The Prevalence of Non-Surgical Complications in the Ehlers-Danlos Syndrome  

By

¹David F. Hickok Memorial Cancer Research Laboratory, Abbott Northwestern Hospital, and the University of Minnesota Cancer Center, Minneapolis, MN.  ²Minnesota Gastroenterology, Minneapolis, MN. ³ Department of Pediatrics, University of Minnesota, Minneapolis MN. 

Address correspondence to: Pamela Popken-Harris, Ph.D., David F. Hickok Memorial Cancer Research Laboratory, Abbott Northwestern Hospital, Minneapolis, MN 55407; telephone (612) 863-4439, fax (612) 863-4936. 

Introduction

Although surgical complications can be associated with invasive procedures, particularly in those individuals diagnosed with type IV (Vascular Type of EDS)(2, 48, 72, 77), the prevalence of non-surgical complications in this syndrome are much less well known. Therefore, we performed a study to determine the prevalence of other types of medical conditions or complications, primarily in individuals diagnosed with EDS types I, II, and III as they comprise approximately 90% of those diagnosed with this syndrome. A detailed questionnaire was mailed out to EDS support groups world-wide to evaluate the types of conditions that may be common to this syndrome including those from the gastrointestinal, musculoskeletal, respiratory, cardiac and genitourinary systems.  Questions about the types of medications commonly prescribed in this population were also included.  Only those results where a diagnosis of EDS confirmed by a physician are presented.   Our findings indicate that arthritis, cardiac and skeletal thoracic abnormalities were common as were symptoms related to gastrointestinal system. Our findings are compared to those in the literature.

Patients and Methods

In compliance with institutional review board guidelines and through the cooperative efforts of the Ehlers-Danlos National Foundation (EDNF), Canadian Ehlers-Danlos Association (CEDA), and Ehlers-Danlos Support Group in the United Kingdom, a call for participants to complete a detailed questionnaire to determine the prevalence of cardiac and or skeletal abnormalities, medication use, and medical conditions including the various forms of arthritis, gastrointestinal ulceration, post-operative infections, general infections, respiratory type complications, allergy, asthma, autoimmunity and cancer was issued.  Demographic questions as to age, sex, and EDS type were also included.  In the period in which we collected data, 140 responses were received, including those from single individuals and sometimes extended families diagnosed with EDS types I-IV, VI, and unknown.  We could verify through medical records that 43 of our survey respondents were diagnosed with EDS by a geneticist or rheumatologist, and report only on these.  Only those responses to individual questions that were definitely positive were included in the analyses, and any response that was considered questionable was scored as negative.  In those instances where an abnormal response may have been indicated, such as a report of a coagulation defect, a recurrent or suspicious infection such as pyelonephritis or endocarditis, an autoimmune disease, inflammatory bowel disease or cancer, written verification in the form of medical records of the abnormal response was requested.   

Statistical analyses were also performed on some data sets to determine an exact two-tailed p-value (95% confidence level) using Fisher’s exact test for unpaired samples with the aid of a computer program Graph Pad Prism, version 2.01 (Graph Pad Software, San Diego CA). 

Gastrointestinal Complications

Out of 43 respondents, there were 10 who reported at least one prior gastrointestinal ulceration. Only one of these could be positively associated with Helicobacter pylori infection; however, only the six gastric ulcers (6/10) were tested.  Esophageal ulcers, previously associated with non-steroidal anti-inflammatory drug (NSAID) use (8), were the second most common type of ulcer reported (3/10), with only one of the ten reported ulcers (1/10) left as unspecified.  In this regard, we also found that 14/43 or 32.6% of the population also indicated the need for one or more types of daily anti-reflux medications (Table 2) including one or more of those agents designed to increase gastric motility as well as those that decrease or neutralize gastric acid production.

