7%) and sex matched controls rationale, therefore, exists for an influ- [Nelson et al., 2015]. About 13 out of ence of connective tissue disorders on 46 (28%) patients who underwent (37% vs. 11%). The most gut structure and function. Evidence colonic transit studies had abnormal common GI symptoms were now exists of involvement of the entire results; nine with slow transit and four GI tract in EDS. with fast transit. A total of 60% of these nausea, abdominal pain, patients with abnormal colonic transit constipation, and diarrhea. had hEDS In the same study, 17 out of EDS AND ABNORMAL GI 76 (22%) patients had abnormal gastric TRACT emptying half being fast and half being As that landmark study, other slow Abnormal oesophageal manome- studies in various hospital settings and EDS and Abnormal GI Anatomy try was present in 5 out of 11 (31%) countries, have confirmed that GI In a study of EDS patients, only 11 out of patients. About 7 out of 16 patients symptoms are common in patients 143 (7.7%) who underwent endoscopic (44%) had pathological acid reflux on with an existing diagnosis of hEDS. In assessment had a hiatus [Nelson reflux testing. a study of 21 hEDS patients attending a et al., 2015]. A study in patients with genetics clinic in Italy, 87% of patients lower urinary tract dysfunction demon- were found to have GI symptoms, most Association Between hEDS and GI strated that patients with hEDS were commonly dyspepsia (67%), gastro- Symptoms significantly more likely to have symp- oesophageal reflux (57%), recurrent toms of rectal evacuatory dysfunction The association between hEDS and GI abdominal pain (62%), alternating con- and evidence of rectal morphological symptoms was first described 12 years stipation and diarrhea (33%), and ab- anomalies, for example, rectal prolapses, ago by Hakim and Grahame [2004]. dominal hernias (5%) [Castori et al., compared to those without hEDS They found that hEDS patients attend- 2010]. Furthermore, the same author [Manning et al., 2003]. In a case series ing a hypermobility clinic had signifi- demonstrated that the incidence of GI of EDS patients at the Mayo clinic, all 4 cantly more GI symptoms compared to symptoms increased with age, and that patients who underwent an MR procto- age and sex matched controls (37% vs. older hEDS patients were more likely to gram had an anterior rectocele [Nelson 11%). The most common GI symp- have GI symptoms than their younger et al., 2015]. In the same study, 12 (11%) toms were nausea, abdominal pain, counterparts. out of 110 who underwent colonoscopy constipation, and diarrhea. It was felt In a prospective cross-sectional had diverticulosis or . that dysautonomia was one mechanism study of over 600 new patients in 184 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE secondary care GI clinics, Fikree et al. hEDS and Organic GI Disorders patients were assessed further by a [2014] looked at three groups of patients rheumatologist, and found to have Only two published studies exist which including those with established hEDS hEDS. Patients with hEDS tended to demonstrate a possible association be- from rheumatology clinics (hEDS-Rh), have motility problems in their gut on tween hypermobility and organic dis- those with hEDS albeit previously physiological testing, for example, small orders, and these were done in patients undiagnosed (hEDS) and those without bowel dysmotility, delayed gastric emp- with inflammatory bowel disease (IBD) hEDS (non-hEDS). They demonstrated tying and delayed colonic transit. This and celiac disease. The first was per- that approximately one-third of unse- study suggested that in a tertiary neuro- formed in a Greek Hospital setting lected patients attending GI clinics have setting, hEDS was [Vounotrypidis et al., 2009] which de- previously undiagnosed hEDS based on associated with GI dysmotility. scribed that the prevalence of hEDS in validated clinical criteria; however, the In studies demonstrating the presence Crohn’s disease (12.2%) was higher than GI symptom profile in these patients