To report on diagnosis and management of pelvic congestion including the May-Thurner syndrome (MTS) as potential etiologies for intractable pelvic neuropathic pain.Retrospective study of women presented with intractable pelvic neuropathic pain, who had left sided venous uterine plexus above 6mm with reversed and slow flow on Doppler, with dilated arcuate veins passing through the uterine muscle. Those with suspicion of MTS underwent further radiological investigations and if applicable, endovascular interventions.61 consecutive patients were included. 14 with visceral pain presumed to be caused by Pelvic Congestion Syndrome were treated by ovarian vein embolization. An improvement of pain was observed in all patients – mean pain reduction of 3.93 points, from 7.21  to 3.28 pts  over 6 months (p<0.01). 47 presented with pelvic somatic neuropathic pain; 19 underwent endovascular intervention  and finally all of them a laparoscopic exploration/decompression of the sacral plexus and the endopelvic portion of the pudendal nerves, with an overall VAS reduction from 8.56  to 2.63  at one-year- follow-up (p<0.01).Laparoscopic exploration/decompression of the nerves seems to be effective in a carefully selected group of patients. Endovascular interventions for pelvic somatic neuropathies may not be an effective treatment. We recommend that Doppler studies of the uterine vessels are performed as an extension to gynaecological examination in women with intractable pelvic pain. Pelvic varicose veins are very common in multiparous women, and are most often asymptomatic, but what seems to be underestimated is that pelvic varicose can be secondary to MTS or NCS and may lead to both visceral pain (pelvic congestion) and even somatic pain by compression and irritation of the sacral plexus and its endopelvic collaterals, causing pudendal and/or gluteal neuralgias and sacral radiculopathies . These mThe May–Thurner syndrome (MTS), also known as Cockett’s Syndrome or the iliac vein compression syndrome  is a conIn this article, we report on our neuropelveological experience with these two syndromes, especially the MTS.This retrospective study, included all patients who presented at the Possover International Medical Center between 2014 and 03/2020 with chronic pelvic pain with dilated veins >6mm predominant on the left side (<4mm on the right) and dilated arcuate veins passing through the uterine muscle . PatientIn neuropelveological assessment for chronic pelvic pain of unknown etiology, clinical examination focuses on inspection of the internal/ external genital organs and the pelvic nerves  supporteThe ovarian veins at the anterior side of the psoas muscle . In MTS,The iliac vessels: In a MTS, a stenosis of the left common iliac veins can be observed between the right common iliac artery and the 5th lumbar vertebra .Patients were classified in two groups: “Visceral Pain” (by irritation of the inferior hypogastric plexus) and “Somatic Pain” (by irritation of the pelvic somatic nerves). All included patients underwent a routine MRI FSE T2-weighted sequence with fat saturation (and/or 3D volumetric protocol) to evaluate dilated ovarian veins and possible stenosis of the iliac vein . When MTAll patients signed informed consent forms prior to surgery and provided written informed consent for the use and publication of case details, personal information, images, and videos, including their faces. Pre and post interventional pain was assessed by visual analogue scale (VAS score).No ethical approval was needed for this retrospective study, since the interventions were based on a routine clinical practice for referred patients in the Possover Medical Center.The decision to carry out an endovascular intervention  was made by radiologists. An endovascular treatment was considered successful if the reduction is VAS score was more than 50% at 6 months follow-up. Embolization of the ovarian veins as in a Pelvic Congestion Syndrome is not a therapeutic option of MTS or even increases the downstream venous pressure and thus may aggravate the symptomatology of the patient.If the pain reduction was less than 50%, a laparoscopic exploration and decompression of the pelvic somatic nerves suspected to be involved in pain generation was performed  Possove.Laparoscopic access to the pelvic somatic nerves is obtained by:Dissection of the pararectal space and transection of the sacral hypogastric fascia to expose the infra- cardinal part of the sacral plexus (S#1-4/5).Dissection of the lumbosacral fossa outside the external iliac vessels and mobilization of the interiliac nodes from the pelvic wall for exposure of the supracardinal part of the sacral plexus , the endopelvic portion of the sciatic nerve and of the pudendal nerve .Following laparoscopic nerve decompression, all patients received Pregabalin 75mg x2/d  and we advised the patients to increase the doses by steps of 50mg per week depending on pain intensity, under control of their general practitioner.The evolution of the pain was recorded on a monthly basis over a period of one year recorded during post-operative consultations or by e-mail for patients living abroad.All statistical analyses were conducted by using SPSS/PC for Windows . Data are presented as mean -standard deviation (SD). For all analyses, the level of statistical significance was set at P less than 0.01 (paired t-test SPSS).The clinical flow chart is shown on Eleven patients underwent unilateral embolization of the left ovarian vein, and two had bilateral embolization of the ovarian veins. The successful embolization rate was 100% with no significant complications during or after embolization. An improvement of pain was observed in all patients - pain decreased by 3.93 points on average, from 7.21  to 3.28 pts  in 6 months follow-up (p<0.01). In 4 patients, due to an insufficient pain improvement, laparoscopy was performed with intraoperative detection of small peritoneal endometriosis spots or adhesions. Pain significantly improved in these four patients.In one patient, due to the development of a non-neurogenic left genitofemoral neuropathy approximately 9 months after embolization, laparoscopy was indicated: Coils of the left ovarian vein were found in direct contact with the genitofemoral nerve at the anterior surface of the psoas muscle. The vein was resected and the coils removed. The neuropathic pain almost disappeared during the months following the procedure.In one patient, MRI/Phlebograpy showed MTS, which required endosvascular angioplasty. At 6 months follow-up, due to the persistence of pain symptoms, laparoscopy was performed: some adhesions and small spots of peritoneal endometriosis were found and treated, with significant pain relief.Some of the patients included in the group “Somatic pelvic pain” group were also suffering from pelvic visceral pain, but predominant symptoms were the somatic pains.MRI showed MTS requiring endovascular stenting in nineteen patients. Despite a degree of initial pain relief in some patients, there was no consistent pain relief at 6 months follow-up in any of the patients undergoing stenting for MTS (VAS reduction <10%). In the remaining 28 patients imaging found minimal MTS or NCS which did not require either an angioplasty or a stenting.All forty-seven patients underwent laparoscopic exploration with decompression of the left pelvic nerves in forty-one patients, bilateral in six patients.Regardless of whether the preoperative assessment was suggestive of entrapment of sciatic L5-S1, sacral radioculopathy S2-S4 or neuralgia of the endopelvic portion of the pudendal nerve, the laparoscopic intervention consisted of the systematic exploration of all three anatomical regions with coagulation/transection of all veins showing a direct contact with the nerves . All veiNo major intraoperative complications occurred and no conversion to open surgery was required. All patients reported some slight weakness in the leg  due to manipulation of the obturator nerve for access to the sciatic nerve) and some hypoesthesia especially in genital areas, which subsided spontaneously after several days or weeks in all patients. One patient presented with a pelvic hemorrhage two months after the intervention following a vaginal examination extra muros of the operated area. Since then, we advise our patients to strictly avoid any digital manipulation/massage of the pelvic sidewall for at least four months after such a neuropelveologic procedure.In the nineteen patients who had an endovascular treatment for MTS, we found intraoperative dilated veins >1cm in diameter  but also “caput medusa” formations covering and entrapping the sciatic nerve, the sacral roots and/or the endopelvic portion of the pudendal nerve. Sixteen of them reported at 1-year-follow-up a pain reduction ≥50% (84.2%) and three a pain reduction 30-50% (15.8%) – with an overall VAS reduction from 8.56  to 2.63  at one-year- follow-up (p<0.01). The long-term pain evolution seemed to be correlated with pain improvement right after the procedure: Those patients who had the least pain immediately after the operation, had the best results at one year. On the contrary, patients who did not feel any difference in the intensity of pain in the days following the procedure, did not benefit from the procedure at 12-months follow-up.Chronic Pelvic Pain is a major challenge to healthcare providers because of their unclear etiology, complex natural history and poor response to therapy. Pathology of the pelvic nerves and plexuses may explain such “unknown pain conditions” and associated pelvic organs dysfunctions. However, the current understanding of pelvic nerve pathology is generally limited to pathology of the spinal cord with herniated disc responsible for sciatic pain, and the Alcock’s canal Syndrome responsible for genital pain when sitting. However, pathologies of the pelvic nerves may explain many cases of chronic pelvic pain syndrome including neuropathic pain in the lower back, the genito-anal areas and the lower extremities, but also pelvic organ dysfunctions. The incidence of pelvic nerve pathologies seems widely underestimated, mainly due to a lack of awareness that such lesions may exist, a lack of diagnosis and acceptance, as well as declaration and report of such lesions. Considering the number of pelvic pathologies, pelvic tumors, endometriosis of the pelvic nerves and invasive procedures in proximity of the pelvic nerves that could potentially induce neuronal compression, entrapment or damage, reports in the literature are rare.Pelvic congestion syndrome, also known as pelvic vein incompetence, is also a condition responsible for Chronic Pelvic Pain due to enlarged pelvic veins in the lower abdomen. The fact that pelvic dilated veins may also induce pelvic somatic neuropathic pain is much less known. Even less known in Gynecology are two different pathologies of the venous system responsible for the formation of pelvic varicose veins predominant on the left, the MTS and the NCS. While MTS was initially presumed to be rare when it was first anatomically defined in 1957 , the popIn view of our results, it is important to inform patients after laparoscopic nerves exploration/ decompression, that after a pain improvement of several days/weeks, the pain reappears in most patients (>95% of the patients according to our experience over the last 15 years) and even increases. Pain relief may take up to 8 months after the procedure so it makes no sense to reduce pain therapy before. Further pain, tingling sensations, electrical shots may appear in sacral/pudendal dermatomes. In patients who do not appear to experience any improvement in pain in the days following the laparoscopic nerves decompression, the long-term results are not good enough and treatment has failed.Our study has the major limitation to be a retrospective study. These drawbacks can be overcome by prospective, randomized, and controlled trials with a larger number of participants.