Of relevance to the incidence of non-Helicobacter related gastric ulceration in the adult EDS population, and the prevalence of various arthritic signs and symptoms, was the observation that 19/43 or 44.2% of our respondents also indicated the need for the daily use of NSAIDs or aspirin for pain relief (Table 2).  Accordingly, approximately half of our respondents (5/10), who indicated a prior gastrointestinal ulceration attributed their ulcer directly to the use of NSAIDs. In accordance with the known epidemiological risk factors associated with IBD (4, 52), our further inquiry of these three respondents indicated that 2/3 were current or past smokers, 2/3 had experienced a prior NSAID induced gastrointestinal ulceration, and 1/3 was Ashkenazic Jewish in persuasion and thus belonged to an ethnic group reported to have a higher prevalence of IBD.

Medication Use

Table 2 is a summary of the types of medications commonly prescribed to our respondents. The most common type of medications used by our survey respondents were those designed to ameliorate or reduce pain. These included NSAIDs (44.2%), non-NSAID pain relievers such as acetaminophen and tramadol (18.6%), and narcotic type pain relievers such as codeine or slow release morphine (7.0%).  Overall, the next two most common types of daily medication were those from the anti-reflux and the anti-depressant/anti-anxiety/tranquilizers categories with 14/43 or 32.6% of our respondents reporting the use of these two types of agents.  It was also evident that for women over the age of 21, that hormone replacement therapy was frequently reported (35.3%), indicating a high level of hysterectomy.  Daily allergy and asthma medication were common, while somewhat suprisingly, relatively few individuals (11.6% overall), indicated the need for a daily cardiac type medication. Types of cardiac related medications that were reported as being used on a daily basis included b-blockers (1/43), calcium channel blockers (2/43), and blood thinners (2/43). Additionally, while almost one third of the respondents indicated the occasional need for oral prednisone (13/43 or 30.2%), we found that the actual indication for use was often for the relief of allergic and asthmatic type symptoms (7/43), or joint pain (3/43), as there were only 3 reports of prednisone use for an actual autoimmune disease. Quite a number of respondents (44.2%) also indicated the need for at least one steroid type injection into a joint for pain relief. We also found that while there was only one respondent who reported requiring an osteoporosis modifier, that there were three reports of mesalamine use for the treatment of IBD (see patient reports 1-3 above). There were also two reports of methotrexate use, including one report from a type II female who had IBD (see patient 2 above), and the other, also from a type II female, who received methotrexate to treat chronic costochondritis. Finally, 5/43 or 11.6% of our respondents indicated the use of prophylactic antibiotics for a joint replacement.

Cardiac and Skeletal Thoracic Abnormalities

As shown in Table 3, reports of cardiac defects such as mitral valve prolapse either alone or in combination with certain other types of skeletal thoracic abnormalities including scoliosis, straight backs, and/or pectus deformities were also common. Overall, these types of abnormalities were reported by 22/43 or 51.2% of the total respondents with 12/43 or 27.9% reporting scoliosis, 3/43 or 7.0%, a straight back, and 3/43 or 7.0% the presence of kyphosis or lordosis. Cardiac abnormalities reported included mitral valve prolapse (MVP) or regurgitation (9/43 or 20.9%), and less commonly tricuspid valve abnormalities (2/43 or 4.6%).  Mild pectus deformities including pectus carinatum and pectus excavatum were also common and reported by 6/43 or 14.0% of our total respondents.  We also found from inspection of the data presented in Table 3 that none of these abnormalities appeared to be EDS type specific.

All of the respondents with a cardiac valve defect also indicated the use of prophylactic antibiotics (Table 2).  Two of these respondents with a cardiac valve defect also had at least one episode of bacterial endocarditis. One respondent, had both endocarditis and subsequent cerebral embolization associated with a tricuspid valve replacement. The other respondent had recurrent endocarditis associated with the presence of a MVP (twice due to Streptococcus viridans, and once due to Staphylococcus aureus).  In the last patient, a final episode of endocarditis was the most serious, as it was also associated with a cerebral vascular accident (CVA).  In all of these episodes of infection, the respondent improved with standard antibiotic therapy and recovered.

Coagulation Factor Abnormalities

In agreement with other reports which indicate that mild coagulation factor deficiencies can sometimes occur in EDS (3, 21, 56), we also received two verified reports of a coagulation factor deficiency, including a mild factor VII deficiency, and a mild factor XI deficiency from type unknown and type III individuals respectively.

