Mayer-Rokitansky-Küster-Hauser Syndrome Research Articles

Sexuality in women with Mayer-Rokitansky-Küster-Hauser syndrome

Evaluation of the quality of sexual life of women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) after neovagina creation using dilation and surgical techniques. Literature search of articles published in the years 2000–2021 using the databases Web of Science, Google Scholar and PubMed by key words: Mayer-Rokitansky-Küster-Hauser syndrome, neovagina, female sexuality and Female Sexual Function Index. We used a standardized international Female Sexual Function Index and other quantitative and qualitative parameters of sexual satisfaction to assess sexual function and overall satisfaction in women with neovagina. It is possible to develop functional neovagina in women with MRKHS by either conservative or surgical techniques. The choice of the method used depends on the experience and skill of the surgeon, on the technical possibilities and equipment of the department, and on the anatomical predispositions and preferences of the patient. Satisfaction with sexual life also depends on the psychosexual maturity and sexual demands of both partners as well as on regular vaginal rehabilitation and quality of long-term psychological support. The functional results of dilation and surgical methods are comparable according to objective criteria. They only differ in individual aspects which correspond to the overall personality traits as well as to the character and quality of cohabitation. Women with MRKHS are primarily handicapped by coital insufficiency and inability to reproduce naturally. Creating a neovagina technically allows them to realize satisfactory coitus, but in most cases, they are still frustrated by the primary problem of „physical indisposition“ and complicated path to motherhood.

Successful trachelectomy and re‐vaginoplasty for cervico‐vaginal stenosis following unsuccessful uterovaginal anastomosis and vaginoplasty in congenital cervical and vaginal aplasia: description of technique and a case report

We describe a successful surgical technique of abdominal trachelectomy and re-vaginoplasty for cervico-vaginal stenosis following unsuccessful uterovaginal anastomosis and vaginoplasty in a patient with congenital cervical and vaginal aplasia. After the surgical procedure, cervico-vaginal stenosis was resolved and periodic menstruation without dysmenorrhoea resumed. While long-term follow-up is essential to ensure successful pregnancy and delivery, we conclude that this novel surgical procedure is a promising alternative for improvement of the quality of life and normal sexual function, and for preservation of fertility in patients with cervical and vaginal aplasia.

MO029CLINICAL CHARACTERISTICS AND PATHOGENIC GENES OF CONGENITAL SOLITARY KIDNEY WITH REPRODUCTIVE SYSTEM MALFORMATION*

Abstract Background and Aims Congenital solitary kidney – one category of congenital anomalies of the kidney and urinary tract (CAKUT) may combine with other system malformations such as reproductive, cardiac, skeletal system, and so on. Our study analysed the clinical characteristics among congenital solitary kidney patients and their reproductive system malformations. And further work about probable pathogenic genes was explored. Method The information of CAKUT patients who were indicated by Doppler ultrasound was collected. The clinical and imaging features including reproductive system abnormalities were retrospectively reviewed in patients with congenital solitary kidney. In patients with Mayer-Rokitansky- Küster-Hauser (MRKH) syndrome, a disorder of congenital agenesis of uterus and vagina, whole exome sequencing was performed. Rare variants in CAKUT-related genes were analysed. Trio analysis was conducted to identify de novo mutations. Results We identified 209 patients with congenital solitary kidney from July 20, 2017 to July 19, 2020 among 1160 CAKUT patients in Peking Union Medical College Hospital. There were 152 females. The average age of congenital solitary kidney patients was 35.26±18.42 years when they were diagnosed. 53.2% showed different degrees of proteinuria and hematuria. Serum creatinine elevating was proved 13.1% and 40% in women and men separately. Among 81 females who also had a gynecological ultrasound report, 88.9% combined with genital malformation, oblique vaginal septum syndrome 48.7%, the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome 22.2%, malformed uterus 23.5%, vaginal atresia and other genital malformation 7%. Congenital heart disease, complete transposition of viscera, and scoliosis were also found in some patients with congenital solitary kidney. Furthermore, based on the whole exome data of 443 patients with MRKH syndrome, seven function-lost mutations were confirmed. And also two De nove mutations (NOTCH2 (NM_024408.3: c.703A>T(p.Thr235Ser), ESRRG (NM_001243512.1:c.-169-8delT)), one homozygous patients with parents heterozygous (NM_133433.3:c.8084C>T(p.Thr2695Me) were identified as possible pathogenic genes caused CAKUT. Conclusion We should be aware of reproductive system malformations in CAKUT patients. Whole exome sequencing may suggest common pathogenic genes between the two kinds of diseases.

