{"paper_id":"85656ff1-acf6-478d-8703-8dec92d35ad8","body_text":"Journal of Biosciences and Medicines, 2025, 13(12), 166-181 \nhttps://www.scirp.org/journal/jbm \nISSN Online: 2327-509X \nISSN Print: 2327-5081 \n \nDOI: 10.4236/jbm.2025.1312013  Dec . 11, 2025 166 Journal of Biosciences and Medicines \n \n \n \n \nUrogenital Findings in Ehlers-Danlos Syndrome \nCorrelate with Underlying Tissue Laxity \nMechanisms  \nSahil S. Tonk1, Golder N. Wilson2* \n1School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA  \n2Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock and Kinder Genome Genetics Private Practice, \nDallas, TX, USA \n \n \n \nAbstract \nUrogenital complications of Ehlers- Danlos syndrome are highlighted in an \nexample patient and documented in 1261 others of whom 566 had DNA vari-\nants judged relevant by whole exome sequencing. Females with the condition \nhad frequencies of menorrhagia, endometriosis, ovarian cysts, and bladder is-\nsues of 70, 21, 34, and 41%, respectively; under-represented males had a 16% fre-\nquency of bladder issues. Less common complications like pelvic floor slip-\npage (7.2%), umbilical (3.5%) or inguinal (2.7%) hernias, polycy stic ovarian \nsyndrome (5.6%), or vulvodynia (0.56%) were mentioned by women, frequent \nurination (6.1%), inguinal hernias (5.6%), and cryptorchidism (1.5%) the only \nones recurring in men. The pattern of skeletal and neuro-autonomic findings, \ntheir age-related occurrence, and their few unique gene changes suggested that \npatients with more urogenital findings were a more severe version of the typ-\nical condition, their recognition adding therapeutic options like mesh surgery, \npelvic vein embolism, or urodynamic optimization to the exercise, hydration, \nand medications known to benefit patients with Ehlers-Danlos syndrome. Recog-\nnition of underlying connective tissue dysplasia-dysautonomia mechanisms as \nthe cause of these urogenital complications can optimize patient care and in-\ncrease clinical genetic understanding of disorders like interstitial cystitis, dys-\nmenorrhea, pelvic floor/congestion, and polycystic ovarian syndrome. \n \nKeywords \nEhlers-Danlos Syndrome, Urogenital Complications, Bladder Issues, Pelvic \nCongestion, Hernias, Interstitial Cystitis, Polycystic Ovarian Syndrome, \nCollagen Gene Change \nHow to cite this paper: Tonk, S.S. and Wil-\nson, G.N. (2025) Urogenital Findings in \nEhlers-Danlos Syndrome Correlate with \nUnderlying Tissue Laxity Mechanisms. \nJournal of Biosciences and Medicines, 13, \n166-181. \nhttps://doi.org/10.4236/jbm.2025.1312013 \n \nReceived:  November 12, 2025 \nAccepted: December 8, 2025 \nPublished: December 11, 2025 \n \nCopyright © 2025 by author(s) and  \nScientific Research Publishing Inc. \nThis work is licensed under the Creative \nCommons Attribution International  \nLicense (CC BY 4.0). \nhttp://creativecommons.org/licenses/by/4.0/   \n  \nOpen Access\n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 167 Journal of Biosciences and Medicines \n \n1. Introduction \nEhlers-Danlos Syndrome (EDS), traditionally defined by hypermobile joints and \nhyperelastic skin [1], is increasingly recognized as a multisystemic disease [2] as-\nsociated with significant orthopedic [3] neuro-autonomic [4]-[7], and urogenital \n[8]-[10] complications. Recognition of the latter proble ms is particularly im-\nportant given the greater hypermobility in women [2] and their 4 to 5-fold major-\nity when EDS is systematically evaluated [11]. Their pain [12] from recurring uri-\nnary tract infections/cystitis [8] , pelvic/lower limb varicosities ( congestion, [9] \n[10]), and vulvodynia [13] is too often attributed to hypersensitivity or psychiatric \ndisease [6] in a reprise of historical dismissals of female symptoms as hysteria [14] \n[15]. \nPreviously described but inadequately quantified are the menorrhagia, endo-\nmetriosis, and ovarian cysts of females with EDS and their bladder complications \n(urgency, leakage, susceptibility to urinary tract infection) that parallel those in af-\nfected males [8]-[10]. Better detailing of these urologic symptoms is needed in order \nto facilitate timely recognition and referral by patients and healthcare workers with \ndevelopment of evaluation and treatment guidelines by specialists.  \nHere we document the frequencies of urogenital complications by focusing on \ntheir prevalence in 1261 patients who were holistically diagnosed [1] [2] and sys-\ntematically evaluated [2] [11], 906 of them shown by whole exome sequencing to \nhave a range of DNA [11] [14] and particularly of collagen gene [16] changes that \nrelate urogenital and reproductive abnormalities to general effects of tissue laxity \nand vessel distensibility. The results suggest mechanisms for common complica-\ntions like interstitial cystitis, emphasize the importance of early acknowledgement \nand treatment of pain [17] , and document low pregnancy risks for the average \nEDS patient that reverses the aura of hazard promoted by focus on rare EDS types \n[18] [19].  \n2. Methods \nPrior reports [2] [11] describe the systematic evaluation of 1261 out of 1899 EDS \npatients diagnosed in a medical genetics private practice fro m July 2011 through \nOctober 2020. Severe EDS types like periodontal [18] or vascular [19] were easily \nrecognized clinically by their severe periodontitis [18] , chiseled facies with tight \nskin, prominent eyes [19], and their frequent bowel and vessel ruptures [18] [19] \nand excluded from this population. Included patients were shown by evaluation \nof 80 histories and 40 physical findings to meet criteria for the hypermobile or clas-\nsical EDS types [20]. \nThese clinical findings and results from 967 undergoing DNA testing ( 906 by \ncommercial whole exome sequencing using standard methods— [11] [21]) were \nentered into a password -protected MS Excel© GW patient database approved by \nthe North Texas IRB (centered at Medical City Hospital, Dallas) in 2014 (exempt \nprotocol number 2014- 054). Deidentified Excel tables containing the clini-\ncal/DNA data reported in this article are available in the Supplementary Materials \n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 168 Journal of Biosciences and Medicines \n \nof the recent article [11]. Average frequencies, standard deviations, and significant \ndifferences at the p < 0.05 level were determined using Excel functions and online \nresources [22], the latter comparing means by two-tailed t and proportions by N-\n1 chi-squared tests. \n3. Results \n3.1. Example Patient Presentation \nA 30-year-old female was referred from cardiology for evaluation of EDS after \nhaving multiple urogenital and Postural Orthostatic Tachycardia Syndrome (POTS) \nsymptoms with minimal evidence of hypermobility. More severe symptoms began \nat puberty when painful and prolonged periods began along with intermittent \npain from ovarian cysts. Later, a partial hysterectomy was needed for endometri-\nosis and the patient had recurrent bladder problems before and after her two preg-\nnancies which included frequency, urgency, and frequent urinary tract infections. \nShe also developed severe migraines in her teens, subsiding somewhat in her 20 s \nbut accompanied by daily headaches with posterior neck pain and poor balance. \nHead MRI studies showed a 3  - 4 mm Chiari herniation that was not deemed to \nrequire surgery. Adolescent fatigue became more severe in her mid -twenties and \nwas exacerbated during her first pregnancy, which was related to POTS by positive \ntilt-table testing and improved by hydration and salt protocols. Additional \nsymptoms of bowel irregularity, stomach pain, reflux, and reactive airway disease \nwith food-medicine intolerances provided additional indications of dysautono-\nmia. \nThe patient was not noted to be a flexible baby and was not aware that she was \nmore flexible as a child. She developed pain in her R hip and L leg after her second \npregnancy and at evaluation reported some looseness of her R shoulder that may \nbe mild subluxation. She realized upon questioning that her joints do pop with \nmovement and she had scoliosis diagnosed in junior high, wearing a lift in her shoe \nthat may have corrected the problem.  An increase in joint pain after pregnancy \nled to rheumatology evaluation with a diagnosis of fibromyalgia; she had a transi-\nent positive ANA and was begun on Synthroid© for a diagnosis of hypothyroidism. \nSignificant in view of her DNA testing were normal echocardiograms and aneu-\nrysm screens; pelvic ultrasound did show dilated veins with some downward and \nbackward tilting of the uterus. \nThe family history  included a son aged 10 who was tall and thin with his ankles \nturning in, having knee and foot pain with occasional headaches. A daughter 7 did \nnot yet have EDS-dysautonomia complications; these were only pregnancies hav-\ning no complications besides some worsening of fatigue and joint pain. A brother \nwas the only sibling among three who had symptoms (joint pain), her mother had \ndiagnoses of lupus and fibromyalgia with a hip replacement. \nPhysical examination  showed her height and weight to be proportionate at the \n60th centiles for age. This fit build likely minimized the patient’s joint complica-\ntions along with her lower-than-average Beighton score [23] of 3 over 