Arthritis

The most common arthritic signs and symptoms included dislocations occurring in one or more joints (67.4%), bursitis (62.8%) and temporomandibular joint (TMJ) symptoms defined at least as pain and clicking (53.5%) (Table 4). In regards to the prevalence of various arthritic signs and symptoms, our analyses indicated that in general, these were not EDS type specific, with the exception that there may be an increased tendency for those individuals of the type III (hypermobile type) to report osteoarthritis (Table 4).  This was particularly true for those type III individuals over age 40 where osteoarthritis as indicated by an X-ray change was found in 5/5 or 100% of the respondents.  Despite the presence of osteoarthritis as indicated by a x-ray change across a broad range of types, the only individuals under age 40 to report osteoarthritis were those who had experienced one or more dislocations in this same joint (Table 4).  Three of the oldest type I (classical) respondents, (ages 55, 64 and 73), did not indicate the presence of osteoarthritis.  Together, this data suggests that at least in the Ehlers-Danlos syndrome, that the presence of increased hypermobility and or dislocation seemed to be more significant than age as a risk factor for the subsequent development of osteoarthritis. Of relevance to this, we found the rate of dislocation to be quite high as 29/43 or 67.4% of respondents indicated at least one prior dislocation (Table 4).  Overall, in decreasing order of frequency, joints which were reported to be affected by osteoarthritis were the knee (n=9), temporomandibular joint (TMJ) (n=3), hip (n=2), spine (n=1), shoulder (n=1) and hand (n=1).  Of those who reported osteoarthritis, 7/17 or 41.2% (with a mean age of 56.4 years) also reported requiring a total joint replacement.  Altogether, there were 3 reports from individuals with a single knee joint prosthesis, 3 individuals with a Christenson TMJ prosthesis (including one individual with bilateral implants), and 1 individual with a distal phalangeal index finger prosthesis.  There was also one individual who in addition to her index finger prosthesis, had required both an anterior cruciate ligament replacement and a spinal fusion. 

In addition to actual osteoarthritis as indicated by an X-ray change, there were also several other types of non-specific musculoskeletal arthritic signs and symptoms that were commonly reported (Table 4).  Unlike osteoarthritis, which was associated with hypermobility and or dislocation, no characteristic patterns emerged as these signs and symptoms seemed to be reported by individuals of every type.  Somewhat surprisingly however, several individuals (16.2% of the total) did report occasional inflammatory type changes in association with exacerbations of their arthritis including mild elevations of their erythrocyte sedimentation rate, white blood cell count or C-reactive protein, indicating that the various arthritic signs and symptoms associated with the connective tissue defect may have at times, a mild inflammatory component. 

Genitourinary type Complications

As mentioned above, a large number of our female respondents over 21 years of age  (35.3%) indicated the need for hormone replacement therapy, thus verifying a high rate of hysterectomy in adult women with this syndrome. Problems that may be associated with a need for hysterectomy included the common report of endometriosis (20.6%) or adenomyosis (uterine fibroids) in (32.3%) of the adult women within in our study population.

With special attention to the urinary tract, we also found that there were 6 reports from adults of actual pyelonephritis (Table 5), and one of a “bladder reflux” from the mother of a seven-year-old type I (classical type) female which was associated with cystitis, but not pyelonephritis. Although we requested further information from all the adults who reported pyelonephritis to determine whether there was a common predisposing factor, we did not find one.  Reports which we received included three associated with stone formation, one of nephritis associated with lupus erythrematosus, one of a nephritis and recurrent infection associated with type II diabetes, and one with no other association.

Immune Abnormalities

We received no report from any individual with any known immunodeficiency; however, we did receive one report from a type IV individual of a mildly decreased gamma globulin level, specifically the IgG₂ and IgG₄ fractions. Furthermore, even though our data set was relatively small, our inspection of the data by type of EDS for the presence of certain fungal, bacterial or viral infections at the rate that would be expected if a specific immunodeficiency was present, indicated that none of these types of infections were prevalent enough to raise this suspicion (data not shown, and see below).