To evaluate temporomandibular disorder (TMD) treatment with a prefabricated, hydrostatic oral splint (HOS) based on self-reported patient’s symptoms using a standardized questionnaire.Two hundred fifty-eight questionnaires from patients diagnosed with TMD and subsequently treated with HOS were collected from two independent private practices. Based on patient’s comfort the questionnaire recorded TMD symptoms and symptom regression. Descriptive and comparative statistics was carried out using SPSS.A total of 221 questionnaires were analyzed. Patients reported TMD symptoms such as pain (93.2%), TMJ clicking (66.1%), headache (25.8%), cervical spine disorders (23.5%), restricted mouth opening (22.6%) and tinnitus (11.8%). For most symptoms, improvement was reported mostly after two weeks, except for tinnitus, where positive effects were usually reported after four weeks.HOS seem to be effective for immediate treatment of pain and other TMD symptoms. Based on the available data, a treatment period of four weeks can be recommended. Temporomandibular disorders (TMDs) imply a wide range of clinical patterns, including temporomandibular joint dysfunction, masticatory muscle disorders and disorders of associated structures , 2. The TMDs belong to the group of orofacial-pain conditions and exhibits a multifactorial etiology , 8. ContDue to the variety of symptoms and the multifactorial etiology, a standardized treatment concept is not available . A varieOcclusal splint therapy represents the most common treatment modality for TMDs . There aVarious types of occlusal splints are used for the treatment of TMD symptoms. While the terminology is not consistent, occlusal splints can be divided into the following groups: non-occluding splints, stabilization splints, prefabricated splints, anterior bite splints and anterior repositioning splints . StabiliCompared to stabilization splints, Hydrostatic oral splints (HOS) represent a relatively new occlusal splint system. HOS are prefabricated, splints that contain two water filled pads, connected with a tube for hydrostatic balance of both temporomandibular joints and disclusion of the dental arches. The main advantage of HOS is the possibility of immediate treatment, even in cases with limited mouth opening . FurtherTherefore, the aim of this study was to evaluate an established treatment protocol for TMD treatment with a prefabricated, hydrostatic oral splint based on the patient’s comfort using standardized questionnaires.This retrospective study analyzed questionnaires collected from two independent orthodontic practices which were completed by consecutive patients between 2011 and 2020. Due to the retrospective design, written informed consent was not obtained. It was ensured that the evaluation of all data was anonymized by entering all data in a separate Excel file and by giving each patient a randomly assigned number. Thus, reidentification of the patient’s name was not possible. The study protocol was approved by the Ethics Committee of the LMU University Hospital (ref. no.: 20–467 KB).All patients who received a treatment due to TMD symptoms were examined by an experienced clinician (A.S and A.H) with >20 years’ experience in TMD treatment. Medical history was obtained for each patient, followed by a clinical examination and functional analysis according to the guidelines of the German Society for Functional Diagnostics and Therapy . This anPatients of both genders with with acute, pain-related TMD or headache  and sufficient dental support for HOS (presence of at least two premolars per side) were included.Restricted mouth opening (<40 mm or less than the width of three fingers), limitation of jaw movement or pain during jaw movement or chewing were considered as dysfunction. Patients with chronic pain, history of trauma or congenital syndromes were not included in the study. Pain was regarded chronic if it was reported for >3 months .Patients were asked to wear the splint at least for ten hours per day (two hours a day and eight hours a night) for a period of at least four weeks, as recommended by the manufacturer .A standardized questionnaire, developed by Gedrange et al. was handed out to the patient together with the HOS . The patp value of 0.05 was considered significant.Only fully filled questionnaires from patients who completed treatment with HOS were evaluated. Statistical analysis was performed using SPSS statistics version 26.0 for Windows . Descriptive statistic was carried out to describe the frequencies and Pearson’s Chi Square test was used to determine significant differences. A Two hundred-fifty-eight questionnaires were analyzed in the study. Thirty-seven questionnaires were excluded, primarily because of an incomplete, illegible, or unclear filling out of the questionnaire. A total of 221 questionnaires remained for evaluation, 73 (30.0%) questionnaires of the primary version and 148 (67.9%) of the extended version. The study population consisted of 158 (71.5%) women and 39 (17.6%) men. Twenty-four patients (10.9%) did not report gender. Results for the different items of the questionaire are shown in Table Regarding TMD symptoms, patients most frequently reported pain (93.2%) followed by temporomandibular joint clicking (TMJ) clicking 66.1%), headaches (25.8%), cervical spine disorders (23.5%), restricted mouth opening (22.6%) and tinnitus (11.8%). Seventeen percent of the patients described none of these symptoms  wore the HOS for the recommended time period of 4 or more weeks (Tab. .5% wore Ninety percent of the patients reported an improvement of pain symptoms. Most patients reported an improvement of pain starting after 1 week (48.5%) most frequently rated as a 60% reduction (33.5%) Fig. , whereasIn the majority of patients the improvement of all evaluated symptoms started after one week or two weeks after starting HOS treatment Fig. . By contp > 0.05).Statistical analysis showed no significant association between wearing duration and pain or symptom reduction, and no significant association between gender and pain and symptom reduction  and 39 men (17.6%) this study included a higher proportion of women (ratio of 4.1:1 women:men) compared to previous epidemiological studies (3:1 women:men) , 29. BueMost patients (71.5%) wore the HOS as recommended (minimum 4 weeks). The treatment period with HOS alone should not exceed six weeks because undesirable occlusal effects such as over-eruption of the unopposed teeth may occur, as the HOS covers only parts of the dentition . If HOS Pain is the most frequently reported symptom of patients suffering from TMDs –35. ThesIn this study TMJ clicking was the second most frequently reported symptom (66.1%), a finding in line with previous studies . Joint cPrevious studies have shown that headache and TMDs are comorbidities , 40. In In previous studies the prevalence of otological symptoms of patients with TMDs ranges between 35.8% to 82.4% . In thisPatients with restricted mouth opening (72.0%) reported an improvement of their complaints mostly rated as a 60% reduction. Pain reduction, relaxation of the associated muscles, influence on neuromuscular activity and subsequent joint relief could have led to the improvement , 47. In There is no universally applicable treatment concept for TMDs . The speFurther, prospective studies are necessary to investigate the treatment effects of HOS, especially in comparison with other occlusal appliances and in combination with other treatment modalities. The main benefit of HOS is the possibility of immediate treatment, also representing a more cost-effective and time-effective method compared to stabilization splint therapy.This is a retrospective evaluation of self-reported patients complaints associated with TMDs, documented on the basis of a questionnaire, allowing assignment to rather broad categories of response options. There was no control group, as the study included patients of two private practices following a consistent TMD therapy concept using HOS. However, results of this retrospective analysis may give valuable advice to practitioners about patients’ perceptions following treatment of TMDs with HOS and appropriate treatment period.Clinical functional analysis as it was performed in this study  is a standard method for TMD diagnosis . The DiaThe findings suggest that HOS can be effective for treatment of pain and other TMD symptoms. It appears, that most beneficial treatment effects occurred after two weeks at the latest after starting HOS treatment, with the exception of patients with tinnitus, in whom improvement was most commonly reported after 4 weeks. Further studies are necessary to prospectively investigate the efficacy of hydrostatic oral splints in comparison with other therapeutic measures.Appendix 1


Patient-reported outcomes such as postoperative pain are critical for the evaluation of outcomes after incisional hernia repair. The aim of this study is to determine the long-term impact of mesh fixation on postoperative pain in patients operated by open and laparoscopic technique.A multicenter prospective observational cohort study was conducted from September 2011 until March 2016 in nine hospitals across Switzerland. Patients undergoing elective incisional hernia repair were included in this study and stratified by either laparoscopic or open surgical technique. Propensity score matching was applied to balance the differences in baseline characteristics between the treatment groups. Clinical follow-up was conducted 3, 12 and 36 months postoperatively to detect hernia recurrence, postoperative pain and complications.p = 0.025).Three-hundred-sixty-one patients were included into the study. No significant differences in hernia recurrence and pain at 3, 12 and 36 months postoperatively were observed when comparing the laparoscopic with the open treatment group. Mesh fixation by sutures to fascia versus other mesh fixation led to significantly more pain at 36 months postoperatively (32.8% vs 15.7%, At long-term follow-up, no difference in pain was identified between open and laparoscopic incisional hernia repair. Mesh fixation by sutures to fascia was identified to be associated with increased pain 36 months after surgery. Omitting mesh fixation by sutures to the fascia may reduce long-term postoperative pain after hernia repair. With an incidence of up to 25%, incisional