9 (she could \n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 169 Journal of Biosciences and Medicines \n \nonly hyperextend her elbows somewhat and could touch her palms flat to the floor \nwithout bending her knees). She was able to perform large joint maneuvers by \njoining hands, one arm around her back and one over her shoulder, do the prayer \nsign behind her back, and reach her arm around her back to touch her umbilicus. \nHer face did not have a thin or chiseled aspect, her skin was velvety without unu-\nsual scars and slightly elastic (jaw and forearm stretches of 1.5 inches with fleshy \nrather than thin epidermal folds). She had mild lordosis but no scoliosis, flat feet, \nor gait changes, and her balance assessed by the tandem walk maneuver was nor-\nmal. \nThe impression was a form of AAD/EDS-D with 36 findings by history (more \nthan 50% of EDS patients her age) and 16 by physical (more than 40% of EDS \npatients her age) on the standard forms [11], see Methods). The patient had more \nprominent dysautonomia, urogenital, and neurologic rather than joint laxity/in-\njury symptoms but would best fit the hypermobile type with her lack of scarring \nand her pelvic organ and brain- stem slippage. She also had ev idence of mast cell \nactivation with her food-medication intolerances and transient anti-nuclear anti-\nbody elevation, likely inheriting her EDS and autoimmune predispositions from \nher mother who had hip arthritis and a diagnosis of lupus. Whole exome with mi-\ntochondrial DNA sequencing found a change in the collagen type III gene that sub-\nstituted a linear nonpolar leucine amino acid for the kink-producing proline that \ncan have a positive charge ( COL3 c.24889C > T p.Pro830Leu). Though qualified \nas a variant of uncertain significance by the testing company, this gene change was \ninterpreted as making a significant contribution to her symptoms and rated as hav-\ning the highest grade (MDna4+) of clini cal diagnostic utility [11]. The medically \nqualified DNA diagnosis (MDna 1-4+) emphasizes biochemical factors like amino \nacid structural change, degree of symptom and gene mechanism compatibility with \nthe putative clinical diagnosis, concordance of the gene c hange and with symp-\ntoms in relatives, and prior association of the altered gene  with the disease spec-\ntrum in question [11]. The dramatic amino acid structural change, presence of the \nDNA variant in the patient’s mother and son, and multiple associations of COL3 \ngene mutations with severe [19] and milder EDS patients [11] justified qualifica-\ntion of this variant as having 4+ diagnostic utility. \n3.2. Overview of Urogenital Findings in EDS \nAmong the 80 historical findings registered during evaluations of patients like the \nexample are five genitourinary findings — the menorrhagia, endometriosis, ovar-\nian cysts, bladder issues, and hernias listed as shaded frequencies in Table 1 . Pa-\ntients were asked to add details to each finding — e.g., pelvic congestion/slippage, \ninguinal, or femoral in the hernia category— but these details were not systemati-\ncally ascertained. As a consequence, frequencies of the shaded findings in Table 1  \n(e. g., bladder issues, ovarian cysts) are fairly accurate while their particular man-\nifestations (e.g., leakage, polycystic ovarian syndrome) are under-reported. Rarer \nfindings like rectal prolapse or premature delivery are even more dependent on \n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 170 Journal of Biosciences and Medicines \n \nvoluntary information, pregnancy problems sometimes mentioned but not sys-\ntematically documented on the family-natural history form [2] [11] including he-\nmaturia, increased urinary frequency, sense of urgency, difficulty initiating stream, \nincomplete emptying, incontinence, and bladder diverticula. \nBetter-documented frequencies of EDS female complications, deriving from the \napproximate 5 to 1 (1064 to 197) excess of women over men in Table 1, provide better \nguidance for therapy. Heavy periods or menorrhagia (70%) can be treated with hor-\nmonal regulation (birth control measures) as can endometriosis (21%), both with \nadditional surgical or pain medication options. Ovarian cysts (34%) as single oc-\ncurrences can be reassuringly differentiated from other causes of abdominal pain \nbut may herald polycystic ovarian syndrome that occurs in 5.6% of female patients. \nThese gynecologic manifestations mirror the high frequencies of menorrhagia, dys-\nmenorrhea, and chronic pelvic pain described in other EDS cohorts [10]. Other pel-\nvic problems in women, slippage of the uterus and bladder needing mesh surgery \n[24] [25] and