General and Post-operative Infections

In Table 5 both the prevalence of general and surgical post-operative infections as analyzed by the presence or absence of a cardiac and or thoracic abnormality are presented.  Analyses were carried out on the group of individuals reporting one or more of these types of abnormalities (cardiac, thoracic or both)  (n=22) using the no associated defect group as an internal control (n=21) (Table 3).  In general, we found a modest trend for the presence of streptococcal associated infections in those who also reported a cardiac or thoracic defect. The only statistically significant association was with those who also reported at least one post-operative type infection (p= 0.0268).  However, these types of infections had occurred only in a minority of their procedures.

Allergy, Asthma and Recurrent Respiratory Problems

In regard to the incidence of allergy, asthma, and respiratory disorders, we observed a high incidence of these conditions (Table 6). The most striking group includes those with at least one severe allergic reaction to medication, reported by 20.9% of the total respondents.  Only 1-3% of the general population would normally experience this type of reaction (79). Quite unexpectedly, when we carried out the same type of analyses as we performed above on those reporting certain types of infections, we also detected significant differences for those conditions associated with atopy and whether or not there was a co-existing cardiac or developmental defect. We found the most significant differences between the two groups for those reporting at least one severe or life threatening allergic reaction to medication (p= 0.0212), and those reporting allergic induced asthma (p=0.0089) (Table 5).  However, no significant differences between these two groups for those reporting other chronic respiratory conditions including intrinsic asthma due to stress, cold or exercise, or recurrent problems with sinusitis, bronchitis, or pneumonia was found (Table 6).

Autoimmunity

There were only three reports of autoimmunity (Table 2).  These included one with a systemic lupus erythrematosus (SLE) or mixed connective tissue disease (MCTD) like syndrome in a 38 year old type III female which presented initially as a red cell aplasia and T cell deficiency, one of a Sjogren’s syndrome in a 36 year old type II female which presented initially as numerous dental caries, and one of Hashimoto’s thyroiditis in a ten year old type I female.

Interestingly, 18.6% of the adult population also reported the association of a flare of their arthritis with an ophthalmologic symptom such as redness or photophobia. However, as the majority of those individuals reporting eye symptoms did not likely have an actual autoimmune disease or inflammatory bowel disease, a more satisfactory explanation for these types of symptoms may be the common use of certain medications (Table 2) or possibly the consequence of a common physiologic mechanism related to the connective tissue defect.

Cancer

No verifiable reports of malignancy were found in our study population. In fact, the only report of tumor formation which we were able to verify was that of a probable benign pituitary micro-adenoma detected by MRI in an adult female with type unknown EDS.

Discussion

Collagen Biosynthesis

Defects in the composition or processing of collagen characterize the collection of connective tissue defects known as the Ehlers-Danlos syndrome.  To date, 19 different types of collagen, each with varying compositions, have been described (32, 53, 57, 76) and these can conveniently be divided into the fibrillar versus the nonfibrillar collagens (57). However, in the Ehlers-Danlos syndrome, only mutations in the genes that code for, or the enzymes responsible for the processing of the fibrillar collagens I, III, and V have been definitively linked (22, 35, 41, 50). Theoretically however, as a mutation in any gene that encodes a protein or enzyme responsible for the production, modification, or regulation of a fully functional collagen gene product could also be responsible, we wish to briefly review the common synthetic pathway that all fibrillar type collagens must undergo prior to their incorporation into the various tissue types.

After translation as a prepro precursor molecule in the endoplasmic reticulum, the first step that a precursor fibrillar collagen chain undergoes is an enzymatic hydroxylation resulting in the cleavage of the signal pre-leader sequence to produce a procollagen precursor. The procollagen precursor then exits the endoplasmic reticulum and enters the Golgi, where additional post-translational modifications occur, including the addition of carbohydrates and the linkage of glycine residues. After exiting the Golgi, the procollagen chain is then secreted into the extracellular matrix (ECM) with its secretory pro-leader sequence intact. Once in the ECM, the procollagen is then processed by both amino and carboxy-terminal propeptidases with the resultant cleavage of the pro-leader sequence where the final steps of collagen fibril aggregation, lysyloxidation, and crosslinking occur (29).  An analysis on the collagen content of various tissues has also been carried out (28).  Type I collagen, constituting approximately 90% of total body collagen, was found in the skin, tendons, bones and internal organs. Type II collagen was a major component of cartilage, and a minor component of intervertebral discs, notochords and the vitreous body of the eye, while type III collagens were found in the skin, blood vessels and internal organs.  Types V and XI collagens while minor, only 1-2% of the whole in most tissues, were recently found to be co-expressed in various heterotrimeric forms and broadly distributed (27).