Altered Expression of Candidate Genes in Mayer-Rokitansky-Küster-Hauser Syndrome May Influence Vaginal Keratinocytes Biology: A Focus on Protein Kinase X.

Simple SummaryWomen affected by Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome show an underdeveloped or absent vagina and uterus, frequently in association with renal defects. The aetiology of MRKH syndrome is controversial. Only a few cases could be related to genetic anomalies, while the vast majority of them lack a precise molecular cause. We found that protein kinase X (PRKX) levels are upregulated in vaginal keratinocytes from MRKH patients with respect to healthy women. Through in vitro investigations, we highlighted that PRKX ectopic overexpression is able to influence vaginal keratinocytes’ cell shape and motility through the induction of epithelial-to-mesenchymal transition (EMT). Moreover, PRKX ectopic overexpression exerts a broad effect on the expression of HOX genes, which encode for essential factors implicated in embryo organogenesis. The present study suggests a possible molecular cause for MRKH syndrome and a role for PRKX in vaginal keratinocyte biology.Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a rare and complex disease defined by congenital aplasia of the vagina and uterus in 46,XX women, often associated with kidney and urinary tract anomalies. The aetiopathogenesis of MRKH syndrome is still largely unknown. Herein, we investigated the role of selected candidate genes in the aetiopathogenesis of MRKH syndrome, with a focus on PRKX, which encodes for protein kinase X. Through RT-qPCR analyses performed on vaginal dimple samples from patients, and principal component analysis (PCA), we highlighted a phenotype-related expression pattern of PRKX, MUC1, HOXC8 and GREB1L in MRKH patients. By using an in vitro approach, we proved that PRKX ectopic overexpression in a cell model of vaginal keratinocytes promotes cell motility through epithelial-to-mesenchymal transition (EMT) activation, a fundamental process in urogenital tract morphogenesis. Moreover, our findings showed that PRKX upregulation in vaginal keratinocytes is able to affect transcriptional levels of HOX genes, implicated in urinary and genital tract development. Our study identified the dysregulation of PRKX expression as a possible molecular cause for MRKH syndrome. Moreover, we propose the specific role of PRKX in vaginal keratinocyte biology as one of the possible mechanisms underlying this complex disease.

Laparoscopic Davydov Procedure for Creation of Neovagina in MRKH Syndrome

Introduction: The Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a condition in which there is an absence of the uterus and the upper part (2/3) of the vagina. Women with MRKH syndrome show normal development of secondary sexual characteristics and a normal 46, XX karyotype. MRKH syndrome is a common cause of primary amenorrhea. Ultrasonography examination confirms kidneys, presence of the ovaries, and absence of uterus. Treatment should include a multidisciplinary approach to create a functional vagina. One of the procedures is laparoscopic Davydov vaginoplasty.
 Aim: To report MRKH syndrome case treated with laparoscopic Davydov vaginoplasty.
 Method: Ms. A, 21 years old, P0A0, came to FER clinic Moh. Hoesin Hospital Palembang with complaint, never had menstruation, the patient admitted her breast, and her pubic had growth. She wants to get married in the next six months. From the US result, there was non visualized uterus, genital band (+), and both ovaries within normal limit ~ MRKH Syndrome. Karyotype Examination: 46, XX. Patient was diagnosed with primary amenorrhea caused by MRKH syndrome and was planned for neovagina (Davydov Procedure).
 Result: A woman 21-year-old, P0A0, was diagnosed with primary amenorrhea caused by MRKH syndrome. The Davydov procedure was done to create a neovagina. Intraoperative, after protrusion of the wood mold as a marker shown, an incision is made to the left and right side so that the mold penetrates the abdominal cavity, then the mold is pulled into the vaginal canal slowly. The anterior and posterior peritoneal layers are drawn into the vaginal canal. The anterior and posterior peritoneal layers were withdrawn with an ovum clamp and then interrupted suture. The anterior and posterior peritoneal layers were sutured in a circular method to form a vaginal cuff. The vaginal wall is sutured (interrupted) to hold mold fixed.
 Conclusion: MRKH syndrome is a disorder that occurs in females and mainly affects the reproductive system. This condition causes the vagina and the uterus to be underdeveloped or even absent at birth. Patients with diagnosed MRKH syndrome require interdisciplinary care. Davydov procedure is a laparoscopically-assisted technique, which has an advantage over traditional approaches. It has shorter operating time, lower intraoperative complications, shorter hospital stay, and no external scars. Postoperatively, sexual function is similar to women without gynecological disorders.