blood pooling [pelvic congestion, 9] , are not addressed by the his-\ntory or physical forms [2] [11]. \nComplications affecting structures occurring in both sexes are still influenced \nby anatomic differences, bladder issues (41% female; 16% male) including urinary \ntract infections (9.3%; 0.5%), polyuria (7.6%; 6.1%), leakage (4.8%; 0%), urgency \n(4.1%; 1.0%), and delayed emptying (3.8%; 2.0%) reflecting the shorter female \nurethra and estrogen-mediated reduction in collagen crosslinking and pelvic floor \nintegrity [26]-[28]. EDS-associated tissue laxity, mast cell alteration, and urothe-\nlial signaling also contribute to interstitial cystitis in women [29]-[32], a compli-\ncation undoubtedly more common than its volunteered frequency of 4.4% in \nTa-\nble 1. \n \nTable 1. Urogenital complications in females and males. \nComplication— Group Females (1064 pts) Males (197 pts) \nAge group All 0.3 - 30y 31 - 73y All 0.7 - 30 31 - 63 \nPatients pts 1064 538 526 197 158 39 \nAny urogenital finding pts (%) 883 (83) 404 (75) 479 (91) 42 (21) 30 (19) 12 (31) \nCommon genital issues pts (%) 808 (76)1 360 (67) 448 (85) 17 (8.6) 12 (7.6) 5 (13) \nMenorrhagia2 70%   --   \nEndometriosis2 21%   --   \nOvarian cysts2 34%   --   \nBladder issues2 41% 33% 48% 16% 14% 23% \nUrinary tract infection 9.3%   0.5%   \nFrequent urination 7.6%   6.1%   \nLeakage-night or day 4.8%   0%   \nInterstitial cystitis 4.4%   0%   \nUrgency 4.1%   1.0%   \n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 171 Journal of Biosciences and Medicines \n \nContinued  \nDelayed emptying 3.8%   2.0%   \nHernias2 15% 9.3% 21% 7.1% 5.7% 13% \nPelvic floor slippage 7.2%   --   \nUmbilical hernia 3.5%   1.5% (3 pts)   \nInguinal hernia 2.7%   5.6% (11 pts)   \nLess usual genital issues 13% 15% 11% 1.5% 1.9% 0 \nPolycystic ovarian syndrome 5.6%   --   \nHysterectomy 2.6%   --   \nDyspareunia 0.85% (9 pts)   --   \nVulvodynia 0.56% (6 pts)      \nTilted uterus 0.38% (4 pts)   --   \nCryptorchidism    1.5% (3 pts)   \nReproductive/pregnancy issues3       \nPremature delivery 14 pts   --   \nSevere postpartum bleeding 4 pts   --   \nEarly labor 2 pts   --   \nUterine rupture during delivery 2 pts   --   \nInfertility 1 pt   0   \nGeneral complications are shaded, types of that complication in the unshaded rows below; frequencies in categories may not be  \nadditive since a patient may have more than one complication; 194 females had 4 or 5 of the 5 urogenital findings that were system-\natically evaluated, i.e., on the standard history form; 2systematically evaluated, 3percentages not precisely calculated since the number \nof pregnancies is not known— the 900 or so estimated from my family history forms would suggest that the 14 premature deliveries \namount to 0.15% of the total pregnancies. \n \nAlso contributing to female bladder issues is the pelvic slippage or prolapse that \noccurs in 7.2% of women, resulting  in pressure on the bladder and its distortion \nby pelvic descent increasing all of the listed complications and paralleling normal \nincreases during pregnancy. Although EDS connective tissue fragility should in-\ncrease hernia formation, the frequencies in Table 1 for umbilical (3.5% of females; \n1.5% of males) or inguinal (2.7%: 5.6%) hernias do not greatly exceed those for \nthe general population, the former 2% for both sexes [33] [34], the latter ranging \nfrom 0.43% female; 1.4% male in Denmark [35] to 0.53% female, 6.8% male in the \nUnited States [36]. Frequencies of hernias increase dramatically with obesity [33]-\n[36] or with abdominal complications like cirrhosis [34], pregnancy (0.8% umbil-\nical, [37]), or post-surgery (1%, [34]). Under-reporting of hernias in Table 1 likely \nreflects incompleteness of examination and historical recall since the documented \nskin lacerations and sutural dehiscence in EDS [1] [2] [11] must be accompanied \nby spontaneous and post-operative hernias; lifetime risks for spontaneous or sec-\nondary inguinal hernias are 3% for females and 27% for males in the general pop-\nulation [36].  \n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 172 Journal of Biosciences and Medicines \n \n \n(A) \n \n(B) \n \n(C) \nFigure 1. Female urogenital (A), blood pooling (B), and skin laxity (C) findings by age. Num-\nbers are from systematic evaluation of 1064 female patients as described in Methods; Hx, \nHistory; PE, Physical Examination; y, years. \n3.3. Urogenital Findings by Age \nWarranting notice in Table 1  are the substantial prevalences of urogenital issues \n\n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 173 Journal of Biosciences and Medicines \n \nin younger EDS patients: All urogenital (female 75% versus 91%, male 19% versus \n31%), common genital (female 67% versus 85%, male 7.6% versus 13%), urinary \ntract (female 33% versus 48%, male 14% versus 23%) when those under 30 versus \nthose over are compared. More detailed relations to age are shown in panel A of \nFigure 1, menorrhagia increasing dramatically with puberty, ovarian cysts and blad-\nder issues somewhat later, endometriosis and hernias (including pelvic slippage) \nhaving more delayed increases with age (panel A of Figure 1 ). Not shown on the \nvery gradual and parallel increases of bladder issues and hernias in EDS males that \nwould likely be more striking if more in the 41 to 50- year (18 patients) or 51 to \n63-year (6 patients) groups were included.  \nRelevant to the pathogenic mechanisms causing these urogenital complications \nin female EDS patients are increases parallel to those of menorrhagia in panel B--\nthe dizziness, tachycardia, and food-medicine intolerances that reflect the sympa-\nthetic stimulation producing postural orthostatic tachycardia and mast cell acti-\nvation syndrome [5], the nausea reflecting the parasympathetic suppression man-\nifest as low bowel motility/irritable bowel syndrome [7]. That these symptoms of \nautonomic imbalance in panel B as well as the increases in bladder issues and her-\nnias with age in panel A reflect tissue laxity is suggested by the parallel increase in \nskin fragility (softness, scarring, slow healing) in panel C of \nFigure 1 ; bleeding \ntendencies reflected by easy bruising (not shown) that are relevant to menorrhagia \nshowed had a similar age profile to the other findings in \nFigure 1 (C). \n3.4. Reproductive Issues \nAlso in need of better documentation are the prevalence of reproductive and sex-\nual issues in EDS females, the more involved EDS subspecialists like cardiologists, \nrheumatologists, or medical geneticists rarely perform pelvic examinations. Labial \nand vaginal introitus pain can occur with yeast and other infections, but such pain \nwith no obvious cause that lasts 3 months or more is called vulvodynia. This com-\nplication was mentioned incidentally by only 6 female patients with EDS in Table \n1, the dyspareunia caused by this and other pelvic issues was mentioned only by \n9 women but is much more common in literature reports [8]-[10]. Not systemat-\nically queried but voluntarily mentioned were male concerns about penile sensi-\ntivity or sexual dysfunction in their smaller cohort. \nMore optimistic for reproduction is the low prevalence of pregnancy and deliv-\nery problems volunteered by women, premature delivery occurring in 14 patients \n(1.3%), premature labor reported by 2, severe complications like severe postpar-\ntum bleeding or uterine rupture occurring in only 4 (\nTable 1). Although plausible \nto some degree from laxity of the genital ducts or pelvic blood pooling, mention \nof infertility was made by one woman and none of the men (bottom row of \nTable \n1). \n3.5. Clinical and DNA Variant Profiles of EDS Patients with More \nUrogenital Findings \nThe 42 o f 197 male patients with bladder issues or hernias and the 94 of 1064 \n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 174 Journal of Biosciences and Medicines \n \nfemale EDS patients with 4 or 5 urogenital findings were grouped as Urogenital+ \nand compared with the Other group (1125 patients) having systematic evaluations \nand fewer urogenital findings in Table 2  and Table 3. \nNote first in Table 2  the expected difference in average number of urogenital \nfindings between the male and female groups selected for more (UroGenital+) or \nless (Other), males scored for only bladder issues and hernias, females for those \nand three others (menorrhagia, endometriosis, ovarian cysts). Those having more \nurogenital problems have significantly more findings in most categories, indicat-\ning that increased genitourinary issues parallel increases in joint -tissue laxity—\nBeighton score, childhood findings (awareness of hypermobility, performing dou-\nble-jointed tricks), joint (subluxations, pain, injury) plus skeletal deformations (sco-\nliosis, flat feet), and skin elasticity (stretching, scarring) — and neural (migraines, \nmuscle aches) or dysautonomia findings (chronic fatigue, tachycardia, anxiety of \nPOTS; reactive skin, food-medicine intolerances of MCAS; irregularity, bloating, \nnausea of IBS). Parallel increases of urogenital and other EDS findings with age in \nFigure 1 are mirrored here by increased numbers of findings in male or female uro-\ngenital-frequent and other groups. \n \nTable 2. History and physical finding profiles in patients with more or less