Molecular Genetic Analyses and the New Nosology

As mentioned above, and summarized in Table 1, mutations resulting in either the aberrant expression or processing of fibrillar collagens type I, III, and V have been described in the Ehlers-Danlos syndrome. However, almost every collagen mutation identified has been unique for that one individual or one family (22, 35, 41, 50).  For instance, mutations in the a1 and a 2 chains of the COLA5 chain (collagen type V) have now been linked to several pedigrees with the phenotypic characteristics of Ehlers-Danlos types I and II (classical type of EDS) (14, 15, 22, 44, 49, 54, 64, 75, 78) and recent experiments in fact suggest that type V collagen plays a central role in both fibrillogenesis and wound healing (27).  However, demonstrating the heterogeneity of this syndrome, one study has excluded COL5A1 as the candidate gene in one pedigree with Ehlers-Danlos type II (33). While the collagen defect responsible for type III EDS (hypermobile type) still remains undefined, mutations associated with EDS type IV (vascular type) have all been associated with defects in the synthesis or secretion of collagen type III (16, 68, 70). The mutation responsible for EDS type V, described in only one family, remains undefined (10, 46).

Other rare types of EDS are also currently recognized; these include the autosomal recessive kyphoscoliosis type, formally known as EDS type VI, associated with defects in lysyl hydroxylase (PLOD), an enzyme which forms stable hydroxylysine crosslinks between collagen molecules (36, 58), the autosomal recessive dermatosporaxis type, formally known as EDS type VIIC, associated with a defect in the ability to remove the amino-terminal propeptide of type I procollagen (31, 43, 63), and the autosomal dominant arthrochalasia type, formally known as EDS types VII A and B, associated with base substitutions that result in exon-skipping and deletion of the N-terminal cleavage site in the procollagen alpha chains of type I collagen (COL1A1 and COL1A2)(17, 20, 43).  However, according to current classification, the recognition of either type VIII (the periodontal type), or type X  (the fibronectin type) as distinct entities remains uncertain (7).  Additionally, EDS type IX, now known to be caused by a defect in the copper transporting ATPase, ATP7A, has been completely eliminated from the current classification (7, 62).

Cardiac and Thoracic Defects

As shown in Table 3, we found that skeletal thoracic abnormalities such as scoliosis, a straight back, lordosis, kyphosis and pectus deformities were common as 22/43 or 51.2% of our respondents reported this. Three of our respondents also indicated the presence of a combination of these abnormalities.  Even though we relied on self-reported data, we also found that our overall cumulative incidence for these types of abnormalities is in substantial agreement with that of 55.6% previously reported in 18 patients with types I-IV EDS (5).  Further, our inspection of the data presented in Table 3 did not indicate a higher frequency of cardiac or thoracic defects in any one type of EDS; however, we also note that many of these types of abnormalities are characteristic of connective tissue diseases in general, and therefore are not specific to the Ehlers-Danlos syndrome (69).

In regards to cardiac abnormalities, we found a cumulative incidence of 11/43 or 25.6%. With 9 mitral and 2 tricuspid valve abnormalities reported.  Of these, there were two reports of mitral valve repair, one in a 64 year old type I male who also reported a recurrent endocarditis, and a endocarditis related CVA, while the other report of a mitral valve repair was from a 48 year old type II female who indicated no other complications. There was also one report of a tricuspid valve repair in a 53 year old type I female with subsequent bacterial endocarditis who experienced a cerebral embolization directly related to the endocarditis. Therefore, 3/11 of our respondents with a cardiac valve defect eventually experienced a substantial complication(s). We did find however, that of our 11 respondents indicating a cardiac valve defect that only 5 of these had indicated the need for a daily cardiac type medication, and that 3/5 of these were older than 50 years of age. Together, this data suggests that many of the cardiac associated abnormalities that were reported may in fact be relatively mild.  In fact, many of our respondents who indicated a MVP were likely diagnosed by the older less strict single M-mode echocardiographic criteria and if re-evaluated under the current stricter criteria might not be found to have MVP (25). It has been suggested however, that patients with EDS should be evaluated by serial echocardiography as a significant enlargement of the aortic root was recently detected in five patients with EDS types I, II and III (74)