is of GI Symptoms in hEDS, GI symptoms that in UC (3.6%) but this difference was less severe than that observed in patients were often attributable to FGID subtypes not statistically significant. Fikree et al. with established hEDS referred from such as IBS, rectal evacuatory dysfunction, [2015] also demonstrated a relatively rheumatology clinics. In the newly and functional constipation [Manning high prevalence of JHS in Crohn’s diagnosed hEDS patients, there was a et al., 2003; Castori et al., 2010; Zeitoun disease and ulcerative patients significant association with gastro- et al., 2013], all of which are ROME III (32% and 21%, respectively). No other oesophageal reflux and dyspeptic symp- categories of FGID. In another paper, studies have further examined this toms but not with alternating bowel two-thirds of patients with hEDS who association between EDS and IBD. habit, chronic abdominal pain, dyspha- reported having appendectomies for ab- One small study demonstrated a gia, globus, and bloating; however, these dominal pain did not have a positive high prevalence of celiac disease in hEDS symptoms were more common in the outcome of surgery, suggesting that the patients [Danese et al., 2011]. Thirty-one hEDS-Rh group. Autonomic dysfunc- pain was more likely to be secondary to a patients attending a genetics clinic with tion, chronic pain, and analgesic use, but functional cause rather than an established hEDS diagnosis were not psychopathology, showed increasing [Rombaut et al., 2011]. screened for celiac disease using IgA/G trends across the three groups, being Fikree et al. [2015] further studied endomysial antibodies and/or anti-tissue highest in patients with hEDS-Rh. the association between hEDS and FGID transglutaminase, of which six (19%) Thus, they concluded that hEDS is and the impact of this association on tested positive. Duodenal biopsies from common in GI clinics, with increased comorbidities and quality of life (QOL). five had features consistent with celiac burden of upper GI and extra intestinal In a prospective case-control study in disease. The prevalence of celiac disease symptoms. secondary care GI clinics over 2 years, (16%) in the hEDS group was, therefore, Studies from a Genetics Depart- hEDS was assessed prior to consultation significantly higher than the estimated ment in Belgium not only confirm that in consecutive new patients. It was population prevalence (1%) [Danese GI symptoms such as constipation, demonstrated that hEDS prevalence et al., 2011]. However, there are a diarrhea, bloating, and swallowing was higher in FGID compared to organic number of limitations to this study. First, problems are present in hEDS, but that GI disorders (39.0% vs. 27.5%, ORadj: the population prevalence of celiac these GI symptoms are associated with 1.51, CI: 1.07–2.12, P ¼ 0.02), and disease was estimated rather than calcu- clusters of other extra-articular symp- particularly associated with functional lated. Second, the basis on which hEDS toms, in particular cognitive problems, gastroduodenal disorders (44.1%, OR- patients were selected for testing for celiac insomnia, postural dizziness, and syn- adj: 2.08, CI: 1.25–3.46, P ¼ 0.005), disease is not described and, therefore, cope [Rombaut et al., 2011]. This group specifically postprandial distress syn- there may be a degree of selection bias. also recognized that there was large drome (51%, ORadj: 1.99, CI: 1.06– Nevertheless, these results were broadly heterogeneity in presentation and not all 3.76, P ¼ 0.03). FGID patients with corroborated in another study with a patients had the same cluster of symp- hEDS had increased chronic pain, fibro- small sample size, where hEDS was toms. Consequently, they performed a myalgia, somatization scores, urinary diagnosed in fourout of 13 (30%) patients cluster analysis and identified that two autonomic scores, and worse pain- attending GI clinics with a new diagnosis main clusters. In both clusters, muscu- related QOL scores. The authors con- of celiac disease [Fikree et al., 