hernia is a frequent long-term complication of open abdominal surgery , 2. TreaInternational guidelines equivocally advocate for an incisional hernia repair with a non-absorbable mesh, because recurrence is two-fold reduced compared to suture repair , 6. LapaLong-term patient-reported outcomes remain to be studied in detail to refine surgical techniques . With upWe hypothesized that type of mesh fixation technique using tacks, suture fixation to the fascia or the peritoneum is of major importance for the development of chronic pain and might be more important than the actual mesh position.Therefore, we aimed to report long-term outcomes of the applied surgical techniques, mesh position and fixation technique and assess their relationship with the occurrence of long-term pain.A prospective observational study including patients that underwent open or laparoscopic incisional hernia repair was conducted in nine hospitals across Switzerland. Patients were included from September 2010 to March 2016, inclusion criteria were age ≥ 18 years and written informed consent. Exclusion criteria comprised emergency surgery and local or systemic infection at the time of surgery. The primary outcome was recurrence at 3 years after surgery. Secondary endpoints included pain scores on a visual analogue scale , localization of pain, consumption of pain killers, SSI graded according to the definition of the Center for Disease Control .Following parameters were meticulously recorded during surgery: surgical access (laparoscopic vs. open), mesh material (Polypropylene vs. Polyester vs. other), mesh position  and mesh fixation .Follow-up data were collected during patient visits in the outpatient clinic 3, 12 and 36 months after surgery. Patients completed a standardized questionnaire and a clinical examination of the abdominal wall was performed. If there was a doubt regarding hernia recurrence, imaging studies were ordered.U test, respectively. A p-value ≤ 0.05 was considered statistically significant. Propensity score matching was performed by matching for age, sex, body-mass-index (BMI), American Society of Anesthesiologists (ASA) score, hernia size and site of primary incision. Propensity score matching was applied using the MatchIt package for R [eulerr package for R [Categorical variables are reported as numbers and percentages, continuous variables as median and interquartile range (IQR). Statistical differences were analyzed using Fisher’s exact test and Mann–Whitney-ge for R  and Eulege for R . All oth2 were enrolled. Thereof, 154 (42.7%) patients underwent laparoscopic and 207 (57.3%) patients open incisional hernia repair. The detailed flow-chart of the study is displayed in Fig. During the 66 months study period, 361 patients with a median age of 64.0 (IQR 55.0–71.0) years and a median BMI of 28.7 (25.4–33.0) kg/mp < 0.001), the mesh position was more frequently intraperitoneal  and tacks were more often used to fix the mesh  compared to the open group. Operation time was significantly shorter in the laparoscopic group . Figure The operative technique differed significantly between the two study groups Table . In the p = 0.006) and superficial SSI  were less frequent in the laparoscopic group compared to the open group (Table p < 0.001) compared to patients that underwent open incisional hernia repair.During hospital stay, overall postoperative complications .During the whole study period, there were no significant differences in hernia recurrence between laparoscopic and open incisional hernia repair. Frequency of hernia recurrence was not influenced by mesh fixation technique. Superficial SSI were less frequent in the laparoscopic group compared to the open group at three months postoperatively  12 months postoperatively in patients who underwent laparoscopic hernia repair. A similar trend was observed at 36 months after surgery.The prevalence of patients experiencing pain was similar between the open and laparoscopic group at 3, 12 and 36 months after surgery. In those patients experiencing pain, median pain level was significantly higher , regardless of other fixation techniques used. Patients with absorbable tack fixation showed a trend toward less pain when compared with patients with non-absorbable tack fixation during the entire follow-up period  in laparoscopic incisional and ventral hernia repair showed no differences in postoperative pain and quality of life . HoweverAn international multicenter randomized trial comparing tacks alone versus transfascial suture and tack mesh fixation in laparoscopic ventral hernia repair showed less abdominal wall pain in the tacks alone group 3-month postoperatively . Again, p = 0.003). However, at 36 months postoperatively the frequency of pain was equal for both sexes.A registry-based study from Germany found that pain at one-year follow-up after incisional hernia repair is associated with female sex . In our A recent study from the Netherlands suggests that a structured interview on the phone is sensitive to detect recurrence after incisional hernia repair . HoweverThe surgical technique differed considerably between the study groups. However, as this study aims to elaborate pain levels in relation to the type of mesh fixation, different operative techniques were permitted.A limitation of the study is the high dropout rate. Whereas data of close to 85% of included patients is complete at 12 months follow-up, only 61% and 65% of patients presented for the 36 moths follow-up appointment. The study protocol requested a clinical follow-up 36 months after surgery, which might have been the reason for withdrawal from study participation for many participants in this population with 25% of patients above the age of 70. Further, over the 3-year period, dropout due to death and loss of contact were responsible for missing data at 36 months of follow-up.Although propensity score matching is a valid statistical method, this study is limited due to its non-randomized design. Furthermore, the external validity of this study would be increased with a larger patient population.This propensity score matched prospective study did not show differences in the prevalence of pain at 3, 12 and 36 months after laparoscopic versus open incisional hernia repair. Mesh fixation by sutures to fascia was identified to be associated with increased pain 36 months after surgery. Therefore, mesh fixation by sutures to the fascia should be omitted to avoid long-term postoperative pain after hernia repair.


IntroductionTo date, Lichtenstein tension-free mesh hernioplasty is being adopted widely for inguinal hernia repair in adults, although it is accompanied by procedural complications such as recurrences, infection, testicular atrophy, post-operative pain, and nerve injury. As the recurrence rate decreased after Lichtenstein's tension-free hernioplasty, surgeons’ point of focus shifted more toward postoperative groin pain (inguinodynia) after inguinal hernia repair, as it has become a quite significant problem. The nerves of interest in the inguinal region are ilioinguinal, iliohypogastric, genitofemoral, and lateral femoral cutaneous nerves. Out of all the nerves, the ilioinguinal nerve is at the greatest risk of entrapment during meshplasty. Chronic groin pain is quite significant following hernia repair, and irrespective of the severity, it can interfere with normal daily activity. The traditional surgical technique recommends the preservation of the ilioinguinal nerve to avoid the morbidity associated with the cutaneous sensory loss supplied by the nerve. One popular belief is that if we excise the ilioinguinal nerve, then the chance of getting post-operative neuralgia due to entrapment, inflammation, neuroma, or fibrotic reactions will almost become zero. Hence, this study was conducted to evaluate the effect of prophylactic excision of the ilioinguinal nerve in the patients undergoing Lichtenstein hernioplasty for inguinal hernias.MethodsAll consecutive male patients presenting to the Department of Surgery with inguinal hernia and age above 18 years were included in the study. All the patients were operated on under spinal anesthesia. Lichtenstein tension-free hernia repair was taken as the standard procedure for hernia repair. Patients in whom the nerve was preserved were kept in group A, whereas group B comprised patients who had undergone neurectomy. Patients were followed up regarding pain at first, third, and sixth months, at rest, and after exercise. The pain was graded according to the VAS  scoring.ResultsIn the present study, out of a total of 92 patients, 80 patients were included. In the first month, 15% of the patients in group A had mild pain, while 5% in group B had experienced a moderate degree of pain at rest. After exercise, the result was 30% in group B. Similarly, in the third month of follow-up, it was found that 25% of the patients in group A experienced mild pain, while 12.5% complained about a moderate degree of pain who had to take analgesics for a longer period. After putting them to exercise and then grading the pain, it was found that 32.5% in group A and 15% in group B experienced pain. After follow-up for six months in both groups, it was revealed that there was no significant difference in post-operative pain at rest . After exercise, 20% of patients in group A complained of pain, while in group B, only 10% experienced pain. There was no significant difference between both the groups while comparing chronic groin pain at rest and after exercise, and after different time intervals in follow-up .ConclusionProphylactic excision of the ilioinguinal nerve in Lichtenstein tension-free meshplasty decreased the incidence of chronic groin pain after surgery but it was statistically insignificant. Furthermore, this procedure did not affect the quality of life after surgery. By definition, a protrusion of a viscous or a part of viscous through an abnormal opening in the walls of its containing cavity is called a hernia . There aChronic groin pain following inguinal hernia repair is defined as pain lasting more than six months after surgery . ChronicNociceptive pain is the most common of the three, and the etiology is fibrosis over the mesh , mechanical pressure by folding of the mesh by displacement or contraction of the mesh. Nerves may get injured by surrounding structures such as periosteal layers