Musculoskeletal Complaints and Osteoarthritis

In this report, we have found evidence validating the assumption that there may be an increased risk for “wear and tear arthritis” in this population(42). We also found evidence that non-specific arthritic signs and symptoms were common, and that in general these were not EDS type specific, although type III or hypermobile individuals may be more susceptible to actual osteoarthritis as determined by an X-ray change (Table 4).  We also suspect from the majority of reports that we received that pain management and possibly associated problems with depression might be problematic in this population. In fact, pain relievers and tranquilizers/anti-depressants/anti-anxiety type medications were one of the two most frequent types of daily medications reported as being used in this population (Table 2).  Although this data must be interpreted with caution as tranquilizers/anti-depressants/anti-anxiety type medications are also commonly prescribed as sleep aids, a significant association with depression, anxiety disorders and the presence of mitral valve prolapse or joint hypermobility syndrome have recently been reported (12, 18, 34).

Various soft tissue complaints that may be associated with micro-trauma such as tendinitis and bursitis were also common, as well as what seems like a very high rate of temporo-mandibular joint symptoms as 23 of the 43 or 53.5% of the respondents reported TMJ associated pain and/or clicking.  This in fact may not be too surprising, as a high rate of TMJ symptoms have previously been reported in hypermobile individuals (11), and TMJ complications have been reported in the Ehlers-Danlos syndrome (47, 51, 55).   However, to our knowledge, this is the first report to actually document the actual incidence of TMJ symptoms in this population, as well as the actual frequency of severe TMJ associated osteoarthritis in that 3/43 or 7.0 % of the respondents indicated actually requiring a TMJ joint prosthesis.

               
We found that in general, that the presence of increased hypermobility and/or repeated dislocation seemed to be the most significant risk factor for the subsequent development of osteoarthritis as type III (hypermobile) individuals reported the highest incidence of osteoarthritis (Table 3).  We also found that type II (classical type) (n=8) individuals who were thought to be mild in their EDS symptoms, as they do not show skin hyperextensibility, did not appear to be spared in the incidence of any of the major arthritic signs and symptoms, and except for type III (hypermobile type) (n=9) respondents reported the highest rate of arthritic signs and symptoms in every single category (Table 3). 

Paradoxically, the type I respondents (n=11), who all also reported having hyperextensible skin, seemed to have the fewest arthritic signs and symptoms overall.   Although the cause of fibromyalgia is as yet unknown, it is suspected to be associated with disturbed sleep patterns (1), and the relatively high incidence of fibromyalgia found in the EDS population would be consistent with this as disruptions in sleep patterns has previously been reported as being a common problem in EDS (66).

Bleeding Tendencies and Coagulation Abnormalities

 In agreement with several other reports (3, 21, 56), we also found that deficiencies of coagulation factors can sometimes occur in EDS, but suspect that the actual incidence of coagulation factor deficiencies in this population may actually be quite low as only 2 of the 43 respondents spontaneously provided this information.  Furthermore, these deficiencies, one a factor VII, and one factor XI deficiency were seen to be quite mild, and had not led to any serious bleeding events. Our observations are in agreement with other reports (40, 73) which propose that the observed bruising tendency in many patients with EDS is likely due to the associated connective tissue defect and problems with vascular integrity and or wound healing rather than a primary coagulation factor deficiency.  If however, in any given EDS patient, clinical lab studies do find evidence for a coagulation factor deficiency, and a surgical or invasive procedure is being contemplated, then treatment would be empirical based on the type of deficiency found, but prophylactic 1-deamino-8-D-arginine vasopressin (DDAVP) has also been reported as being beneficial in preventing the bleeding complications sometimes seen in EDS (65, 73).