2015]. loskeletal symptoms were most promi- cluded that hEDS is significantly associ- nent; however, the pattern of extra- ated with FGID, and this subgroup of hEDS and Functional GI Disorders articular symptoms differed. GI symp- patients have increased comorbidity and toms were particularly prominent in the Direct evidence for an association decreased QOL. cluster, which also had high levels of between FGID and generalized joint fatigue, cutaneous changes, orthostatic, hypermobility initially came from a hEDSandGISymptomsinChildren immune, urogynecological, visual, and retrospective observational study in respiratory problems [De Wandele et al., tertiary gastroenterology setting [Zarate Data on gastrointestinal manifestations 2013]. et al., 2009]. A subgroup of these in children with hEDS is limited. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 185

However, several studies link constipa- been reported in two siblings with a In a review of surgical complica- tion with childhood generalized joint suspected diagnosis of vEDS with tions of vEDS by Freeman et al. [1996], hypermobility (GJH) as determined by consanguineous parents [Lin et al., 44 gastrointestinal and 45 vascular the Beighton score. These studies found 2006]. The index case was a 3- complications of vEDS have been constipation rates ranging from 11% to year-old girl who had surgery for reported in the literature between 38% in hypermobile children. Consti- CDH at 5 months of age, with recur- January 1975 and July 1995. This pation was more common in hyper- rence 6 months later followed by further included 41 colon perforations, two mobile boys [de Kort et al., 2003; Adib surgery. Recurrence at 3 years of age paraesophageal hernias, 22 spontaneous et al., 2005; Reilly et al., 2008]. prompted further investigations. Two- haemorrhages, 17 aneurysms, and 5 A variety of gastrointestinal symp- dimensional echocardiography revealed arterial dissections. A total of 27 colonic toms and functional GI disorders have an atrial septal defect, dilatation of the perforations were treated with resection also been linked to joint hypermobility pulmonary arteries, and suspected and diversion, 11 with total abdominal in children. Pacey et al. [2015] reported abnormally tortuous aorta. Subsequent colectomy (TAC), and 3 with primary gastrointestinal symptoms in 54% of contrast-enhanced magnetic resonance colon repair. Re-perforation occurred children with GJH. Kovacic et al. angiography revealed marked tortuou- in 15 resection/diversion patients versus [2014] found a 56% prevalence of GJH sity of the aorta and the innominate, left none treated with TAC (P < 0.05). in adolescents diagnosed with complex common carotid, left subclavian, and Seven patients (23.3%) died from their functional GI disorders. In these pa- bilateral vertebral arteries, that was gastrointestinal complications. Twelve tients, fibromyalgia appeared associated suggestive of EDS. Further detailed (30%) patients died from vascular com- with GJH. A large population study in evaluation of the patient revealed hyper plications of vEDS, seven of whom had India found a high prevalence of GJH elastic skin and mild hypermobility of been treated with arterial reconstruction and a possible link of this condition with the knee joints. A chromosome study (P < 0.05). This review supports treat- moderate-severe malnutrition [Hasija did not demonstrate an obvious abnor- ing colon perforations in vEDS patients et al., 2008]. mality but diagnosis of vEDS was made with TAC and end ileostomy to avoid a on clinical grounds. Subsequently, her re-perforation or an anastomotic leak. 1-year-old brother was also diagnosed Stillman et al. [1991] have described GI Symptoms in Other Subtypes of with CDH. spontaneous colonic perforation, a EDS complication traditionally treated by GI symptoms have been described in primary closure of the perforated seg- EDS I, II, and IV subtypes as well as in ment and creation of an end colostomy, patients with Tenascin X deficiency. Various GI manifestation of while attempts