{"paper_id":"66351110-63a0-4b5c-8c1c-db0a38eea50a","body_text":"Mullerian anomalies are a rare group of anatomical malformations of the female\ngenital tract. They occur due to alterations during the development and fusion of\nthe Müllerian ducts (or paramesonephric ducts), which normally develop into\nthe uterus, uterine cervix and the two upper thirds of the vagina. Mullerian\nanomalies are commonly followed by alterations in the development of the Wolff ducts\n(mesonephric), which later originate the kidneys, justifying the frequent\nassociation between Mullerian malformations and urinary tract disorders ( Kudela  et al ., 2021 ).\nThe Herlyn-Werner-Wunderlich Syndrome (HWWS) is a rare congenital malformation of the\nfemale urogenital tract composed of the triad: uterus didelphys, obstructed\nhemivagina and renal agenesis. Its incidence ranges from 0.1-3.8% in the female\npopulation ( Kudela  et al .,\n2021 ). In 2007, the term OHVIRA was created -  obstructed\nhemivagina and renal agenesis  - to describe Mullerian malformations\nthat presented with obstructive uterovaginal syndrome and renal agenesis. The HWWS\nrepresents about 77% of OHVIRA cases ( Gutiérrez-Montufar  et al ., 2021 ).\nThis is the case report of a pubertal patient admitted to the Gynecology Service of\nthe Clementino Fraga Filho University Hospital (HUCFF/UFRJ) in March 2021 with\nsymptoms of abdominal pain beginning right after menarche, associated with a\nprogressive abdominal distension. In her early childhood she was diagnosed with a\nsolitary right kidney, properly located. She was diagnosed with the\nHerlyn-Werner-Wunderlich syndrome and was submitted to a left hemi-hysterectomy with\nipsilateral salpingectomy in June 2022, evolving with complete remission of\nsymptoms.\nOur main goal is to reinforce the importance of acknowledging Mullerian malformations\nin order to maintain an appropriately high index of suspicion, enabling early\ndiagnosis and adequate treatment. Therefore, we are able to improve our patient’s\nquality of life and reduce the frequency and severity of complications such as\ninfertility.\n\nThis is the case of a 12-year-old patient, brown skinned, born in Rio de Janeiro,\nBrazil, attending middle school, without previous sexual activity, with a history of\nmoderate to intense dysmenorrhea, which started right after menarche, refractory to\ncommon analgesics, associated with progressive increase in abdominal volume. In\nMarch 2021, she underwent an abdominal pelvic ultrasonography, which revealed a\nlarge complex image, possibly originating from the left ovary. For this reason, she\nwas referred to a quaternary care unit and then admitted to our Clinic at the\nHUCFF/UFRJ.\nThe patient had a previous diagnosis of congenital - and anatomically positioned -\nsolitary right kidney, found in a scintigraphy performed at one year of age\n(March/2010). There were no other relevant morbid or family/social antecedents. She\nhad thelarche and pubarche at age nine, followed by menarche at eleven. Her five\nfirst menstrual cycles were regular, with normal duration and flow and after that,\nprogressive dysmenorrhea ensued.\nThe physical examination revealed adequate Tanner stage (M3P3) and a palpable mass\noccupying the hypogastrium and left iliac fossa, measuring approximately 10 cm,\nmobile and painful. Vulvar inspection and speculum exam were normal. Gynecologic\nbimanual (two-handed) palpation of the uterine corpus found a mass bulging the\ncul-de-sac on the left side and collapsing the vagina.\nA new pelvic US performed at our institution again in March 2021 showed an elongated\nimage with heterogeneous content with debris (10.7x7.6x6.5cm), compatible with blood\ncontent, located in the left iliac fossa, laterally adjacent with the right uterine\nhorn. The possibility of left uterine horn with hematometra was considered and the\nhypothesis of congenital anomaly of the genital tract with consequent obstructive\nuterovaginal syndrome was raised. We decided to proceed the investigation with a\npelvic MRI for diagnostic confirmation and elaboration of a therapeutic approach. In\nparallel, medroxyprogesterone acetate 150 mg (injectable suspension) was started in\norder to control signs and symptoms. The patient was well adapted to the method and\nevolved with secondary amenorrhea. However, she occasionally had episodes of\nworsening pain, seeking emergency medical care for parenteral analgesia.