Infections, Allergy and Asthma

In specific regards to the immune system, and in agreement with data on the incidence of post-operative surgical infections in EDS patients recently collected by Weinberg and MacFarland (77), we did find evidence for a slightly higher prevalence of post-operative surgical infections (Table 4). However, as we could detect no specific immunodeficiency, it is possible that the majority of post-operative infections were related either to the presence of an abnormal mechanical factor such as tissue dehiscence, or a physiological factor associated with the connective tissue defect such as an abnormality in wound healing.  Furthermore, although a large number of respondents (37.2%) indicated at least one post-operative infection, the majority of respondents also indicated that they had only occurred in a minority of their procedures.  Another type of infection, pyelonephritis, was more frequent than expected in this population.  It is possible that the root cause of many urinary type of infections is mechanical, not immunologic in nature as bladder distension, diverticulae, and even rupture have (9, 13, 19, 26, 39, 67) previously been reported in EDS. Lastly, since we documented four episodes of bacterial endocarditis, it would seem prudent to advise routine antibiotic prophylaxis in all patients with EDS who have a cardiac valve abnormality prior to their dental or surgical procedures.

               
Quite unexpectedly, when we also analyzed the prevalence of allergy and or asthma by the presence of a cardiac or skeletal thoracic abnormality we also found an association with the presence of these abnormalities and those conditions previously associated with the presence of atopy, that of allergy in general (p=0.0546), severe drug allergy (p= 0.0212), and extrinsic asthma (p= 0.0089) (Table 5) (59). Although this was in a smaller series, our results are also in agreement with those presented by Ayres et al. (5), who also found an approximately two-fold increase in allergy as revealed by skin testing in those patients with EDS who had a pre-existing skeletal or thoracic abnormality.

Explanations for this phenomenon may be associated with the  thoracic defects in our respondents (Table 3) which can lead to mechanical and physical factors such as reduced expiratory air volumes, abnormal air flow, or reduced cilary clearance of allergens. However, if this was entirely the case, one would expect the presence of intrinsic asthma due to mechanical or physical factors to be positively associated with the presence of a thoracic defect, yet no difference was found between the two groups for this parameter (p=0.4121)(Table 5).  Our results suggest that pulmonary and immune function studies to further confirm the presence of atopy with a cardiac or thoracic skeletal abnormality in a more objective manner is warranted, particularly as susceptibility loci for familial mitral valve prolapse, atopy, and inflammatory bowel disease (IBD1), have all recently been mapped to the same pericentromeric region of chromosome 16 (24, 38, 60).

Autoimmunity and Inflammatory Bowel Disease

We found no evidence for an increased prevalence of autoimmune disease, as we received only three confirmed reports, including one of Sjogren’s syndrome, one of a systemic lupus erythrematosus (SLE) like or mixed connective tissue disease (MCTD) like syndrome, and one of a Hashimoto’s thyroiditis thought to be inherited from the non Ehlers-Danlos parent. Although a relatively high percentage of respondents (18.6 %) also reported the presence of eye symptoms including redness, pain, and photophobia which they thought was associated with their arthritis, a physiological explanation for this observation including the common use of certain medications or possibly a common physiologic condition related to the connective tissue defect may be more likely. 

Summary

In conclusion, we found that various non-surgically related complications related to the musculoskeletal, cardiac, gastrointestinal, and genitourinary tract systems were common in the EDS population. Our results also suggest that many of these complications were likely directly related to the connective tissue defect. Further, although we found that most of these complications were relatively benign in nature, and compatible with a long life, recognition of the connective tissue defect and how this may contribute to the presenting sign(s) and or symptom(s) could result in an improved therapeutic outcome for patients with EDS. We also found that although patients with type III or the hypermobile type of EDS had evidence for an increased rate of actual osteoarthritis, that the treatment of pain associated with every type of EDS was often problematic.  We also believe that more objective research into the possible causes of the association which we found between EDS and gastrointestinal problems, particularly GERD and IBD, as well as the possible association that we found between the condition of atopy, particularly atopic asthma and the presence of either a cardiac or skeletal thoracic defect will be necessary to understand the mechanism(s) behind this association.