at bowel re-anastomosis In classic EDS (cEDS), diverticular the vascular type of EDS often result in repeated colon perfora- disease has been described [Kitsiou- tions. They present a patient with vEDS Tzeli et al., 2010]. Although spontane- (vEDS) has been described. with colonic perforation proximal to an ous acute has been described Most of these relate to organ end colostomy, and describe the surgical in cEDS, it is not clear if this is a true strategy to prevent recurrences of this association or an incidental finding perforation and or bleeding. and other postoperative complications [Sarra-Carbonell and Jimenez, 1989]. Familial cases of sigmoid associated with the syndrome. Various GI manifestation of the GI symptoms have been described vascular type of EDS (vEDS) has been perforation have also been in patients with Tenascin X (TNX) described. Most of these relate to organ described. deficiency including abdominal pain perforation and or bleeding [Pepin et al., [Lindor and Bristow, 2005] episodes of 2000; Baichi et al., 2005; Diz et al., spontaneous and secondary and 2009; Omori et al., 2011; Anderson and vEDS complicated by eventration of perforations (sigmoid and ), Sweetser, 2014; Yoneda et al., 2014]. the diaphragm and colonic and jujenal with post-operative Familial cases of sigmoid perforation perforation has been described [Iwama and incarceration. Chronic constipation have also been described [Surgey et al., et al., 1989]. Post-operative celiac artery and rectal prolapse, pan colonic diver- 2011]. There also appears to be in- thrombosis [Debnath et al., 2007] and ticulosis with diverticulitis, uterine pro- creased risk of colonic perforation other complications [Freeman et al., lapse, and moderate sized hiatus hernia during colonoscopy [Rana et al., 1996] can also occur in vEDS. In addition, [Lindor and Bristow, 2005] have also 2011]. Occult and overt small bowel spontaneous rupture of the liver [Gelb- been described. Increased incidence of perforation can also occur [Aldridge, mann et al., 1997; Mistry et al., 2000; Ng GI problems in family members of TNX 1967; Leake et al., 2010]. Even esoph- and Muiesan, 2005] and spleen [Privitera deficiency patients have been described ageal perforation has been described et al., 2009] as well as post-operative including chronic constipation since [Habein, 1977]. Furthermore, congeni- bleeding into the liver capsule [Blaker et al., childhood, and rectal prolapse. Spontane- tal (CDH) has 2007] has been reported in these patients. ous perforation of colonic diverticulum, 186 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE multiple intra-abdominal abscesses, du- being critical to normal cellular func- patient with suspected Ehlers-Danlos syn- drome. Int J Surg Case Rep 5:135–137. odenal and sigmoid diverticulae have tion, and there has been increasing Castori M, Camerota F, Celletti C, Danese C, also been reported in TNX deficient research into various signaling compo- Santilli V, Saraceni VM, Grammatico P. patients. Gastric ulceration [Hendriks nents (e.g., growth factors) which might 2010. Natural history and manifestations of the hypermobility type Ehlers-Danlos syn- et al., 2012] and GI bleeding [Schalkwijk provide treatable targets in the future. drome: A pilot study on 21 patients. Am J et al., 2001] has also been described in a Genetic studies such as exome sequenc- Med Genet Part A 152A:556–564. male patient with homozygous for TNX ing on families of patients with hEDS, Castori M, Morlino S, Pascolini G, Blundo C, Grammatico P. 2015. Gastrointestinal and deficiency. and in patients who have had deep nutritional issues in joint hypermobility/ phenotypic profiling perform are some Ehlers-Danlos syndrome, hypermobility FUTURE DIRECTIONS of the methods that may pave the way of type. Am J Med Genetic C Semin Med Genet 169C:54–75. identification of the molecular abnor- It is clear from the above literature Curci JA, Melman LM, Thompason RW, Soper malities that underlie this hitherto NJ, Matthews BD. 2008. Elastic fiber review that