Laparoscopic Davydov Procedure for Creation of Neovagina in MRKH Syndrome

Introduction: The Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a condition in which there is an absence of the uterus and the upper part (2/3) of the vagina. Women with MRKH syndrome show normal development of secondary sexual characteristics and a normal 46, XX karyotype. MRKH syndrome is a common cause of primary amenorrhea. Ultrasonography examination confirms kidneys, presence of the ovaries, and absence of uterus. Treatment should include a multidisciplinary approach to create a functional vagina. One of the procedures is laparoscopic Davydov vaginoplasty.
 Aim: To report MRKH syndrome case treated with laparoscopic Davydov vaginoplasty.
 Method: Ms. A, 21 years old, P0A0, came to FER clinic Moh. Hoesin Hospital Palembang with complaint, never had menstruation, the patient admitted her breast, and her pubic had growth. She wants to get married in the next six months. From the US result, there was non visualized uterus, genital band (+), and both ovaries within normal limit ~ MRKH Syndrome. Karyotype Examination: 46, XX. Patient was diagnosed with primary amenorrhea caused by MRKH syndrome and was planned for neovagina (Davydov Procedure).
 Result: A woman 21-year-old, P0A0, was diagnosed with primary amenorrhea caused by MRKH syndrome. The Davydov procedure was done to create a neovagina. Intraoperative, after protrusion of the wood mold as a marker shown, an incision is made to the left and right side so that the mold penetrates the abdominal cavity, then the mold is pulled into the vaginal canal slowly. The anterior and posterior peritoneal layers are drawn into the vaginal canal. The anterior and posterior peritoneal layers were withdrawn with an ovum clamp and then interrupted suture. The anterior and posterior peritoneal layers were sutured in a circular method to form a vaginal cuff. The vaginal wall is sutured (interrupted) to hold mold fixed.
 Conclusion: MRKH syndrome is a disorder that occurs in females and mainly affects the reproductive system. This condition causes the vagina and the uterus to be underdeveloped or even absent at birth. Patients with diagnosed MRKH syndrome require interdisciplinary care. Davydov procedure is a laparoscopically-assisted technique, which has an advantage over traditional approaches. It has shorter operating time, lower intraoperative complications, shorter hospital stay, and no external scars. Postoperatively, sexual function is similar to women without gynecological disorders.