or musculotendinous tissue or due to post-operative causes . VisceraNeuropathic pain occurs due to direct nerve injuries by either accidental cutting or excessive traction. It may also happen through damage by electrocoagulation, or entrapment by the perineural fibrosis, suture material, stapler, or by the mesh itself . Direct The nerves of interest in the inguinal region are ilioinguinal, iliohypogastric, genitofemoral, and lateral femoral cutaneous nerves. Ilioinguinal and iliohypogastric nerves are encountered in the anterior dissection, and the last two nerves become endangered during laparoscopic repair of the inguinal hernia. Despite the anatomic variation among the nerves in the inguinal region, all the nerves are identifiable individually in 70% to 90% of cases. Out of all the nerves, the ilioinguinal nerve is at the greatest risk of entrapment during meshplasty.The ilioinguinal nerve (L1) arises from the anterior ramus of the first lumbar nerve root in the lumbar plexus. After exiting the plexus, it then travels across the quadrates lumborum as it courses laterally and passes the iliacus as it approaches the iliac crest. Then it wraps anteriorly and pierce the transverse abdominis and internal oblique muscle  to become the content of the canal. It travels in the inguinal canal with the spermatic cord until it leaves a superficial inguinal ring. It provides a sensory supply to the skin of the upper and medial parts of the thigh. In males, it supplies the root of the penis and the upper part of the scrotum, while in females it innervates the mons pubis and labium majus.As per the report, chronic groin pain is quite significant, ranging from 19% to 62.9% following hernia repair, and irrespective of the severity, it can interfere with normal daily activity . Hence, There are two types of options to treat the long-term complications of post-operative inguinodynia, i.e, non-surgical and surgical. Non-surgical options include the use of analgesics , a peripheral nerve block with local anesthesia, transcutaneous electric nerve stimulation, laser therapy, pulsed radiofrequency, whereas surgical options include revise operation for recurrence and meshoma, removal of fixation material, selective neurolysis or neurectomy of ilioinguinal, iliohypogastric, or genitofemoral nerve, and removal of mesh and further hernia repair.The traditional surgical technique recommends preservation of the ilioinguinal nerve to avoid the morbidity associated with the cutaneous sensory loss supplied by the nerve to the groin, medial aspect of the thigh, upper part of the scrotum, and the root of the penis.One popular belief is that if we excise the ilioinguinal nerve, then the chance of getting post-operative neuralgia due to entrapment, inflammation, neuroma, or fibrotic reactions will almost become zero . Hence, The study was conducted in the Department of Surgery at a tertiary care hospital in Eastern India from February 2019 to January 2020. The study was approved by the Ethics Committee of the institute  and has been performed following the ethical standards laid down in an appropriate version of the Declaration of Helsinki (as revised in Brazil 2013).All consecutive male patients presenting to the Department of Surgery with inguinal hernia and age above 18 years were included in the study. The details of the patients and the findings were recorded. Patients with diabetes mellitus, complicated inguinal hernia (obstructed/strangulated), bilateral inguinal hernia, previous surgeries with lower abdominal or paramedian incision or incision in the inguinal region, recurrent inguinal hernia, mesh allergy and subsequent hernia repair, previous history of trauma and pain in the inguinal region, history of low back pain, and any previous spinal disorders were excluded from the study.The study was designed as a prospective, open-labeled, parallel-arm, randomized controlled trial. Block randomization was carried out using a computer program with randomly selected block sizes of four and six. Allocation concealment was ensured by a serially numbered opaque-sealed envelope (SNOSE).All consecutive patients with inguinal hernia were recruited in the primary cohort after obtaining written informed consent.Patients were selected after thorough history taking, clinical examination, laboratory investigations, and radiological investigation (chest X-ray and sonography of the abdomen & pelvis). All the patients were operated on under spinal anesthesia. Lichtenstein tension-free hernia repair was taken as the standard procedure for hernia repair. Patients in whom the nerve was preserved were kept in group A, and group B comprised patients who had undergone neurectomy.Careful dissection of the inguinal canal was performed layer by layer. The ilioinguinal nerve was identified and preserved in group A patients, whereas, in group B, it was cut near the deep inguinal ring. The nerve was identified and stretched back to the point where it came out of the internal oblique near the deep ring. Then it was transected and ligated, and the proximal ligated end was buried in the internal oblique muscle to prevent neuroma formation. At the medial end, the nerve was cut very close to the lateral border of the rectus muscle . Lichtenstein tension-free mesh repair was performed using a polypropylene mesh of size 7x15 cm, which was again cut into the appropriate size of the posterior wall and was placed in position using Prolene 2-0  non-absorbable suture.Patients were given antibiotics and analgesics for five days to decrease post-operative pain and infection. Suture were removed between 8 and 10 days depending on the condition of the surgical wound. Follow-up was done regarding pain at first, third, and sixth months, at rest, and after exercise . The pain was graded according to the VAS  scoring .Statistical analysisData were analyzed using SPSS Statistics for Windows, Version 20.0 . Appropriate statistical tests were used to compare the results of groups A and B. A p-value of <0.05 was considered statistically significant.In the present study, out of a total of 92 patients, 80 patients were included Figure .Due to non-agreement to participate in the study, 12 patients were excluded. The demographic profile of the patients in both groups was comparable. On immediate post-operative days, there was no significant difference in pain between both the groups till the removal of stitches and discharge of the patients. The chronic groin pain at rest and after exercise are given in Tables However, at first month, 15% of the patients in group A had mild pain, while 5% in group B had experienced a moderate degree of pain at rest. After exercise, the result was 30% in group B.Similarly, in the third month of follow-up, it was found that 25% of the patient in group A experienced mild pain, while 12.5% complained about a moderate degree of pain and had to take analgesics for a longer period. After putting them to exercise and then grading the pain, it was found that 32.5% in group A and 15% in group B experienced pain.After follow-up for six months in both groups, it was revealed that there was no significant difference in post-operative pain at rest; it was 10% and 7.5% in groups A and B, respectively. But when they were subjected to minimal exercise, there was a significant difference in results. 20% of patients in group A complained of pain, while in group B only 10% experienced pain.There was no significant difference between both the groups while comparing chronic groin pain at rest and after exercise after different time intervals in follow-up .In the present study, there were neither major complications nor any complaints regarding the recurrence of the hernia. Ilioinguinal nerve excision was not associated with any reduction in the quality of life assessed during the follow-up.As recurrence rates of inguinal hernia have dramatically reduced after the introduction of meshplasty, post-operative chronic groin pain becomes the next concern for the surgeons as it is one of the most common complaints that affects the patient's satisfaction and quality of life after hernioplasty ,14. The Ravichandran et al. were the first to study the effect of ilioinguinal neurectomy . They peIn another study conducted by Dittrick et al. who randomly divided 156 patients into two groups by performing nerve preservation and nerve transection, there was no significant difference between both the groups after one month of follow-up . They alIn the present study, the post-operative pain at rest after one month was 5% in group B population, while it was more (15%) in group A. The pain became exaggerated in both groups after exercise .Similarly, at three months post-operation, groin pain at rest was found in 12.5% of the group B population as compared to 25% of the group A population. This change became more significant when both groups were studied after exercise. The results obtained were 15% in group B vs. 32.5% in group A; these results are comparable with those in the study conducted by Malekpour et al. in 2008 (12.5% [nerve preservation] vs. 26.9% [nerve division]) .At six months, this study showed a result of 7.5% in group B vs. 10% in group A at rest and after exercise, the result became 10% in group B vs. 20% in group A, which was nearly the same as the results obtained by Mui et al. in 2006 (19.2% [nerve preservation] vs. 8.2% [nerve division]) [There was no significant difference between both the groups while comparing chronic groin pain at rest and after exercise after different time intervals in follow-up .In this study, we did not consider the pain experienced during the first week as it might be due to an operative procedure or infection. It was controlled by the use of antibiotics along with analgesics till the removal of stitches.There are a few limitations in the present study. The sample size of the study was small and it was a single-center study.The results of the study revealed that prophylactic excision of the ilioinguinal nerve in Lichtenstein tension-free meshplasty decreased the incidence of chronic groin pain after surgery, but it was statistically insignificant. Furthermore, this procedure did not affect the quality of life after surgery. This procedure also had no specific complications. As the sample size was less, further studies may be needed to establish the conclusion of the study.