GI symptoms can occur in difficult to understand disorders. depletion in the supporting ligaments of all EDS subtypes. GI perforations and the gastroesophageal junction: A structural bleeding complications are less likely in basis for the development of hiatal hernia. J Am Coll Surg 207:191–196. hEDS and most likely in vEDS than in CONCLUSION Danese C, Castori M, Celletti C, Amato S, Lo the other subtypes. There is a high Russo C, Grammatico P, Camerota F. 2011. Current literature suggests an associa- prevalence of hEDS in patients present- Screening for celiac disease in the joint tion between all subtypes of EDS and GI hypermobility syndrome/Ehlers-Danlos ing with the features of FGID especially symptoms. This association is common syndrome hypermobility type. Am J Med functional dyspepsia. hEDS patients Genet Part A 155A:2314–2316. and has hitherto been underestimated. with GI symptoms also often have a de Kort LM, Verhulst JA, Engelbert RH, The group observed that evidence for Uiterwaal CS, De Jong TP. 2003. Lower combination of musculoskeletal, auto- GI symptoms to be included as a major urinary tract dysfunction in children with nomic, and urinary tract symptoms. generalized hypermobility of joints. J Urol EDS diagnostic criteria is compelling. There remain several knowledge 170:1971–1974. However, a causative relationship be- De WandeleI, Rombaut L, Malfait F,De Backer T, gaps and future work will be needed to tween abnormalities in connective tissue De Paepe A, Calders P. 2013. Clinical address these on an epidemiological, heterogeneity in patients with the hyper- and GI symptoms has not yet been physiological, cellular, molecular, and mobility type of Ehlers-Danlos syndrome. established. Similarly, specific evidence Res Dev Disabil 34:873–881. genetic level. The aetiology of GI based guidelines for the management of Debnath UK, Sharma H, Roberts D, Kumar N, symptoms in individuals with EDS Ahuja S. 2007. Coeliac axis thrombosis after EDS patients with GI symptoms are not will need to be determined and this surgical correction of spinal deformity in yet available. type VI Ehlers-Danlos syndrome: A case will require investigation of biomechan- report and review of the literature. Spine 32: ical, autonomic, and sensorimotor func- E528–E531. tion of the upper GI tract. The Diz DI, Ubieto JMOD, Parejto PT, Muinelo AFF, REFERENCES Lorenzo FJG. 2009. Colon perforation and understanding of which EDS individuals Ehlers-Danlos syndrome type IV: Total will develop GI symptoms and how they Adib N, Davies K, Grahame R, Woo P, Murray laproscopic colectomy. Cirugia Espanola progress over time, what other factors KJ. 2005. Joint hypermobility syndrome in 86:47–49. childhood. A not so benign multisystem Fikree A, Aktar R, Grahame R, Hakim AJ, Morris such as poor nutrition, traumatic life disorder? Rheumatology 44:744–750. JK, Knowles CH, Aziz Q. 2015. Functional events, viral infections, and so on, Aldridge RT. 1967. Ehlers-Danlos syndrome gastrointestinal disorders are associated with precipitate the worsening of GI and causing intestinal perforation. Br J Surg the joint hypermobility syndrome in sec- 54:22–25. ondary care: A case-control study. Neuro- extra-intestinal symptoms in these pa- Anderson B, Sweetser S. 2014. A woman with gastroenterol Motil 27:569–579. tients will require longitudinal studies. spontaneous colonic perforation. Gastroen- Fikree A, Grahame R, Aktar R, Farmer AD, Improving our understanding of the terology 147:1224–1225. Hakim AJ, Morris JK, Knowles CH, Aziz Q. Baichi MM, Arifussin RM, Mantry P. 2005. 