Primary Amenorrhea with Mayer-Rokitansky-Kuster-Hauser Syndrome

BACKGROUND: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a rare disorder described as aplasia or hypoplasia of uterus and vagina due to an early arrest in the development of Mullerian ducts. The etiology of MRKH syndrome remains uncertain: Although at the beginning, it was mentioned that this syndrome was the result of sporadic abnormalities. It has recently been assumed the genetic background is the cause of the increasing number of familial cases. CASE REPORT: A 29-year-old female patient presented with amenorrhea. She also has normal pubic and axillary hair and breast development. Routine investigations were normal. Genitalia inspection shows that pubic hair was well developed, labia majora and vagina were seen. Inspeculo show that vaginal wall was smooth, but portio was not seen. Vaginal examination result: The uterus was unpalpable, both adnexa were normal, parametrium was laxed, and Douglas pouch was not protruded. Rectal examination shows that uterus and both adnexa were difficult to identify. Transvaginal sonography revealed absence of uterus, both ovaries within normal. Transvaginal sonography diagnosed a uterine aplasia. With this, the provisional diagnosis made as primary amenorrhea due to suspected MRKH syndrome, the patient was referred for follicle-stimulating hormone, estradiol, testosterone, and prolactin levels by enzyme-linked immunosorbent assay examination and the result was within normal limit followed by genetic karyotyping and the result was normal 46, XX. CONCLUSIONS: We report a 29-year-old woman with primary amenorrhea. From our examination, the patient was diagnosed with MRKH syndrome. Uterus transplant is an alternative for that woman to treat amenorrhea and possibility to get pregnant.

Mayer-Rokitansky-K\xfcster-Hauser syndrome with 22q11.21 microduplication: a case report

BackgroundMayer-Rokitansky-Küster-Hauser (MRKH) syndrome (Online Mendelian Inheritance in Man [OMIM] #277000) is a congenital condition characterized by the total or partial agenesis of vagina and uterus. Agenesis can be isolated (MRKH 1) or associated with other renal, vertebral or cardiac defects (MRKH 2).Case presentationIn this paper, we report a case of a Caucasian patient showing the clinical signs associated with MRKH. Array-based comparative genomic hybridization (a-CGH) analysis revealed a microduplication of approximately 3.01 megabases (Mb) located on the long arm of chromosome 22 (22q11.21). Microduplications affecting the 22q11.21 region have been shown to be associated with MRKH syndrome and Müllerian aplasia. The phenotype of patients with 22q11.2 duplication (OMIM #608363) appears extremely variable, ranging from apparently normal to mild learning difficulties or with multiple defects, sharing features with DiGeorge/velocardiofacial (DGS/VCFS) syndrome.ConclusionsThe altered gene expression together with other genetic, nongenetic, epigenetic or environmental factors can cause the extremely variable phenotype in patients carrying such duplication. Therefore, we can consider MRKH syndrome to be one of the clinical features of DGS/VCFS syndrome.

Partial SHOX duplications associated with various cases of congenital uterovaginal aplasia (MRKH syndrome): A tangible evidence but a puzzling mechanism

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is the most severe form of congenital malformation of the inner female reproductive tract. It is diagnosed as such when the uterus, the upper vagina and optionally the Fallopian tubes are absent. It accounts for approximately 1 in 5000 live-born females and has been classified in two subtypes: type 1 in the presence of isolated uterovaginal aplasia and type 2 when associated in various combinations with extragenital malformations of the kidneys, skeleton, heart and auditory system. Most cases of MRKH syndrome are sporadic, although a significant number of many familial cases have been reported to date. Despite numerous studies, the genetics of the syndrome remains largely unknown and appears to be heterogeneous: chromosomal abnormalities and some candidate gene variants appear to be associated with a few cases; others have been suggested but not yet confirmed. To date, mainly the GREB1L gene appears to be a serious candidate. Among the remaining hypotheses, the controversial contribution of partial duplications of the SHOX gene is still puzzling, as the deficiency of this gene is a major cause of skeletal adysplasia syndromes. We have attempted to resolve this controversy in a study of 60 MRKH cases. Our results tend to show that SHOX duplications can be the origin of a genetic mechanism responsible for MRKH syndrome.