\nA pelvic MRI was performed in May 2021, demonstrating uterine duplicity with\nsignificant hematometra and hematocolpos on the left side ( Figure 1A , 1B, 1C) left renal agenesis, ligament and peritoneal\nendometriosis. However, the method alone could not evaluate the presence of a\nvaginal septum. Therefore, in order to better elucidate the anatomical variation, a\ndiagnostic video-hysteroscopy was performed in August 2021, finding a patent right\nuterine cervix with a small right uterine cavity. Left uterine cervix and vaginal\nseptum were not visualized. At that moment, we concluded she had a single right\npatent vagina, presumed cervix-vaginal atresia on the left side, two hemi-uterus\nwithout communication between them, leading to hematocolpos and hematometra, in\naddition to a previously known left renal agenesis. In view of these findings, the\ndiagnosis of a variant of the Herlyn-Werner-Wunderlich syndrome (HWWH) was\nestablished.\nFigure 1 A. Axial T2-weighted MRI image shows a uterus didelphys with two separate\nuterine cavities (arrows). The left uterine cavity is distended by blood\nproducts due to presumed cervix-vaginal atresia on the left side. B.\nSagittal T2-weighted MRI image shows the left uterine cavity distended\nby blood products. C. Axial T2-weighted MRI image shows a uterus\ndidelphys with two separate uterine cavities (arrows).\nA. Axial T2-weighted MRI image shows a uterus didelphys with two separate\nuterine cavities (arrows). The left uterine cavity is distended by blood\nproducts due to presumed cervix-vaginal atresia on the left side. B.\nSagittal T2-weighted MRI image shows the left uterine cavity distended\nby blood products. C. Axial T2-weighted MRI image shows a uterus\ndidelphys with two separate uterine cavities (arrows).\nConsidering the MRI and hysteroscopic findings, a surgical approach was planned,\ninitially via vaginoscopy, with the aim to drain the left hematocolpos and\nhematometra. If vaginal access was not feasible, a laparotomy approach was suggested\nat the same surgical time for left hemi hysterectomy. The surgical plan was\npresented to the patient and her guardians, who understood and approved it, signing\nan informed consent form.\nThe patient underwent surgery in July 2022. After an unsuccessful attempt at\nvaginoscopy under sedation, laparotomy was performed with left hemi hysterotomy\nfollowed by drainage of hematometra and hematocolpos ( Figure 2 ). Posteriorly, we completed the procedure with a hemi\nhysterectomy and salpingectomy. The anatomopathological analysis revealed a left\nhemi-uterus with extensive stromal decidualization, an atretic left cervix without\nan ectocervical component and a left uterine tube with hematosalpinx. The\npostoperative period followed without complications and the patient was discharged\nwithin 48 hours. She evolved with complete remission of symptoms and is currently\nundergoing clinical follow-up at our Gynecology clinic.\nFigure 2 Drainage of voluminous content of blood from previous hematometra and\nhematocolpos before left hemi - hysterectomy.\nDrainage of voluminous content of blood from previous hematometra and\nhematocolpos before left hemi - hysterectomy.\n\nThe Herlyn-Werner-Wunderlich syndrome (HWWS) is a rare mullerian anomaly,\ncharacterized by the triad: uterus didelphys, obstructed hemivagina and ipsilateral\nrenal agenesis. It was first described in 1922 ( Gutiérrez-Montufar  et al ., 2021 ;  Jomaa  et al ., 2021 ;  Vo Nhu  et al. , 2021 ), but it\nwas only named after publications by Herlyn and Werner in 1971 and Wunderlich in\n1976 ( Gutiérrez-Montufar  et\nal ., 2021 ). In 2007, a new term was suggested to describe\nthe association between obstructive uterovaginal syndrome and renal abnormalities,\nthe OHVIRA syndrome (obstructed hemivagina and renal agenesis), which allows the\ninclusion of its multiple and heterogeneous clinical presentations ( Gutiérrez-Montufar  et al .,\n2021 ;  Vo Nhu  et al .,\n2021 ). In view of the large spectrum of anatomical variations and their\nsubclassifications, in 2021 a new and more descriptive classification was proposed\nby the American Society for Reproductive Medicine (ASRM), which aimed to facilitate\nthe diagnosis and clinical-surgical decision ( Pfeifer\n et al ., 2021 ).