2014. A prospective evaluation of undiag- above-mentioned factors will enable Gastrointestinal bleeding in a patient with nosed joint hypermobility syndrome in better treatment strategies to be devised. Ehlers-Danlos syndrome: An endoscopic patients with gastrointestinal symptoms. Identification of the nature of the dilemma. Dig Dis Sci 50:1342–1343. Clin Gastroenterol Hepatol 12:1680–1687. Blaker H, Funke B, Hausser I, Hackert T, Freeman RK, Swegle J, Sise MK. 1996. The connective tissue defect in EDS and its Schirmacher P, Autschbach F. 2007. Pathol- surgical complications of Ehlers-Danlos relation to the functioning of the GI ogy of the in patients with syndrome. Am Surg 62:869–873. tract is undeniably an important ques- vascular type of Ehlers-Danlos syndrome. Gazit Y, Nahir AM, Grahame R, Jacob G. 2003. Virchows Arch 450:713–717. Dysautonomia in the joint hypermobility tion now and will require genetic studies Braun J, Sieper J. 1999. Rheumatologic manifes- syndrome. Am J Med 115:33–40. in humans and validation studies in tations of gastrointestinal disorders. Curr Gelbmann CM, Kollinger M, Gmeinwieser J, animal models. The mechanism of the Opin Rheumatol 11:68–74. Leser HG, Holstege A, Scholmerich J. 1997. Burcharth J, Rosenberg J. 2012. Gastrointestinal Spontaneous rupture of liver in a patient link between EDS and PoTS also needs surgery and related complications in patients with Ehlers-Danlos disease type IV. Dig Dis further study. Furthermore, signaling with Ehlers-Danlos syndrome: A systematic Sci 42:1724–1730. between the extracellular matrix (com- review. Dig Surg 29:349–357. Habein HC. 1977. Ehlers-Danlos syndrome with Casey MC, Robertson I, Waters PS, Hanaghan J, spontaneous rupture of the . ponent of connective tissue) and intra- Khan W, Barry K. 2014. Non-operative Report of first case. Rocky Mt Med J cellular structures is now recognized as management of diverticular perforation in a 74:78–80. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 187

Hakim AJ, Grahame R. 2004. Non-musculoskeletal bleeding symptoms. Br J Haematol 144: Rombaut L, Malfait F, De Wandele I, Cools A, symptoms in joint hypermobility syndrome. 230–233. Thijs Y, De Paepe A, Calders P. 2011. Indirect evidence for autonomic dysfunc- Mathias CJ, Low DA, Iodice V, Owens AP, Kirbis Medication, surgery, and physiotherapy tion? Rheumatology 43:1194–1195. M, Grahame R. 2011. Postural tachycardia among patients with the hypermobility Hasija RP, Khubchandani RP, Shenoi S. 2008. syndrome—Current experience and con- type of Ehlers-Danlos syndrome. Arch Joint hypermobility in Indian children. Clin cepts. Nat Rev Neurol 8:22–34. Phys Med Rehabil 92:1106–1112. Exp Rheumatol 26:146–150. Meier-Ruge WA. 1998. Desmosis of the colon: A Sarra-Carbonell S, Jimenez SA. 1989. Ehlers- Hendriks AG, Voermans NC, Schalkwijk J, working hypothesis of primary chronic Danlos syndrome associated with acute Hamel BC, Van Rossum MM. 2012. constipation. Eur K Pediatr Surg 8:299–303. pancreatitis. J Rheumatol 16:1390–1394. Well-defined clinical presentation of Eh- Mistry BM, Solomon H, Garvin PJ, Durham RM, Schalkwijk J, Zweers MC, Steijlen PM, Dean WB, lers-Danlos syndrome in patients with Turnage S, Bacon BR, Galvin N, Varma Taylor G, Can Vlijmen IM, Van Haren B, tenascin-X deficiency: A report of four CR. 2000. Spontaneous rupture of the liver Miller WL, Bristow J. 2001. A recessive cases. Clin Dysmorphol 21:15–18. upon revascularization during transplanata- form of the Ehlers-Danlos syndrome caused IwamaT,SatoH,MatsuzakiT,MitakaS,DeguchiK, tion. Transplantation 69:2214–2219. by tenascin-X deficiency. N Engl J Med Mishima Y. 1989. Ehlers-Danlos syndrome Nelson AD, Mouchli MA, Valentin N, Deyle D, 345:1167–1175. complicated by eventration of the diaphragm, Pichurin P, vAcosta A, Camilleri M. 2015. Stillman AE, Painter R, Hollister DW. 1991. colonic perforation and jejunal perforation—A Ehlers Danlos syndrome and gastrointestinal Ehlers-Danlos syndrome type IV: Diagnosis case report. Jpn J Surg 19:376–380. manifestations: A 20-year experience at and therapy associated bowel perforation. Kitsiou-Tzeli S, Leze E, Salavoura K, Giannatou Mayo Clinic. Neurogastroenterol Motil Am J Gastroenterol 86:360–362. E, Fretzayas A, Makrithanasis P,Kanavakis E. 27:1657–1666. Surgey EG, Bignall JR, Brown SR. 2011. Familial 2010. Long term follow up of a woman with Ng SC, Muiesan P. 2005. Spontaneous liver spontaneous sigmoid perforation. Aetiology classic form of Ehlers-Danlos syndrome rupture in Ehlers-Danlos syndrome type