Clinical characteristics of 1,055 Chinese patients with Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide multicentric study

To reveal the proportion of concomitant extragenital malformations in a large cohort of Chinese patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Retrospective study. Tertiary teaching hospitals in China. A total of 1,055 Chinese Han women with MRKH syndrome diagnosed and treated at 11 Chinese tertiary teaching hospitals from January 2015 to January 2020. Karyotype analysis, hormone profiling, pelvic ultrasonography, spinal roentgenograms, urologic ultrasonography, and Chinese female reproductive tract malformation registry platform (https://ecrf.linklab.com/). Patients' demographic and clinical characteristics, concurrent malformations, and family histories. Of the 1,055 Chinese Han patients with MRKH, 69.6% had type I MRKH syndrome and the remaining 30.4% had type II MRKH syndrome. Among the type II patients, 12.6% had müllerian duct aplasia, unilateral renal aplasia/ectopic kidney, and cervicothoracic somite dysplasia association. Skeletal malformations were the most common associated extragenital malformations in the study (22.0%, 232/1,055), of which idiopathic scoliosis and congenital vertebral malformations were the 2 main skeletal malformations (80.6% and 14.2%, respectively). Renal malformations were the second-highest associated extragenital malformations (9.7%, 102/1,055), with unilateral renal agenesis and ectopic kidney being the most common renal malformations (48.0% and 22.5%, respectively). Type II disease was less common among Chinese patients with MRKH syndrome compared with European patients. Skeletal malformations were more common extragenital malformations than renal malformations in our cohort.

Long Term Findings Concerning the Mental and Physical Condition, Quality of Life and Sexuality after Laparoscopically Assisted Creation of a Neovagina (Modified Vecchietti Technique) in Young MRKHS (Mayer-Rokitansky-Küster-Hauser-Syndrome) Patients.

The Mayer-Rokitansky-Küster-Hauser-syndrome (MRKHS) is characterized by a congenital uterine and vaginal aplasia. A large body of literature reports that a diagnosis of MRKHS has a variety of psychological effects on patients and doubts about female identity. The aim of the underlying study was to detect the patient-reported physical and mental health and sexual function before and after laparoscopically assisted creation of a neovagina. 160 women with MRKHS who underwent this type of surgery between September 2009 and December 2015 were invited to complete the questionnaires. Packages consisting of six questionnaires were handed out before surgery, six and 12 months after surgery. Data from 82 patients could be included in the study. Patients had a mean age of 19.9 years at inclusion in the study. We detected an impairment of the health-related mental quality of life. There was no higher risk for psychological disorders. MRKHS patients show similar self-acceptance and normal body image compared to the general population. The sexual function is limited before surgery and normalizes after surgery. Useful factors for coping with the disease are an interdisciplinary approach in diagnostics and treatment, psychosocial adaptation as well as a supportive social environment.

Anesthetic Considerations for Cesarean Delivery After Uterine Transplant.

Infertility has many etiologies and can have devastating consequences for young couples attempting to bring children into the world. Uterine factor for infertility is related to either uterine agenesis (Mayer-Rokitansky-Küster-Hauser [MRKH] syndrome), unexpected hysterectomy, or presence of a nonfunctioning uterus. In this review, a patient with MRKH syndrome underwent donor uterus transplantation at the Cleveland Clinic, conceived, and delivered the first healthy baby in the United States and the second worldwide. Additionally, we review the pertinent literature on anesthesia problems. Donor-related uterine transplant is a recent medical innovation requiring multidisciplinary expertise. In patients who deliver successfully, according to the current literature, the transplanted uterus can be used for one more pregnancy only if the mother so desires, otherwise cesarean hysterectomy (C-Hyst) should be performed. In the observed case, C-Hyst was performed because the patient developed placenta accreta and the couple desired no further pregnancy. In summary, with our limited data, careful management of these patients is required to ensure the best outcome for the mother and the newborn fetus.