urogenital findings. \nTrait/category  M-UroGenital+  M-Other F-UroGenital+  F-Other \nPatients  42 155 94 970 \nAge (years)  23 ± 14 20 ± 13 38 ± 9.3* 30 ± 13 \nAge distress (years)  14 ± 14 14 ± 9.9 18 ± 9.1 17 ± 9.0 \nTotal Hx findings of 80  31 ± 6.8* 24 ± 7.8 46 ± 8.1* 35 ± 9.4 \nTotal PE findings of 40  17 ± 5.0 16 ± 4.7 20 ± 5.1 19 ± 4.5 \nBeighton score (PE) of 9  5.4 ± 2.1* 4.2 ± 1.9 7.0 ± 1.9* 5.1 ± 1.9 \nChildhood (Hx) of 10  4.7 ± 1.4* 1.7 ± 1.2 5.8 ± 2.1* 1.4 ± 1.1 \nJoint (Hx) -Sk (Hx + PE) of 21  7.9 ± 2.5* 6.4 ± 2.6 11 ± 2.9* 8.4 ± 2.9 \nSkin (Hx + PE) of 11  4.4 ± 2.4 4.3 ± 2.2 6.9 ± 2.0* 5.5 ± 2.3 \nGenitourinary (Hx) of 2M -5F 1.1 ± 0.3* 0.0 ± 0.3 4.1 ± 0.3* 1.6 ± 1.0 \nNeuromusc (Hx + PE) of 16  4.7 ± 2.3* 3.6 ± 2.4 7.5 ± 2.4* 5.5 ± 2.6 \nDysautonomia (Hx) of 20  11 ± 3.3* 8.5 ± 3.8 15 ± 3.1* 12 ± 3.7 \nBuild-Face-Sk (PE) of 18  6.2 ± 3.0 5.7 ± 2.9 6.5 ± 3.2* 5.8 ± 2.8 \n*Significantly different at p < 0.05 level; Hx, History, PE, Physical Examination; Sk, Skeletal; there were 12 history and 7 physical cate-\ngories on the standard evaluation forms, each category having 4 to 12 findings [see the Supplementary Materials of reference for all \nfindings]; mean number of findings for several categories are added, e.g., joint history + skeletal history + skeletal physical or dysau-\ntonomia (POTS, MCAS, and IBS categories). \n \nThe upper left cells of Table 3  show that the 136 patients with more urogenital \nfindings had similar yields to the 1125 (1261 -136) with less, 91%  or 67% having \nDNA testing and 61 (67%) having positive results with 98 DNA variants judged \npotentially significant by commercial report (see Methods). A similar 78% of the \n1125 other EDS patients had DNA testing (>95% of both groups by whole exome \n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 175 Journal of Biosciences and Medicines \n \nsequencing), 507 having significant variants by commercial report. Although only \n20 of the 568 results were qualified as definitely contributory to the EDS diagnosis \n(pathogenic, likely pathogenic) by commercial report, 565 were qualified by clin-\nical protocol as having 2-4+ diagnostic utility for EDS, one of 1+ (uncertain) di-\nagnostic utility, and with 4 incidental and one of 1+ uncertain diagnostic utility). \nThe lower left cells of Table 3 compare the 68 genes altered in the UroGenital+ \nwith the 330 in the Other groups, 16 genes with 1 variation in the entire EDS co-\nhort being unique to the urogenital group (see legend). The overall profile of gene \nchange is remarkably similar, with proportions of voltage-gated calcium channel \n(CACNA1/2), connexin or gap junction 2 (GJB2), and ankyrin (ANK2/3) genes the \nonly ones significantly higher in the urogenital group. These genes, respectively \nassociated with neurologic, skin-deafness, and cardiac diseases do not provide any \nobvious correlation with urogenital issues unless the reactive and ulcerating skin \nof the \nGJB2-related Keratitis-Ichthyosis-Deafness (KID) syndrome (entry 148210 \nin http://www.omim.org/) indicates predisposition to vulvodynia. Listed symptoms \ncharacteristic of mucosal/skin fragility (conjunctivitis with corneal ulceration, fis-\nsured tongue, inflammatory erythroderma, absence of foreskin) and of connective \ntissue dysplasia (elbow-knee contractures, flat feet) suggest potential impact of GJB2 \ngene changes on the urogenital connective tissue and mucosa if adequately inves-\ntigated [38]. \nSimilarity between the tissues impacted or types of gene product associated with \nthe gene variations in the urogenital and other groups is shown to the right of \nTable \n3, of the 17 of 98 variants affecting immune -inflammatory functions based on \ntheir associated diseases, is more striking in the former group. Significantly fewer \nvariants in genes encoding transcription factors were found in the urogenital group, \nsuch changes predicting that the 40% or so of EDS patients not having DNA var-\niants found by whole exome sequencing will be found when whole genome sequenc-\ning can meaningfully analyze the non-exonic or dark genome. \n4. Discussion \n4.1. Clinical Management \nDocumenting the pattern of genitourinary complications in patients with EDS has \nseveral implications for medical care, particularly in the area of women’s health \ngiven their disproportionate affliction. Foremost is appreciation that the combi-\nnation of dysmenorrhea (menorrhagia, 70% of women; ovarian cysts 34%; endo-\nmetriosis 21%), bladder issues (41% of women with various urodynamic changes \nand interstitial cystitis), and other causes of pelvic pain like pelvic floor  slippage \n(7.2% of women) can be part of