WAGR syndrome is a rare genetic disorder characterized by Wilms tumor, Aniridia, Genitourinary anomalies, and Range of developmental delays. In addition to the classic features, patients affected by WAGR syndrome can develop obesity and kidney failure, and a wide variety of non-classical manifestations have also been described. This suggests that a broader phenotypic spectrum beyond the classic syndrome exists and here we demonstrate that spectrum using data from the WAGR Syndrome Patient Registry. In the present study, we collected information from 91 individuals enrolled in the registry to explore self-reported health issues in this patient population. A wide variety of common clinical issues not classically associated with the disorder were found, prompting the redefinition from WAGR syndrome to WAGR spectrum disorder to incorporate the phenotypic variations that occur. A comprehensive care management approach is needed to address the wide range of clinical issues and we propose a care model for patients affected by WAGR spectrum disorder. Further research is needed to solidify the breath of the phenotype and confirm the observations in this study to advance individualized patient care in this population. WT1 and PAX6 are thought to cause the phenotypic features and clinical issues in patients; however, much is still unknown about the specific molecular role of these genes in patients with WAGR syndrome. More recently, deletions in BDNF have been found in ~50% of patients with WAGR and the BDNF gene has been associated with obesity , Aniridia, Genitourinary (GU) anomalies, and Range of developmental delays. The disorder is caused by a deletion in chromosome 11p13  ultrasounds every 3 months until the age of 7–8 years , 3. In aA previous study from 2005 reported on the health status of 54 patients with WAGR syndrome . The resIn the present study, we utilized data collected through the WAGR Syndrome Patient Registry to evaluate the rates of self-reported health issues in a large patient population, the WAGR Discovery Cohort, which consisted of 91 individuals. The main objective was to determine the frequency of specific health issues to identify those potentially associated with the disorder. Secondary objectives included identification of commonly affected health categories to determine care management recommendations, and investigation into the phenotypic characteristics.Participants and data were collected through the WAGR Syndrome Patient Registry, an online specific rare disease registry platform managed through the Coordination of Rare Diseases at Sanford (CoRDS) in partnership with the International WAGR Syndrome Association (IWSA). Researcher access to the data utilized in this study was obtained through CoRDS. This research was not considered human subjects research as the provided dataset was de-identified.The CoRDS Rare Disease Registry is an online database in which patients affected by rare diseases can enroll and provide health information. At time of enrollment in the CoRDS registry, the individual or parent/legal guardian provide consent and basic information about demographics and rare disease information.The IWSA questionnaire is a disease-specific questionnaire created for patients in the WAGR Syndrome Patient Registry through CoRDS. Participants can provide information on a variety of health issues, with questions organized into health categories , with additional questions about specific health issues within each category. In addition to health information, the questionnaire gathers information on genetics, birth, and psychosocial data. Two primary response methods are utilized in the questionnaire, depending on the question type: checkbox selections or multiple-choice options. For health status questions, the multiple-choice options were: “Currently a problem;” “Not a problem today, but was in the past;” “Never a problem;” or “Unsure.” All questions are optional, and participants can choose not to respond to particular questions or sections. Participants have the opportunity to update their information at any time and are encouraged to update their information annually with longitudinal data collection.CoRDS data were provided in the form of an Excel database with two spreadsheets: CoRDS enrollment information (de-identified) and the IWSA Questionnaire. For all questions or sections that were not completed by the participant, the data input was “NULL” for relevant columns in the provided dataset.The dataset provided by CoRDS was reviewed to determine eligibility for the study. Eligible participants included those with a self-reported diagnosis of WAGR syndrome in the CoRDS enrollment and/or IWSA Questionnaire. Participants in the initial dataset who reported a diagnosis other than WAGR syndrome  were excluded.Participants who updated their information at least once had multiple rows in the database, with one row respective to each entry. For these participants, the data from each individual entry were reviewed and summarized to create a single composite row for each participant. Participants who completed the questionnaire a single time had a single row of data provided. Individual spreadsheets were created to evaluate the questions.For each specific health issue question, participant responses were grouped as: Affected  or Not Affected (“Never a problem” response). Participants were also grouped to evaluate health categories as: Affected (one or more issues in the category reported or selected); or Not Affected .The Excel database was used to perform descriptive statistics and data were summarized as frequencies. The evaluated frequencies were considered the proportion of affected participants compared to the total number of participants who provided a valid response for the question evaluated (affected and not affected). Participants who did not complete a specific question or category in the questionnaire (“NULL” response) and those who responded as “Unsure” were not included in the total count of valid participants for each question and excluded as applicable to the relevant questions.n = 66) or the legally authorized representative if the participant was an adult (n = 24); one participant was an adult who self-enrolled.A total of 91 participants who selected a diagnosis of WAGR syndrome were identified through the CoRDS registry, with enrollment completed between August 2014 and May 2020. Participants were enrolled and surveys were completed by a parent of a child under the age of 18 years (n = 52) and United Kingdom (n = 10). At least one individual from every continent (except Antarctica) participated. The majority of participants were reported as white (n = 79); other races reported included Asian (n = 4); Black/African American (n = 1); and Mixed African-European (n = 1). Ethnicity was reported by 48 participants, with 10 identified as Hispanic or Latin American.Facial images of individuals with WAGR syndrome are shown in WT1, PAX6, and BDNF deletions  and/or nephrogenic rests (NR) . Six parRelapse was reported by three participants: one at 11 months after diagnosis (n = 15). Tumor stage and histology information were provided by 32 participants. The majority of tumors were reported as Stage I (n = 18) or Stage II (n = 8); others included Stage III (n = 4), Stage IV (n = 1), Stage V (n = 1). All tumors were reported as favorable histology. The questionnaire did not ask participants whether tumors were diagnosed through routine surveillance.Among the 36 participants with WT, 41.7% also reported NR , autism spectrum disorder (ASD), and issues such as pervasive developmental disorder (PDD), conduct disorder, and oppositional defiance disorder (ODD). Males were also more commonly affected by a behavior condition without a psychiatric condition  were reported more often by males. Difficulty emptying the bladder was the most common issue affecting both sexes. Female participants commonly reported streak ovaries and males frequently reported cryptorchidism (n = 14/41).More than half of the cohort was affected by a GU anomaly, with males affected at twice the rate of females . Disorderchidism . InternaMore than a third of participants reported an issue that was consistent with a congenital anomaly of the kidney and/or urinary tract (CAKUT) . In addiAll participants reported at least one issue within the ocular category and a variety of different issues were reported . The mosParticipants were frequently affected by the majority of the health categories . A numbeRespiratory issues (Lung/Breathing category) were frequent, and more than 60% of participants reported frequent illnesses; additional common issues included apnea, asthma, and obstructive sleep apnea (OSA) . MusculoHearing loss was reported by close to 15% of participants, and sleep problems were common . A numbeApproximately two-thirds of the cohort was affected by abnormal muscle control or tone, and more than a third of the cohort was affected by at least one neurological problem . FrequenParticipants were asked which neurology tests had been performed and the overall result  for each test. Neurology testing was reported by 50 participants, and 27 (54%) reported at least one abnormal result. Brain CT (computed tomography) was abnormal in 50%; brain MRI (magnetic resonance imaging) was abnormal in 48%; and abnormal EEG  was reported by ~39% of the cohort.High rates of cardiometabolic issues were reported by participants and hypertension was present in more than a third of the cohort . Congenin = 17) and close to a third (n = 7/22) reported obesity with short stature. A variety of other endocrine/metabolic issues were reported  were considered positive; those with obesity and less than two features, and those without obesity, were considered as negative; participants with missing data related to criteria were excluded. An approximate rate of 12% of participants with potential metabolic syndrome was observed .n = 18/42) and 32.3% of males (n = 10/31) affected. A range in degree of CKD features that affected each participant was observed: 17 participants reported kidney failure with or without FSGS (most in Stage 1 or 2); four reported FSGS without kidney failure; and seven reported isolated proteinuria (Participants were frequently affected by features of chronic kidney disease (CKD), with rates of proteinuria, kidney failure, and/or focal segmental glomerulosclerosis (FSGS) reported between 20 and 33% in the total cohort . No partteinuria . CardiomA gradient in the degree of CKD and presence of cardiometabolic features was observed . Partici. Cardiometabolic issues were frequently reported by these participants  did not report history of WT or NR development icipants : hyperteThe majority of participants were naturally conceived, singletons, and were not premature; among the full-term participants, most reported normal birth length and weight . A varieHalf of participants reported use of least one assistive device from the checkbox options, and almost all participants reported receiving at least one therapy type . The majWe compiled the evidence from cohorts of patients with WAGR starting with the information from the first description of aniridia-WT association published in 1964 by Miller et al.  and compMany of the clinical issues characterized in the WAGR Discovery Cohort have been described in at least one or two patients previously, and we observed comparative rates or increased rates of features across the selected studies . The risFrom the historical literature evidence perspective, gastrologic findings are less well-characterized but also appear common and can range from milder issues such as GERD to more serious complications such as pancreatitis . A high The results of the WAGR Discovery Cohort are consistent