English

Certain rare congenital defects can occur during the prenatal development of the female reproductive system, resulting in an abnormal or absent vagina.1 It is a part of the female genital tract. It is muscular and an elastic organ with a soft epithelial lining making it susceptible to disruption during crucial times of organogenesis.1,2 There are different malformations that occur in the female genital organ, many of which are classified under the broader term “Müllerian duct anomalies”. 1,2 Müllerian agenesis is also referred to as congenital absence of the uterus and vagina (CAUV), müllerian aplasia (MA), genital renal ear syndrome (GRES), and Mayer-Rokitansky-KüsterHauser syndrome (MRKH). It has been considered as a sporadic anomaly, but the increase in familial cases now supports the hypothesis of a genetic cause characterised by a failure of the Müllerian ducts to develop, resulting in a missing uterus and variable malformations of the vagina.1-7 According to scientific data, its incidence is reported to be 1 in 4,000 to 10,000 females occurring due to a heterozygous transformation of WNT4 gene on chromosome 1p36.1-7 Additionally, traumatic vaginal injury in females, which is not uncommon, results in vaginal stenosis.5 This results in formation of scar tissue causing stricture of the vagina.5 Based on the family history, the patient must undergo medical examination supported by gynaecologic assistance to provide a sensitive and specific means of diagnosis.1,2 It is essential for the patients and their families to attend counselling before proceeding for treatment as this syndrome can cause severe psychological stress in a young woman. Patients with vaginal agenesis in MRKH syndrome can be treated by both surgical and non-surgical procedures and there has been no evidence of the superiority of one technique over another.6,11 Abbe–McIndoe operation is a common surgical method using split thickness skin graft for reconstruction and Frank’s dilators is a common nonsurgical method for the creation of neovagina.3,7 Frank's initial technique used hand-held vaginal dilators in the lithotomy position and had technical limitations such as uncomfortable positioning, loss of time spent during the process of dilation, and fatigue of patient's hands. Ingram's method overcame these difficulties by using the sitting position to take advantage of the patient's body weight.8,9 This method used vaginal dilators mounted on a specially designed bicycle seat stool that provided perineal pressure via the narrow and elevated anterior portion of the bicycle seat.10 Despite the favourable clinical outcome of this method, there were some practical difficulties in making and handling these in an outpatient clinic. However, irrespective of the procedure opted, prosthetic vaginal dilators or long-term vaginal stents are required to prevent the possible contraction of the reconstructed neovagina, to maintain vaginal width, depth and to avoid vaginal stenosis.6

Menarche in primary ovarian insufficiency after a month of hormone replacement therapy: a case report

BackgroundGynecologic anomalies, including uterine agenesis and ovarian dysgenesis, are some of the several differential diagnoses in adolescent females with primary amenorrhea and delayed puberty. Primary ovarian insufficiency is reported in the clinical practice of reproductive endocrinology can be determined by conducting sex hormone tests to evaluate the hypothalamic-pituitary-ovarian axis. However, confirmation of Mullerian agenesis by image modalities can be extremely challenging. Once the diagnosis is established, breakthrough bleeding usually occurs 2 to 3 years after hormonal replacement therapy.Case presentationWe report a case of a seventeen year old Taiwanese female, 46 XX karyotype, with ovarian dysgenesis and an initial tentative diagnosis of uterine agenesis who experienced a breakthrough bleeding after a month of hormonal replacement therapy.ConclusionsThe breakthrough bleeding after a month of estrogen therapy in primary ovarian insufficiency is uncommon, and the diagnosis of the absent uterus can have an extensive psychological impact on patients and their families.