\nSeveral combinations of these malformations are currently described and since the\n80’s there have been various attempts to categorize them ( Tuna  et al ., 2019 ). However, to date, none of\nthe proposed classifications has been sufficient to fully describe all the possible\nexisting variations ( Pfeifer  et al .,\n2021 ). This reflects the great difficulty in diagnosing and managing\npatients with these anomalies, which justifies the recurrent delay in diagnosis and\nfrequent complications, such as endometriosis and infertility.\nThe HWWS corresponds to 77% OHVIRA syndrome cases ( Gutiérrez-Montufar  et al ., 2021 ) and its\nincidence varies around 0.1-3.8% in the female population (Kudela e t\nal. , 2021;  Vo Nhu  et\nal ., 2021 ;  Girardi Fachin\n et al ., 2019 ). The advance of imaging methods\nfacilitated the diagnosis of congenital Mullerian anomalies, including the HWWS\n( Gutiérrez-Montufar  et\nal ., 2021 ;  Kudela  et\nal ., 2021 ).\nThe coexisting disorders of the urinary and reproductive systems in a female patient\nsuggests a simultaneous alteration in the embryonic development of the Wolff\n(mesonephric) and Müller (paramesonephric) ducts ( Vázquez Gómez  et al ., 2021 ;\n Vo Nhu  et al ., 2021 ). In\nfemales, the mesonephric ducts regress while the paramesonephric ducts fuse at their\ndistal end to yield the uterus, cervix, and upper two-thirds of the vagina; and\npersist uncombined near its proximal part to generate the fallopian tubes ( Jomaa  et al ., 2021 ;  Sharma  et al. , 2016 ). The\nembryologic formation of the reproductive and urinary tract systems occur\nsimultaneously and while the kidneys originate from the wolffian ducts the lower\nthird of the vagina derives from the urogenital sinus ( Vo Nhu  et al. , 2021 ). It is important to note\nthat the ovaries and fallopian tubes are not affected in these conditions, since\nthey go through a distinct developmental process ( Jomaa  et al ., 2021 ).\nThe main cause of congenital Müllerian or paramesonephric duct anomalies is\ndefective fusion (vertical or horizontal) or septal resorption failure ( Vo Nhu  et al ., 2021 ). If the\nmullerian ducts do not fuse, the uterine horns, cervix, and endometrial cavities\nappear separately ( Jomaa  et al .,\n2021 ;  Sharma  et al. ,\n2016 ). On the other hand, unilateral renal agenesis comes from an\nabnormality of the mesonephric ducts ( Gutiérrez-Montufar  et al ., 2021 ). Therefore, in\nthe face of female patients presenting with urinary system malformations, it is\nmandatory to investigate associations with genital tract anomalies, and vice versa\n( Kudela  et al .,\n2021 ).\nRegarding the heterogeneities in its clinical presentation, variations in urinary\ndisorders stand out, renal agenesis being the most common, although there are\nreports of multicystic kidney, dysplastic kidney, horseshoe kidney, pelvic kidney\nand ectopic ureters ( Kudela  et al. ,\n2021 ;  Jomaa  et al. ,\n2021 ). On the other hand, among the uterine variations, most patients\npresent with a didelphys uterus, but bicornuate, septate or single uterus have also\nbeen reported ( Kudela  et al. ,\n2021 ). The right side is usually the most affected.\nThe multiple anatomical presentations justify the great variability of reported\nsymptoms, along with their frequency and intensity, modifying the amount of time\nrequired to establish a final diagnosis and the ideal surgical approach for each\ncase. The main related variation is the type of vaginal obstruction, which can be\ncomplete or incomplete ( Vo Nhu  et\nal ., 2021 ;  Zhu  et\nal ., 2015 ). Thus, Lan Zu  et al.  (2015)\nproposed a subclassification of HWWS into type 1 and type 2, according to the type\nof obstruction ( Zhu  et al .,\n2015 ).\nIn type 1, there is a hemivagina with complete obstruction, which is subdivided into\nblind hemivagina or cervicovaginal atresia. In the case of blind hemivagina, the\nvaginal septum results in a complete obstruction, so that there is no communication\nbetween the two hemi uteri or between the vaginas. Therefore, the obstructed side\ndevelops hematocolpos, which may evolve with hematometra and hematosalpinx. In these\ncases, the age of onset of symptoms is earlier with a short time from menarche\n( Girardi Fachin  et al .,\n2019 ;  Zhu  et al .,\n2015 ;  Nishu  et al .,\n2019 ).\nEndometriosis is the most frequent complication ( Girardi Fachin  et al ., 2019 ;  Zhu  et al ., 2015 ), but pyocolpos, pyosalpinx\nand pelvic adhesions are also associated ( Zhu\n et al. , 2015 ). In the subtype that courses with\ncervicovaginal atresia, without communication with the uteri, there are rudimentary\nuterine cervix and hemivagina, which therefore also maintains complete obstruction,\ncoursing with a similar clinical presentation and the later complications described\nabove.\nType 2, characterized by a hemivagina with incomplete obstruction, on the other hand,\nis subdivided into partial reabsorption of the vaginal septum and the presence of\nuterine communication. In cases where there is partial reabsorption of the septum,\nthere is communication between the two vaginas, so that, despite the uteri being\nisolated from each other, a drainage orifice is created. These patients have a later\nage of onset. The attack often comes years after menarche and the symptoms are more\ntolerable. However, the presence of this communication favors the occurrence of\npurulent or bloody vaginal discharge and ascending genital system infections. In\ncases where there is uterine communication, menstruation flows from one hemiuterus\nto the contralateral one, even in the presence of obstructed hemivagina, reducing\nthe accumulation of menstrual flow and delaying both the age of diagnosis and the\ncomplications associated with the syndrome ( Girardi\nFachin  et al ., 2019 ).\nThe 2021 ASRM classification is based on nine major findings: mullerian agenesis;\ncervical agenesis; unicornuate uterus; uterus didelphys; bicornuate uterus; septate\nuterus; longitudinal vaginal septum; transverse vaginal septum and complex\nanomalies. These findings may undergo variations and are often related to each\nother, composing the various existing anomalies. In addition to these, there are\nalso several anomalies in the urinary tract ( Pfeifer\n et al. , 2021 ).\nConsidering all the possible anatomical variations, it is understandable that most\npatients remain asymptomatic until puberty ( Nishu\n et al ., 2019 ). Commonly, after menarche, pelvic\npain, dysmenorrhea and menstrual alterations appear, worsening at each menstrual\ncycle, associated with an increase in abdominal volume and a palpable abdominal mass\n( Gutiérrez-Montufar  et\nal ., 2021 ;  Jomaa  et\nal. , 2021 ;  Vo Nhu  et\nal ., 2021 ;  Nishu  et\nal ., 2019 ). It is common to seek emergency services in the\ncontext of pain exacerbation, simulating acute abdominal conditions. Most of the\ndiagnoses are made during this period, already in adolescence ( Vázquez Gómez  et al ., 2021 ;\n Vo Nhu  et al ., 2021 ;\n Girardi Fachin  et al .,\n2019 ). Other symptoms reported were dysuria and a prolapsed mass via the\nvagina. Urinary retention is a rare form of presentation ( Gutiérrez-Montufar  et al ., 2021 ).\nIn pre-pubertal patients, the main finding is a palpable abdominal mass ( Gutiérrez-Montufar  et al. ,\n2021 ;  Sharma  et al. ,\n2016 ). Although uncommon, this malformation can be diagnosed in the\nneonatal period before any clinical manifestation, usually after a prenatal US\ndiagnosis of renal agenesis. Hydrocolpos can also be detected in the neonatal period\nor even in the prenatal period, being reported as early as the 25 th  week\nof pregnancy. The most common finding in the neonatal period is a soft vulvar mass.