with those reported by Fischbach, Trout  and demoStandard criteria for WAGR diagnosis has included the presence of aniridia and at least one of the three other classic features . A varieFocusing on the main associations of the WAGR phenotype may have led to under-characterization of the disorder and our results suggest that a number of additional systems are involved. These features are common in addition to the classic features, and build upon the previously expanded phenotype reported by Fischbach, Trout . These oWAGR spectrum disorder,” which serves as an umbrella term to describe the various clinical and molecular subgroups and their presentations. The concept of a spectrum disorder rather than syndrome disorder will hopefully allow for a broader view of this disorder and pave the way for future investigations beyond the classic W-A-G-R manifestations that have historically been evaluated. Two separate spectrums could be used to characterize patients: the clinical spectrum to describe the frequency and combinations of features; and the molecular spectrum to describe subgroups of patients affected by specific genes within the 11p13 region. In the future, these spectrums could serve to help establish genotype-phenotype associations within the full WAGR spectrum. For the purposes of consistency, we will now refer to all previously reported patients and Discovery Cohort participants as being affected by WAGR spectrum disorder.The range of clinical issues caused by the same molecular region of chromosome 11p13 can be characterized within the concept of “In the initial conceptualization of WAGR spectrum, the clinical phenotype can be described by Classic features, Common features, and Isolated features. Clinical presentations could be considered as “classic WAGR” to describe those with the classic and common features and/or 11p13 deletions, as well as “atypical WAGR” to describe those with 11p13 deletions without the classic phenotype. As the phenotype of WAGR spectrum expands, further cohort studies could help delineate which features are more prevalent than others among patients to characterize specific features into groups .We utilize observations from the Discovery Cohort to initially characterize the phenotype of WAGR spectrum and describe the classic features of the disorder in addition to other considerations. This cohort represents the largest group of patients affected by WAGR ever reported.The diagnosis of WAGR spectrum disorder can be considered the combination of clinical WAGR features and molecular abnormalities consistent with 11p13 deletion. We propose the initial spectrum as ranging from the presentation of isolated aniridia to classic WAGR features and/or molecular diagnosis of 11p13 deletion in the WAGR region.The “classic” features of W-A-G-R can represent phenotypic spectrums within each respective letter, rather than the clinical issue that defines them. Our findings confirm the approximate 50% risk of WT within the WAGR spectrum population. We observed multiple participants with reported nephrogenic rest development but without development of WT, suggesting that the “W” may be better defined as “Wilms tumor or WT precursor risk” in order to highlight this important issue among all patients. Aniridia may be better defined as “Aniridia and other ocular issues” in order to highlight the wide range of common ocular issues in this population. Genitourinary anomalies  are frequent, and we observed a number of participants affected by congenital anomalies of the kidney and urinary tract (CAKUT), which has not previously been associated with the disorder. As a result it may be more appropriate to conceptualize “G” as “Genital and nephro-urological anomalies” to describe the spectrum of issues that can present and highlight the potential specialists needed to manage care. The “R” that defines WAGR has previously been reconceptualized from mental retardation to “Range of developmental delays” and our findings support this designation; the term “range of neurodevelopmental issues” could also be considered.We characterized WAGR syndrome and WAGR spectrum criteria in 61 participants with information available for all relevant data . SyndromA variety of combinations of features and phenotypes were observed . One thiWAGR spectrum criteria that includes isolated aniridia, or a combination of aniridia or ocular issues and other classic WAGR features allows for classification of 100% of the WAGR Discovery Cohort. Previous criteria for WAGR syndrome that includes aniridia and one or more other classic features classified between 90 and 95% of participants .A small subset of participants were only affected by aniridia, which could be considered “isolated aniridia” or an “isolated feature” of the WAGR spectrum phenotype in the initial characterization. While aniridia is present in the large majority of patients, examples of patients without aniridia affected by WAGR have previously been reported  and we oThe classic features of WAGR spectrum can be considered those that characterize the disorder, however the results of the WAGR Discovery Cohort suggest that a number of other features and clinical issues frequently affect patients, termed “common features” for WAGR Spectrum disorder. We observed high rates of obesity, hypertension, and chronic kidney disease (CKD), in addition to a variety of cardiac, pulmonary, and other health issues. Given these associations, it can be considered that patients with WAGR spectrum share an increased risk for adverse cardiometabolic health and CKD in addition to WT development, and this notion is an important concept within the WAGR spectrum. Specific considerations for common health issues are discussed below.As commented above, it is likely that this phenotype may change as more evidence becomes available regarding WAGR spectrum characteristics. Further phenotypic investigations into WAGR spectrum can help determine which features are more frequent than others to better define categorical features of the spectrum.We observed a high rate of reported ear and other craniofacial abnormalities, suggesting that a craniofacial phenotype may exist within WAGR spectrum. It has previously been reported that no characteristic facial dysmorphism is associated with WAGR syndrome , and thiPAX6  and WT1 ; among others. More recently a disorder distinct from the other characterized 11p13 region spectrum disorders has been termed “chromosome 11p13 deletion syndrome” (OMIM# 616902). It is possible that these disorders could be considered separate entities within an umbrella term of “11p13 deletion/mutation spectrum disorder” (or similar terminology) due to shared clinical issues and/or phenotypes; however, the emerging evidence is too novel to establish this terminology, and this may create more confusion than clarity in the medical and research community. Determination of specific nomenclature, diagnostic criteria, and potential overlapping management strategies will require collaboration between various patient advocacy organizations, researchers, and physicians to determine whether these similar genetic abnormalities and/or phenotypic and clinical consequences may represent a wider spectrum that can be characterized in the future.In the present study, we reclassify the historical disorder “WAGR syndrome” to describe “WAGR spectrum” to broaden the characterization of phenotypic presentation and improve recognition of this complex rare genetic disorder. The genes involved in the 11p13 deletion and some of the phenotypes described in the WAGR population overlap with other disorders characterized by deletions or mutations of An individualized care management approach is warranted in all patients with WAGR spectrum, as a variety of clinical issues can occur. A number of common issues observed in the population suggest that a team of core specialists is needed for a multi-disciplinary care team approach to patient care. We propose a care management model for WAGR spectrum , and disAny patient presenting with aniridia should prompt referrals to a core team of specialists , with adWe recommend a genetics referral in patients presenting with aniridia or those suspected of having WAGR spectrum. A geneticist can determine the most appropriate molecular analyses to be performed, as a variety of molecular tests have been suggested for these patients and often a combination of multiple methods is needed for an accurate diagnosis.in-situ hybridization  and karyotyping to detect 11p13 rearrangements, however these methods do not always allow for a complete picture of the high complexity of chromosomal deletions and breakpoints that can occur . Previoudization .Once the diagnosis of WAGR spectrum is established, geneticists and genetic counselors can serve as the “medical home” for patients and help determine appropriate referrals as well as provide anticipatory guidance based on the patients” specific molecular diagnosis to support an individualized care management approach. Genetic counselors can also be considered part of the psychosocial and anticipatory care team approach. An increased focus on educating families about the specific diagnosis is recommended, as we observed a high frequency of participants in the WAGR Discovery Cohort who were unsure of their child's specific genetic results .Routine follow-up with genetics is recommended, with specific frequency determined by individual patient issues. Annual follow-up can be considered for all patients, with more or less frequent visits depending on clinical history and family preferences.The pediatrician can assist in routine monitoring of development and growth and should serve as the initial point of contact for non-urgent medical issues. Pediatricians caring for patients with WAGR spectrum should be prepared to refer patients to specialists for management at the initial suspicion of potential clinical issues. Pediatricians can work with other specialist teams to help monitor and order health screening, and other clinical laboratory or imaging testing needed such as Wilms tumor screening. Increased attention to cardiometabolic health is suggested, with prompt referral to appropriate specialists if abnormalities arise. Transitioning to specialized care teams should also be a focus as patients age throughout childhood and into adulthood—the pediatrician, care teams, and family should work together identify the specialists that are involved throughout the patient's life.The need to establish a medical home and involve families in the care of patients with WAGR spectrum has been previously highlighted  and we aOnce a diagnosis of WAGR spectrum is established, referrals to a core multi-disciplinary team of specialists should occur to identify the clinical issues present and determine an individualized care management approach. Core specialists and considerations are summarized in Ocular issues beyond aniridia were previously reported by Fischbach, Trout  and we oCaring for patients affected by WAGR extends beyond childhood, as evidenced by almost all the Discovery Cohort adult population reported as dependent and living with parent/relative or at a skilled care facility. A variety of specialists and support services are needed for patients and their families; these should be initiated at the same time as suspected/confirmed diagnosis and modified for the patient and family's needs throughout their lives.Collaborative teamwork is essential to create a supportive environment to facilitate individualized patient care and management approaches. A recent cross-sectional study among patients living with 81 different rare diseases found common unmet needs related to health system information and patient care, and patients additionally felt lack