IV. and management. Colorectal Dis 13: associated with rare manifestation and J R Soc Med 98:320–322. e185–e186. review of the literature. Genet Couns Omori H, Hatamochi A, Koike M, Sato Y,Kosho Tinkle BT. 2009. Joint hypermobility handbook 21:75–83. T, Kitakado Y, Oe T, Mukai T, Hari Y, —A guide for the issues & management of Kovacic K, Chelimsky TC, Sood MR, Simpson P, Takahashi Y, Takubo K. 2011. Sigmoid Ehlers-Danlos syndrome hypermobility Nugent M, Chelimsky G. 2014. Joint colon perforation induced by the vascular type and the hypermobility syndrome. hypermobility: A common association type of Ehlers-Danlos syndrome: Report of Illionois: Left Paw Press, LLC. with complex functional gastrointestinal a case. Surg Today 41:733–736. Vounotrypidis P, Efremidou E, Zezos P, Pitiakou- disorders. J Pediatr 165:973–978. Pacey V,Adams RD,Tofts L, Munns CF,Nicholson dis M, Maltezos E, Lyratzopoulos N, Leake TF, Singhal T, Chandra A, Ashcroft A, LL. 2015. Joint hypermobility syndrome Kouklakis G. 2009. Prevalence of joint Doddi S, Hussain A, Smedley F. 2010. subclassification in paediatrics: A factor hypermobility and patterns of articular Occult small bowel perforation in a patient analytic approach. Arch Dis Child 100:8–13. manifestations in patients with inflammatory with Ehlers Danlos syndrome: A case report Pepin M, Schwarze U, Superti-Furga A, Byers bowel disease. Gastroeneterol Res Pract and review of the literature. Cases J 3:57. PH. 2000. Clinical and genetic features of 2009:924138. doi: 10.1155/2009/924138 Lin IC, Ko SF, Shieh CS, Huang CF, Chien SJ, Ehlers-Danlos syndrome type IV, the vascu- Whiteway J, Morson BC. 1985. Elastosis in Liang CD. 2006. Recurrent congenital lar type. N Engl Med 342:673–680. diverticular disease of the sigmoid colon. diaphragmatic hernia in Ehlers-Danlos syn- Privitera A, Milkhu C, Datta V,Sayegh M, Cohen R, Gut 26:258–266. drome. Cardiovasc Intervent Radiol Windsor A. 2009. Spontaneous rupture of the Yoneda A, Okada K, Okubo H, Matsuo M, 29:920–923. spleen in type IV Ehlers-Danlos syndrome: Kishikawa H, Naing BT, Watanabe A, Lindor NM, Bristow J. 2005. Tenascin-X defi- Report of a case. Surg Today 39:52–54. Shimada T. 2014. Spontaneous colon per- ciency in autosomal recessive Ehlers-Danlos Rana M, Aziz O, Purkayastha S, Lloyd J, Wolfe J, forations associated with a vascular type of syndrome. Am J Med Genet Part A Ziprin P. 2011. Colonoscopic perforation Ehlers-Danlos syndrome. Case Rep Gastro- 135A:75–80. leading to a diagnosis of Ehlers Danlos enterol 8:175–181. Manning J, Korda A, Benness C, Solomon M. syndrome type IV: A case report and review Zarate N, Farmer AD, Grahame R, Mohammed 2003. The association of obstructive defeca- of the literature. K Med Case Rep 5:229. SD, Knowles CH, Scott SM, Aziz Q. 2009. tion, lower urinary tract dysfunction and the Reilly DJ, Chase JW, Hutson JM, Clarke MC, Unexplained gastrointestinal symptoms and benign joint hypermobility syndrome: A Gibbs S, Stillman B, Southwell BR. 2008. joint hypermobility: Is connective tissue the case-control study. Int Urogynecol J Pelvic Connective tissue disorder—A new sub- missing link? Neurogastroenterol Motil 22: Floor Dysfunct 14:128–132. group of boys with slow transit constipation? e78. Mantle D, Wilkins RM, Preedy V. 2005. A novel J Pediatr Surg 43:1111–1114. Zeitoun JD, Lefevre JH, De Parades V, Sejourne therapeutic strategy for Ehlers-Danlos syn- Reinstein E, Pimental M, Pariani M, Nemec S, C, Sobhani I, Coffin B, Hamonet C. 2013. drome based on nutritional supplements. Sokol T, Rimoin DL. 2012. Visceroptosis of Functional digestive symptoms and quality Med Hypotheses 64:279–283. the bowel in the hypermobility type of of life in patients with Ehlers-Danlos Mast KJ, Nunes ME, Ruymann FB, Kerlin BA. Ehlers-Danlos syndrome: Presentation of a syndromes: Results of a national cohort 2009. Desmopressin responsiveness in chil- rare manifestation and review of the litera- study on 134 patients. PLoS ONE 8: dren with Ehlers-Danlos syndrome associated ture. Eur J Med Genet 55:548–551. e80321.