\nHowever, perineal examination is difficult at this age, making the differential\ndiagnosis with imperforate hymen a challenge ( Tuna\n et al ., 2019 ).\nThere are few cases of patients diagnosed in the adult stage ( Kudela  et al ., 2021 ), with symptoms such as\ndysmenorrhea and chronic pelvic pain having been reported ( Gutiérrez-Montufar  et al ., 2021 ;  Jomaa  et al ., 2021 ).\nEndometriosis was identified in approximately 10.3% ( Gutiérrez-Montufar  et al ., 2021 ) to 13.6% ( Kudela  et al ., 2021 ) of the\ncases, being the theory of “retrograde menstruation” the pathophysiological basis\n( Jomaa  et al ., 2021 ).\nVaginal discharge, pyocolpus, dyspareunia, and infertility have also been described\n( Gutiérrez-Montufar  et\nal ., 2021 ;  Kudela  et\nal ., 2021 ;  Jomaa  et\nal. , 2021 ). Abnormal uterine bleeding is less frequent, but\nhas also been reported, mainly in cases of partial vaginal septum. There are also\nreports of diagnosis performed during pregnancy, after bleeding in the first\ntrimester ( Gutiérrez-Montufar  et\nal. , 2021 ).\nDelay in the diagnosis of HWWS is common due to factors such as the assistant\nphysicians’ lack of knowledge, the presence of a regular menstrual cycle due to an\nunobstructed type of malformation and improvement of symptoms with prescription of\ncommon analgesics, NSAIDs and hormonal contraceptives ( Jomaa  et al ., 2021 ;  Girardi Fachin  et al ., 2019 ). Chronic pelvic\npain syndrome, endometriosis, infertility and habitual spontaneous abortion are\nfrequent complications and the severity of these complications is directly related\nto this delay ( Girardi Fachin  et\nal ., 2019 ;  Nishu  et\nal ., 2019 ).\nHWWS diagnosis is made by imaging tests, the most frequently used are pelvic US and\nMRI ( Gutiérrez-Montufar  et\nal ., 2021 ;  Kudela  et\nal ., 2021 ). The gold standard, however, is direct\nvisualization via laparoscopy, being reserved for selected cases, where there is\nsurgical indication, as it is an invasive method ( Gutiérrez-Montufar  et al. , 2021 ). Other\ncomplementary tests such as hysteroscopy may be indicated, but they are not\nessential and are often insufficient for the diagnosis.\nAbdominopelvic US is a good initial choice due to its greater accessibility, lower\ncost and lack of associated adverse effects ( Vo Nhu\n et al ., 2021 ;  Sharma\n et al ., 2016 ). This method may be enough to\nestablish the diagnosis and determine treatment onset ( Jomaa  et al. , 2021 ). It can identify uterine\nanomalies, such as uterus didelphys and urinary alterations, such as renal agenesis.\nThere may also be hematocolpos, hematometra or hydrosalpinx. However, it is not an\nadequate method for evaluating the vagina and vaginal septum ( Gutiérrez-Montufar  et al ., 2021 ;  Kudela  et al ., 2021 ;  Jomaa  et al ., 2021 ;  Vo Nhu  et al ., 2021 ).\nMRI is more expensive and less accessible, but it is more accurate in diagnosing\nuterine malformations ( Gutiérrez-Montufar\n et al. , 2021 ;  Kudela\n et al ., 2021 ;  Girardi\nFachin  et al. , 2019 ). This method is adequate for cases\nin which the US was not sufficient to assess the vaginal septum and to better\nevaluate the malformation itself. It also enables the assessment of associated\ncomplications, such as endometriosis and pelvic adhesions ( Vo Nhu  et al ., 2021 ;  Girardi Fachin  et al. , 2019 ;  Nishu  et al ., 2019 ). It is\nespecially recommended if surgical treatment is indicated ( Kudela  et al ., 2021 ;  Jomaa  et al ., 2021 ). Computed tomography (CT)\ncan be an alternative exam; however, it is less accurate for the evaluation of\npelvic structures, in addition to exposing the patient to ionizing radiation and,\ntherefore, it should be used only in exceptional cases, when MRI is not available\n( Girardi Fachin  et al. ,\n2019 ).\nThe definitive treatment for the syndrome is surgical, seeking not only to relieve\nsymptoms, but also to improve reproductive outcomes and reduce long-term\ncomplications ( Jomaa  et al .,\n2021 ;  Girardi Fachin  et\nal ., 2019 ). Timing of surgery is still controversial in the\nliterature. Some authors advocate conservative management until puberty, while\nothers suggest that, upon diagnosis, surgery should be promptly indicated.