of adequate psychological support and education . PsychosReferral to services such as Early Intervention, developmental and behavioral specialists, and special education services will help support children as they age . More thBDNF, ELP4, PRRG4, and SLC1A2 have been identified in relation to autism, cognitive/developmental delays, and behavioral problems , occupational therapy (OT) and speech therapy may benefit patients, as a high rate of these services were used by the WAGR Discovery Cohort participants. We observed a high rate of speech disorders in the present study, which has not been highlighted in previous WAGR cohorts. Deletions in the ate gene . The ranate gene , and it At time of diagnosis, referral to psychosocial services is encouraged for all patient families as the diagnosis of a rare disease not only affects patients, but their families as well. Genetic counselors can assist in long-term monitoring and counseling. Other providers such as psychologists, psychiatrists, social workers, etc. can also assist in supporting patients and families. Patient advocacy organizations such as the International WAGR Syndrome Association (IWSA) can play a key role in helping families adjust to the diagnosis, share their concerns and experiences, and obtain appropriate care. Families should be given contact information for organizations such as the IWSA at time of diagnosis, or soon after.https://wagr.org/Website: reachingout@wagr.org.Email: The primary goals and key considerations for monitoring health in patients with WAGR spectrum are described in We observed higher rates than previously reported of hearing issues within the WAGR Discovery Cohort (~15% affected). Consistent rates of tympanostomy tube placement have been reported between 2005 and the present study , and it As patients with WAGR spectrum are typically affected by compromised vision, preservation of hearing is crucial for quality of life. We suggest careful monitoring of hearing function in patients, with prompt treatment of ear infections and other illnesses that could affect hearing status.It appears that participants are frequently affected by both GU and kidney abnormalities; however genital or urinary tract anomalies were observed to occur without kidney abnormalities and vice versa. As discussed above, it may be more appropriate to define the “G” in WAGR spectrum as “genital or nephro-urological anomalies” to properly characterize the disorder. This reclassification may aid in the initial diagnosis work-up, as GU anomalies are typically less frequent among females compared to male patients. This reclassification additionally highlights the need to include nephrology specialists in addition to urologists and potentially gynecologists within the core care team.Patients may not present with any obvious external genital anomalies; however, our results suggest a number of patients are affected by internal genital anomalies and may benefit from referral to gynecology or specialist for disorders of sexual differentiation in addition to the core referral to urology.The proportion of female patients affected by internal GU anomalies may have been underappreciated in the past, as streak ovaries were reported by ~36% of female participants in our study, and close to 15% were affected by bicornuate uterus. The overall rate of internal GU anomalies reported by females in the WAGR Discovery cohort (34.1%) was double the rate of 17% previously reported in 2005 by Fischbach et al. .Although the GU system includes the kidney, the presence of kidney abnormalities appears to be underrepresented in previous WAGR cohorts, with the focus primarily on genital and urinary tract abnormalities. In 1984, it was reported that renal malformations were rare in patients with WAGR, with four cases affected among 37 literature cases at the time . In moreWT1 and/or PAX6). It has previously been reported that PAX2 is one of the most common mutations found in patients affected by CAKUT  surveillance seems as an appropriate strategy to manage risk in the interim. We discuss considerations for development of a screening program specific to patients with WAGR spectrum in the sections below.All patients with predisposition for Wilms Tumor (WT) development should be referred to cancer predisposition or oncology clinic as these specialists can provide up-to-date information and work with the patient's general pediatrician to manage surveillance. Current recommendations for WT screening in all predisposition syndromes include renal ultrasounds every 3 months from birth or diagnosis until 7 years of age Birth−8 years: High risk (~(multiple patients reported)8 years−15 years: Potential risk (up to 25 years of age reported)>15 years: Possible risk Risk for development of precursors, including nephrogenic rest and nephroblastomatosis, should be considered in addition to risk for WT, and early detection of these precursors may aide in facilitating intervention to prevent full WT progression, as previously reported .The benefit of WT surveillance in the WAGR population was recently highlighted by Hol et al., who reported a significant decrease in tumor volume in patients diagnosed through screening compared to symptomatic individuals which enabled a high rate of nephron-sparing surgery . The redThe primary purpose of screening is to enable earlier detection and reduce treatment burden to improve outcomes, which is essential within the WAGR population due to the association of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in patients. In the study by Hol et al., the decreased tumor volume enabled a high rate of nephron-sparing surgery , which iIn addition to WT and precursor development risk, it also appears that some patients may develop non-malignant growths in their kidney(s). Renal cysts were reported at a rate of 5.6% by the WAGR Discovery Cohort, which have been reported previously , 7. We aDue to the rarity of WAGR spectrum and lack of consistent outcome data regarding length of risk, monitoring past the age of 7–8 years can be considered. The potential for lifelong WT surveillance was previously suggested . More reAlthough the evidence provided by Hol et al. supports the role of tumor screening within the WAGR population, this study also reported an alarming rate (30.8%) of patients with WAGR and WT or nephroblastomatosis who presented with a palpable mass or symptoms (hematuria) rather than diagnosed through screening . In two The guidelines for WT screening programs are to detect tumors in 90–95% of the population at risk, with routine surveillance performed within the age range of this risk , 31. Witsection The WAGR Spectrum Screening Program). As more evidence specific to the WAGR population emerges, specific WT screening recommendations are likely to change; however extended renal ultrasound surveillance will also help monitor the kidneys for other non-malignant issues and detect any signs of kidney damage.At the age of 8 years, a discussion between the patient's family and multidisciplinary care team including at least the geneticist, oncologist, and nephrologist can help determine the appropriate follow-up schedule for WT monitoring. Specialists should consider the patient's previous medical history, as well as current issues that could help inform an appropriate screening interval. Recommendations for screening intervals for patients older than 8 years of age are discussed below in The WAGR Spectrum Screening Program  has been prevalent within this population from early reports but was not widely recognized until the early 2000s when patients presented with severe kidney failure and unfavorable long-term outcomes . More reIn patients affected by WAGR and WT, it was initially estimated that the risk of chronic renal failure ranges from 38 to 53% in patients at 20 years from diagnosis of WT, and that risk is high compared to WT survivors without WAGR . A folloOne previous study evaluated the overall proportion of kidney disease in the overall WAGR population, reporting 60% of patients with WAGR over the age of 12 years had evidence of renal failure and two patients did not have a history of WT  is associated with WAGR spectrum and patients should be considered at risk for its development. Chronic kidney disease (CKD) is defined as “ health” . The Kidfactors” . A varieWT1; and some patients may have additional risk identified early through history of low birth weight and/or detection of abnormal kidney(s) at birth with a diagnosis of CAKUT. As patients age, additional common clinical issues such as recurrent urinary tract infections, history of nephrogenic rest or full WT development, and adverse cardiometabolic profiles can create additional harm to the kidneys, contributing to the progression of CKD within this population.All patients with WAGR Spectrum could be considered to have a predisposition for CKD development at birth due to the 11p13 deletion and affected genes such as Although statistical exploration was outside the scope of the present study, we recently presented evidence at the 53rd Congress of the International Society of Pediatric Oncology (SIOP 2021) evaluating risk for CKD within the WAGR Discovery Cohort population . We founThese results suggest that WT development may contribute to CKD risk, and nephrectomy appears to provide an increased risk for severe CKD manifestations such as renal failure. In patients without history of WT and/or nephrectomy, it is likely the burden of other clinical factors present contribute to the progressive development of CKD disease forms. All patients should be routinely monitored for these clinical issues, with specific follow-up and screening determined by the individual's unique clinical history and current clinical status.To manage CKD risk, we suggest a multi-disciplinary care team approach that consists of at least nephrology and endocrinology to monitor cardiometabolic and renal health. Cardiology may be involved and can be determined by the patient's unique needs. Routine monitoring of kidney function and cardiometabolic health is warranted, and specific monitoring schedules can be determined by the care team. As discussed in the WT section above, one could consider performing routine renal ultrasound (RUS) screening to detect non-tumor kidney abnormalities that may be present. Evidence suggests that kidney failure typically presents during or after adolescence in patients with WAGR  which raPatients with WAGR should be considered at high risk for development of urinary tract infection (UTI) and may be affected by multiple or recurrent infections throughout their lifetime. It does not appear this clinical issue has been described in association with WAGR in previous cohort studies. Approximately 20% of participants in the Discovery Cohort reported ‘recurrent UTIs’ within the kidney/renal category, which provides a concerning observation in relation to preserving kidney health for this population as the risk for renal damage after childhood UTI has been estimated at ~15% . These rThe increased UTI risk presents a challenge to preserving kidney health, as there is risk for permanent kidney damage that can lead to long term consequences such as hypertension and impaired renal function . The fre, the routine performance of RUS could help provide evidence to correlate with other clinical values such as urine and serum screening for CKD, or additional imaging studies if WT and/or NR is suspected.Infants and young children have been shown to present with non-specific signs and symptoms of UTI, while after ~5 years of age the “classic urinary tract symptoms” are usually present . FurtherA variety of structural or other imaging abnormalities detectable by RUS that suggest potential CKD risk or etiology have been