 Primary care physicians as well as specialists who have patients with EDS should be aware of the various types of non-surgical complications that we found in this syndrome, as early recognition of these complications, and how a connective tissue disease could contribute to their development may result in an improved therapeutic outcome for their patients. Individuals with the phenotypic manifestations that can be seen in EDS should also have a genetic evaluation to confirm their diagnosis and determine which type of EDS they have.

 Table 1.  The New Nomenclature in the Ehlers-Danlos Syndrome:Correlation of Genotype with Phenotype

Current classification of EDS based upon the revised nosology (7). ^bThe corresponding genetic mutation if known, with relevant references provided underneath. ^cThe major phenotypic manifestations of each type according to the current nosology, with minor diagnostic criteria prefaced by a ± sign. ^dThe definate classification of other rare forms of EDS which have previously been described including X-linked EDS (EDS type V), the Periodontitis type (EDS type VIII) and Fibronectin-deficient EDS (EDS type X) await further molecular definition before inclusion. The occipital horn syndrome (EDS type IX), and the benign familial hypermobility syndrome (EDS type XI) have been removed from classification  (7)

Table 2.  Medication Use by Category and Frequency            

a.The number of respondents who reported the use of various medications by category. ^bThe non-daily use of immune modulators, both injectable and oral were also occasionally reported.  ^cWomen respondents over the age of 21 (n=34).  ^dThe use of other types of daily immune modulators were also occasionally reported: 3 reports of mesalamine for Crohn’s disease, 2 reports of methotrexate (including one for Crohn’s disease and one for costochondritis), and 1 report of the use of chloroquine for a systemic lupus or mixed connective tissue disease like syndrome.

Table 3.  Demographic Characteristics of Survey Respondents by Type and the  Presence or Absence of a Cardiac and or Thoracic Defect        

^aThe age range for male respondents was 28-72, and ^b for female respondents was 7-73. ^cPectus deformities reported included 4 reports of “funnel chests”and 2 reports of “barrel chests.”

Table 4.  Arthritic Signs and Symptoms by Type of Ehlers-Danlos Syndrome

^aNeuritis was defined as the presence of numbness or tingling in any extremity not caused by sitting or lying down. ^bThe presence of osteoarthritis in those age 40 and under and those over age 40 was scored as positive only if an x-ray change was present. ^cTMJ= Temporomandibular joint  symptoms that were defined at least as the presence of pain and or clicking.

Table 5.  Incidence of General Infections by the Presence or Absence of Cardiac and or Thoracic Defect

^aSee materials and methods for derivation, no significant difference if p>0.05. ^bOral thrush not associated with diabetes or the use of steroids. ^c Not including oral thrush, these infections were often associated with previous antibiotic use.

Table 6.   Incidence of Allergy, Asthma and Recurrent Respiratory Problems by the Presence or Absence of a Cardiac and or Thoracic Defect

^a See materials and methods for derivation, no significant difference if p>0.05. ^bAllergy was defined by a positive skin or blood test to any allergen, including contact, food and respiratory type allergens. ^cA severe allergic reaction was defined as one or more anaphylactic type reactions with angioedema, or severe dermatitis. ^dIntrinsic asthma was defined as asthma induced by stress, cold, or exercise. ^eExtrinsic asthma was defined as allergic asthma. 

Acknowledgements: 

This work is dedicated to the memory of DMA.  We also gratefully acknowledge the assistance of Cornelia Weyand, M.D., Ph.D. of the Departments of Immunology and Medicine at the Mayo Clinic for critical comments during the preparation of this manuscript, and for the assistance obtained from the Ehlers-Danlos National Foundation (EDNF), the Canadian Ehlers-Danlos Association (CEDA), and Ehlers-Danlos support group of the United Kingdom whose combined efforts made this study possible. All original surveys and medical records have been given to the Ehlers-Danlos National Foundation for inclusion in their newly formed database.

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