\nTherefore, safe conservative clinical management until puberty is acceptable.\nPossible hydrocolpos that present after birth usually resolve spontaneously in the\nfirst months of life, when circulating maternal estrogen levels decline. If there\nare recurrent urinary tract infections or urinary incontinence in childhood, or even\nlarge vaginal masses, drainage procedures or early vaginal septectomy may be\nindicated ( Kudela  et al. ,\n2021 ). The surgical approach depends on the type of anatomical variation.\nIn general, the access can be via vaginoscopy or laparoscopy/laparotomy, with\nsatisfactory results in both cases ( Jomaa  et\nal. , 2021 ).\nIn cases where there is a vaginal septum, it can be resected via vaginoscopy with\ndrainage of the hematocolpos ( Kudela  et\nal ., 2021 ;  Jomaa  et\nal ., 2021 ;  Vo Nhu  et\nal. , 2021 ) and preservation of the hemiuterus ( Girardi Fachin  et al. , 2019 ),\nbeing sufficient as treatment in 86.5% of cases ( Kudela  et al ., 2021 ). There is no need to suture the\nvaginal wall after resection of the septum, and it may heal by second intention\n( Kudela  et al. ,\n2021 ).\nOn the other hand, in the presence of HWWS associated with cervicovaginal atresia, a\nmore complex approach is necessary, since vaginal access may not be possible,\nrequiring a hemihysterectomy. Ipsilateral salpingo-oophorectomy is a possibility\n( Kudela  et al. , 2021 ; Vo\nNhu et  al. , 2021). The preferred approach is laparoscopic, as it is\nless invasive, but laparotomy can be used if laparoscopy is not available, with\nacceptable results ( Jomaa  et al., \n2021 ;  Sharma  et al., \n2016 ).\nOne of the main concerns of patients and their families is future fertility. Based on\nthe analyzed studies, the obstetric results after resection of the vaginal septum,\nwere satisfactory in most cases ( Kudela  et\nal. , 2021 ). However, these pregnancies are conditioned to\nmore frequent complications, such as spontaneous abortions, ectopic pregnancy,\npreterm delivery and cesarean delivery ( Kudela\n et al. , 2021 ;  Jomaa\n et al. , 2021 ).\nThe work of Lan Zu et al. of 2015 found that the percentage of patients wishing to\nconceive who had at least one pregnancy was around 64-95% ( Zhu  et al. , 2015 ); and of these, most\npregnancies occurred on the side, contralateral to the surgical approach ( Kudela  et al. , 2021 ). However,\nit is possible that it occurs on the affected side in about 52.9% of the cases,\nafter resection of the vaginal septum ( Salastekar\n et al. , 2019 ).  Girardi Fachin et al. (2019)  retrospectively analyzed 36 patients with\nHWWS for a period of 30 years and concluded that, after treatment, 87% of the\npatients with a desire to become pregnant had a successful pregnancy, with a total\nrate of 77% live births (15% premature, 62% at term).\nRegarding endometriosis and chronic pelvic pain, surgical treatment with\ncytoreductive laparoscopic surgery was recently considered, without significant\nobstetric outcomes, considering the complications inherent to the procedure\n(adhesions, fibrosis and tubal obstruction). It was therefore concluded that\nlaparoscopy should only be performed in patients, refractory to medical treatment\nand with evidence of deep/invasive disease ( Kudela\n et al. , 2021 ).\n\nThe Herlyn-Werner-Wunderlich syndrome should be known by clinicians who are involved\nwith child and youth health care in order to improve these patients’ quality of\nlife. The diagnosis is clinical and radiological, and should be confirmed as early\nas possible in order to reduce further complications. Future fertility is one of the\nmain concerns, which can be successfully preserved, even though obstetric\ncomplications occur more often. The definitive treatment is surgical, although the\nbest timing is still under debate. The approach must be individualized according to\nthe anatomical variation presented by the patient. A multidisciplinary approach\ninvolving clinicians, surgeons and radiologists is essential to achieve the best\noutcomes.","source_license":"CC0","license_restricted":false}