established , 43, andThere are a variety of underlying congenital anomalies and clinical issues that commonly affect patients with WAGR that likely contribute to the multifactorial progression of unfavorable kidney health and outcomes previously associated with the disorder . While sWe propose the initial recommendations that will comprise “The WAGR Spectrum Screening Program.” The goal of this program is to promote optimum health within the WAGR spectrum population to improve overall health status and long-term patient outcomes. We anticipate the specific recommendations that comprise this program will likely evolve over time as the WAGR spectrum population is better characterized, however we provide the initial framework and propose revisions to the duration of renal ultrasound (RUS) screening for all patients with a diagnosis of WAGR spectrum disorder. This program has been endorsed by representatives of the International WAGR Syndrome Association (IWSA).Lifelong kidney surveillance is warranted in the WAGR Spectrum patient population. The composite observations collected from the WAGR Discovery cohort and previous literature evidence suggest that patients with WAGR can be considered to have congenital kidney abnormalities and/or other adverse health profiles that can establish risk for kidney damage warranting routine lifelong imaging to assess kidney health. As discussed above, RUS has been shown to provide benefits for diagnostic work-up of common issues in the WAGR population that include CAKUT, CKD, UTI, and/or WT; aspects related to screening programs designed for these issues were taken into consideration when developing the suggested intervals for RUS screening in the WAGR population.The following intervals to perform RUS could be considered until additional evidence is available:3-month interval: required until age 8 years for WT screening (minimum frequency).◦ Consider more frequent interval if the patient has CAKUT, UTIs, or WT recently diagnosed 6-month interval: consider between ages 8 and 18 years ◦ Consider moving to 3-month intervals to monitor clinical status if abnormalities present or are detected by imaging.Annual: required in patients >18 years for CKD screening .◦ Consider moving to 3- or 6-month intervals to monitor clinical status if abnormalities present or are detected by imaging.Care teams are encouraged to consider the aspects of this program in the context of each individual patient with WAGR spectrum to determine the best care approach. The preference of the patient and/or family should also be taken into consideration when developing the screening interval for each individual with WAGR, as recommended by KDIGO for CKD screening programs  and the Patients experience risk for other organ and internal GU anomalies that may not be initially detected during infancy or early childhood. At time of the scheduled RUS follow-up, additional ultrasonography (U/S) imaging of the abdomen or pelvis could be considered to enhance the surveillance process for clinical issues beyond the kidneys. Full abdominal U/S (rather than targeted RUS) could be performed in patients with clinical issues that warrant internal imaging to aide in the diagnostic work-up or to monitor the effectiveness of current treatment approaches. A pelvic U/S could also be performed to assess for internal GU anomalies that may present as patients enter puberty and adulthood.We recommend performing these additional ultrasonography studies in conjunction with the RUS to allow for “same-time” data collection on the internal status of patients and to reduce the burden of medical visits and imaging on patients/families.The initiation, frequency, and cessation of CKD screening should be individualized based on kidney and cardiovascular risk profiles and individual preferences” , we suggest that there is a potential for WT development after age 8 years, with the possibility of lifetime WT risk for patients with WAGR spectrum. This stratification may lead to parental worry; however, it was designed to increase awareness of the necessity for routine surveillance in this population beyond the first 8 years of life. We anticipate the increased duration of surveillance will likely contribute a psychosocial benefit to parents in the WAGR community, as parents in other cancer predisposition populations have reported decreased worry and overall benefit provided by tumor screening programs  with WAGR affected by seizures; Dahan et al. reported one patient among seven (14.3%) with epilepsy; and Fischbach et al. reported epilepsy was present in four of 54 patients (7.4%) within their cohort . Taken tSLC1A2 and ELP4 genes have been suggested . Many of these issues were previously reported by Fischbach et al. , with a As a result of these observations, it is suggested that patients with breathing concerns and/or frequent infections/pneumonia receive referral to a pulmonologist or other respiratory specialist to determine the presence of underlying causes. Referrals can also be considered for patients affected by feeding issues, dysphagia, and/or GERD without response to standard treatments to determine whether an underlying airway issue is the cause for the GI issues. A sleep study should also be considered for patients with abnormal sleeping habits or breathing concerns.WT1 gene deletion may represent the mechanistic cause for the lung issues observed. Animal models have shown that Wt1 is rapidly downregulated in mesothelial-derived cells, which contribute to pulmonary mesodermal tissues that include vascular and bronchial smooth muscle and tracheal cartilage  was reported by 30% of participants in the present study. Although it is likely that OSA alone is not responsible for sleep issues that can affect patients, the presence of OSA can contribute to abnormal sleep. As a result, in all patients with WAGR spectrum affected by sleep issues, a referral to pulmonology or a sleep medicine specialist is recommended to help determine the need for a sleep study to detect OSA and determine the best individual treatment approach.The gastrointestinal (GI) system appears commonly affected in patients with WAGR with 76.3% of participants reporting at least one issue within the GI system category of the questionnaire. Fischbach et al. previously reported an association between GERD and WAGR , howeverFeeding issues were reported by 48.1% of participants and dysphagia was also reported by 16.2% of the Discovery Cohort suggesting that patients may experience problems related to food intake. Gastroenterologists and feeding specialists are required to identify the underlying reason for the GI problems that present in patients and determine the appropriate management strategy. It is possible that mismanagement of nutrition intake may contribute to development of obesity and the biometry of patients receiving Supplementary feeding should be carefully monitored to detect differences in growth chart trends indicative of increasing weight and/or BMI percentiles.Proper nutrient intake is required to help patients maintain a healthy cardiometabolic profile and the combination of gastroenterologists, feeding specialists, and a weight management team can help assist in determining a patient's unique nutritional needs to support their health.PAX6 gene appears to play an important role in pancreas development , anorectal malformation (n = 1), and colon polyps (n = 1).Pancreatitis was reported by 7.2% of the WAGR Discovery Cohort, with five participants affected (unknown whether acute or chronic). Previously, chronic pancreatitis was found in three of 54 patients (5.6%) with WAGR . The PAXelopment  thereforc issues . In the Further evidence is needed to establish risk—care teams should be aware of the possibility of these issues developing in patients with WAGR until further information is available. Performing an abdominal ultrasound instead of renal ultrasound could help provide surveillance and detection in patients who have clinical issues that may suggest an underlying GI abnormality is present.Patients with WAGR spectrum will likely undergo surgical procedures as a result of their disorder. Prior to anesthetic procedures, patients should receive a thorough evaluation, as a number of clinical issues can complicate management. In patients with these issues, procedures should be performed at a specialized center in order to properly manage patient care.In a previous case series, two of three patients with tracheomalacia experienced respiratory distress after general anesthesia and it was suggested that anesthesiologists caring for patients affected by WAGR should be alerted to this possibility . In the Acute pancreatitis after administration of propofol has been reported in two patients with WAGR and hypertriglyceridemia , 70. AltThe results of this study can be considered preliminary evidence, as all information collected was self-reported and medical records were not evaluated to confirm the health issues reported, representing a limitation in our results. Another limitation is selection bias, as participants more affected by health issues may be more likely to complete the questionnaire than those with less health issues. A recent cancer registry-based study commented that involving parents of patients can provide a more complete picture of the “phenotypic spectrum of WAGR syndrome” , which pDemographic information regarding diversity groups and geographic regions represented in WAGR cohorts have been rarely reported in the literature . In the It is unclear whether there is a racial or ethnic predominance associated with WAGR Spectrum. In other rare disease syndrome/spectrum disorders, subtle differences in the phenotypic presentation and clinical features between patients of diverse populations have been described, including another cancer predisposition disorder caused by chromosome 11p15 abnormalities . The potIn the present study we compiled self-reported health information from 91 individuals affected by WAGR syndrome to create the WAGR Discovery Cohort, which represents the largest cohort evaluated to date. Our results build upon previous findings in the WAGR patient population and suggest that a spectrum of clinical features and health issues can affect patients, prompting reclassification of this genetic disorder from WAGR syndrome to WAGR spectrum. A multi-disciplinary care team model is needed to address the variety of common health issues in this population. Considerations common to all patients include the need for routine surveillance to manage cardiometabolic health and monitor for chronic kidney disease and Wilms tumor (WT) development.https://research.sanfordhealth.org/rare-disease-registry/researchers.The data that support the findings of this study are available from Coordination of Rare Diseases at Sanford (CoRDS). Restrictions apply to the availability of these data, which were used under agreement for this study. Requests to access the datasets should be directed to Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.JG, JM, KT, and SK contributed to the initial conception and design of the WAGR Syndrome Registry. JK and KD contributed to the conception and design of the study. KD organized the study database, performed the data analysis, and wrote the first draft of the manuscript. JK and KT wrote sections of the manuscript. All authors contributed to interpretation of results, manuscript revision, read, and approved the submitted version.This study was funded by Alex's Lemonade Stand Foundation and Miranda's Mission. The Coordination of Rare Diseases at Sanford (CoRDS) is a rare disease registry wholly funded by Sanford Health, a hospital system headquartered in South Dakota.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.