a  tissue laxity-dysautonomia, multisystem syn-\ndrome (\nTable 1 ). The parallel increase of urogenital complications with those of \nadrenergic stimulation (e.g., tachycardia), cholinergic suppression (e.g., low bowel \nmobility/nausea), and tissue/skin laxity (e.g., scarring, slow healing) around the \ntime of puberty in \nFigure 1 cements these relationships and adds a natural history \nelement for EDS consideration. The data of Table 2 and their eventual recognition \n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 176 Journal of Biosciences and Medicines \n \nin our example patient reinforce the consonance of urogenital problems with other \nEDS complications, their presence associated with more severe EDS expression as \nshown by significantly more hypermobility, childhood, joint-skeletal, and neuro-\nmuscular symptoms in males and females. \n \nTable 3.  Comparison of DNA testing results in EDS patients with and without more urogenital findings. \nGroup \nUroGenital+  Other Variant gene impact on \ntissue/function  \nUroGenital+  Other \nNo. (%) % of 98  % of 795  \nEDS patients  136 (100)  1125 (100)  Neural 27 33 \nDNA tested 1 91 (67)  876 (78)  Heart 12 13 \nDNA change  61 (67)  507 (58)  Autonomic 13 14 \nTotal variants 98 (100)2 795 (100)2 Muscle 6.1 12 \nAll COL3 10 (10) 58 (7.3) Immune-Inflammatory 17* 7.7 \nAll Mito. 15 (15) 143 (18) Bone 7.1 6.9 \nFBN1 5 (5.1) 17 (2.1) Joints 7.1 6.2 \nMT-CYB 5 (5.1) 18 (2.2) Clotting 5.1 4.0 \nFLG 5 (5.1) 35 (4.4) Skin 5.1 3.3 \nCACNA1/2 4 (4.1) * 2 (0.25) Gene product  % of 98  % of 795  \nGJB2 4 (4.1) * 2 (0.25) Structural 30 24 \nCOL1A1/A2 4 (4.1) 11 (1.4) Enzyme 27 28 \nMT-ND1/2/4/5/6 4 (4.1) 27 (3.4) Membrane channel 15 10 \nSCN9A 3 (3.1) 8 (1.0) Signal 15 12 \nHFE 3 (3.1) 13 (1.6) Receptor 6.1 9.5 \nVWF 3 (3.1) 15 (1.9) Adhesive 3.1 6.7 \nANK2/3 2 (2.0)* 1 (0.13) Transcription factor 2.0* 9.0 \n195% by WES; 298 or 893 DNA variants found in the 61 or 568 patients, many having more than one variant; 3COL1A1/A2, COL3A1, \nCOL6A1/2/3, COL7A1, COL12A1 were the collagen genes, ABCA4, COL27A1, FOXP2, KCNH2, IFIH1, IGF1R, LAMA5, MED12, \nMEFV, MYLK, NLRP3, PPT1, PRKAG2, SCN2B, THRB, and TIMP the genes with single variations found only in the urogenital group; \ngene names, the nature of their protein product, and diseases associated with their variation can be found at http://www.omim.org/; \nfindings of the principal associated disease determined the contribution of that gene change to a particular tissue (neural, bone) or \nfunction (autonomic, clotting). *, significantly different at p < 0.05 level. Data on the overall EDS patient population is from Wilson \nand Tonk [11]. \n \nThe approach to the woman with multiple urogenital problems, particularly \nwhen pelvic pain, pelvic floor/organ slippage, and lower body blood pooling [pel-\nvic congestion, 9; varicosities] are present, should assess hypermobility (large joint \nflexibility as with the reverse prayer or palms to floor signs of the example patient \nis easy to examine) and then look for accompanying symptoms of orthostatic in-\ntolerance (dizziness, feeling faint, brain fog), adrenergic stimulation (tachycardia, \nchronic fatigue, anxiety), and cholinergic suppression (bowel irregularity, bloat-\ning-reflux) that further the diagnosis of EDS- dysautonomia [1]-[10]. Knowledge \n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 177 Journal of Biosciences and Medicines \n \nof these underlying tissue laxity/vessel distensibility/lower body blood pooling mech-\nanisms will in turn encourage evaluation of women with more common bladder \nissues (7.6%, 4.8%, and 4.1%/3.8% of EDS women had frequent urination, leakage, \nor urgency/delayed emptying in Table 1 ) for problems like pelvic congestion [9] \n[39] or pelvic organ/floor slippage [8]-[10]. \nRecognition that these common urologic symptoms may be part of a broader \nEDS pattern adds treatment measures like mesh surgeries [24]  [25], pelvic vein \nembolization [40], or bladder exercise/stimulation ( in these women who likely \nneed urodynamic study after failing conservative management, [41]). Benefits for \nosteoporosis by estrogen replacement after menopause [28] must be balanced with \nits increase of tissue laxity [26] [27]. Relating urogenital symptoms to EDS mech-\nanisms also gives insight into cause and therapy, interstitial cystitis seen as a thin-\nning and fragility of bladder adnexal tissue; polyuria, urgency, delayed emptying, \nand stress incontinence [41] seen as part of the adrenergic imbalance [5]; hernias \nand pelvic organ/floor slippage reflecting the general tissue laxity/skeletal insta-\nbility of EDS [1]; vulvodynia [8] perhaps reflecting its skin fragility [2] [11]. Note \nthat our example patient waited until age 30 for EDS diagnosis despite the occur-\nrence of treatable urogenital symptoms with puberty.  \nHighlighting a major flaw of this study that counterbalances its virtue of sys-\ntematic evaluation is its minimal insights into urogenital problems of the EDS \nmale, with only 21% of them having urogenital findings in \nTable 1 . Of these, fre-\nquent urination and inguinal hernia at 6.1% and 5.6% were the only substantive \ncontributors at levels not convincingly more than those of the average male. Fre-\nquencies of penile irritation/dyspareunia, erectile dysfunction/infertility, and pros-\ntate/urinary tract problems in EDS males are of particular importance based on \nthe well-documented complications of skin-mucosal fragility, pelvic blood pool-\ning/slippage, and ureteral/urethral laxity/reflux in affected females [1] [2] [8] [9]. \nThis and existing surveys [8]-[10] would be improved by prospective and system-\natic documentation conducted by urologic and gynecologic specialists in concert \nwith those knowledgeable about the genetics and DNA contributors to EDS.  \n4.2. Research Implications \nGenomic testing of a substantial fraction (906) of the 1261 EDS patients having \nsystematic evaluation along with preliminary data showing low levels of pregnancy \nor fertility problems (\nTable 1) provides a major benefit needing further documen-\ntation: The overwhelming majority of EDS patients and their physicians can dis-\ncount concerns from rare EDS types [18] [19] and look forward to low reproduc-\ntive risks. Screening of all genes for mutations through exome and mitochondrial \nDNA sequencing [11] emphasizes that the clinical finding pattern and not changes \nin a particular gene determine EDS type, our example patient having a change in \nthe oft-associated collagen type III gene but none of the vessel-bowel ruptures or \nchiseled facial features of vascular EDS [18] [19]. \nClinical interpretation of genomic change using grades of diagnostic utility ra-\n\nS. S. Tonk, G. N. Wilson \n \n \nDOI: 10.4236/jbm.2025.1312013 178 Journal of Biosciences and Medicines \n \nther than qualifications of uncertain significance [11] will encourage physician use \nof this testing and the accumulation of clinical-DNA correlations that are needed \nto know if genes altered preferentially in EDS patients with more urogenital symp-\ntoms (Table 3 ) are prefiguring a unique type of that disease. More likely, in view \nof the 286 nuclear and 31 mitochondrial genes showing changes in the 566 of 1261 \nEDS patients having a DNA variant relevant to EDS, the gene network proposed \nto produce the EDS-dysautonomia panoply of symptoms [11] also acts on the uro-\ngenital system. The few genes found exclusively in EDS patients with urogenital \nsymptoms in \nTable 3  will likely be accompanied by many others as genomic test-\ning becomes commonplace. This view would fit with the clinical data in Table 1 , \nTable 2  which frame EDS patients with urogenital symptoms as having a more \nsevere version of the same EDS profile; it also accords with the actions and prod-\nuct functions of genes changed in urogenital-impacted versus usual EDS patients \nthat significantly differ only in immune-inflammatory action and transcription fac-\ntor function (Table 3 ). \nA more focused example of research issuing from the association of urogenital \ncomplications with EDS concerns the 34% of women who reported ovarian cysts, \nmost with single and painful ones that rarely required excision but 5.6% with the \nmultiple cysts of polycystic ovarian syndrome or PCOS (\nTable 1 ). Recent studies \n[42] suggest a higher incidence of sleep -disordered breathing in PCOS that is \nsomewhat independent of the higher rate of obesity (~75%) in women with that \ncondition, both of these problems (disordered sleep, 66%; obesity 17% - 30%) be-\ning frequent in EDS [2 ] [11] [14]. Another direction is suggested by the 10% of \n426 patients with acute and 43 with long CO VID-19 who had urogenital symp-\ntoms [43], the latter disorder and EDS showing remarkable overlap of joint-skel-\netal and neuroautonomic symptoms [14] [44]. \nConflicts of Interest \nThe authors declare no conflicts of interest regarding the publication of this paper. \nReferences \n[1] Tinkle, B.T. and Levy, H.P. (2019) Symptomatic Joint Hypermobility:  The Hyper-\nMobile Type of Ehlers -Danlos Syndrome and the Hypermobility Spectrum Disor-\nders. Medical Clinics of North America, 103, 1021-1033.  \nhttps://doi.org/10.1016/j.mcna.2019.08.002 \n[2] Wilson, G.N. 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