Possibilities of physiotherapy in Mayer–Rokitansky–Kuester–Hauser syndrome

BACKGROUND: MayerRokitanskyKuesterHauser syndrome occurs in 1 of 40005000 newborn girls. The first-line treatment of aplasia of the vagina is considered a vaginal dilation. The use of physiotherapy capabilities in the practice of obstetricians and gynecologists is quite widespread and has firmly established itself in clinical practice.
 AIMS: To evaluate the effectiveness and tolerability of dilation in combination and without physical effects in the formation of vagina in adolescent girls.
 MATERIALS AND METHODS: A prospective cohort study of 64 adolescent girls 15 to 18 y with a first-time diagnosis of vaginal and uterine aplasia was conducted. Their psychophysiological features were analyzed with testing according to the questionnaire well-being, activity, mood (SAN), physical and sexual development, a gynecological examination was performed to determine the depth of the vaginal fossa. Teenage girls were randomized into 2 groups: 1 (n=36) to create an artificial vagina, with the method of dilation. The second group of patients (n=28) underwent preformed physiotherapy with subsequent dilation. All the girls daily made a graph of the increase in the length of the vagina and determined the intensity of pain using a visual-analog scale (VAS). After the treatment was completed, the patients were re-tested according to the SAN method.
 RESULTS: A significant increase in the length of the neovagal space was noted in the group of complex treatment with physiotherapy already at the 8th procedure, with an increase after the completion of 20 procedures. In group 2, the dynamics of pain intensity significantly decreased in comparison with the 1st group. The psychological status of the patients according to the SAN before the start of treatment was characterized by an unfavorable state.
 CONCLUSION: Conducting course procedures of complex dilation with the use of heat-magneto-vibration in girls with vaginal aplasia has a significant reduction in pain and allowed to achieve the required anatomical length in a shorter time compared to monomethodics.

Effects of different vaginal mould use approaches after vaginoplasty with artificial dermis in patients with Mayer-Rokitansky-Küster-Hauser syndrome.

ObjectiveTo assess the therapeutic effects of different vaginal mould use approaches after vaginoplasty in patients with Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome.MethodsPatients with MRKH syndrome who underwent surgery from 2010 to 2015 in our hospital were retrospectively evaluated. Vaginoplasty was performed with artificial dermis, and vaginal moulds were used for 6 months postoperatively. The patients were divided into an intermittent group and continuous group according to the vaginal mould approach.ResultsThirty-five patients were evaluated (intermittent group, 19 patients; continuous group, 16 patients). One month postoperatively, the mean vaginal length and width in the intermittent group were 9.26 ± 0.56 and 3.82 ± 0.25 cm, respectively, and those in the continuous group were 9.44 ± 0.51 and 3.86 ± 0.22 cm, respectively. Six months postoperatively, the mean vaginal length and width in the intermittent group were 8.94 ± 0.71 and 3.76 ± 0.26 cm, respectively, and those in the continuous group were 8.69 ± 0.48 and 3.65 ± 0.30 cm, respectively. The mean Female Sexual Function Index scores in the intermittent and continuous groups were 28.61 ± 0.71 and 28.4 80 ±0.79 respectively, after normal sexual life.ConclusionBoth intermittent and continuous use of postoperative vaginal moulds may be effective.

917 Pregnancy outcomes following uterus transplant

To examine the maternal and fetal outcomes of pregnancies following uterus transplant. We conducted a retrospective cohort study of women attempting to conceive following uterus transplant at a single institution. Maternal and neonatal outcomes are reported for all pregnancies that resulted in live birth following uterus transplant from either living or deceased uterus donation. The indication for uterus transplant was absolute uterine factor infertility with the etiology being MRKH syndrome in all cases but one (previous hysterectomy). All uterus recipients received tacrolimus plus either azathioprine or everolimus as anti-rejection treatment. Twelve pregnancies carried to viability following uterus transplant between 2017-2020. Median maternal age at the time of delivery was 31 years (range 21-39 years). Fifty percent of pregnancies were delivered preterm (<37 weeks), with the median gestational age at delivery being 36w6d (range 30w6d - 38w0d). All infants were born via cesarean section. In five pregnancies (four first deliveries and one second) the uterine graft was removed at the same time as the cesarean section. Decision to remove uterus at time of cesarean section was made based on plans for future fertility. Median fetal weight was 2,890 gm (Range 1,770 g to 3,470 g). One infant was small for gestational age (2400 gm at 32w4d) and one was large for gestational age (2350 gm at 36w6d). Three mothers developed gestational hypertension and one was diagnosed with preeclampsia without severe features. Additional complications included single incidents of the following: placenta previa with antepartum hemorrhage requiring preterm delivery, PPROM at 35w5d gestation, and cervical dilation at 23w4d with rescue cerclage placement with delivery at 30w6d. Maternal or obstetric complications were present in eight of the twelve of the pregnancies. Pregnancies conceived following uterus transplant are successful in producing healthy, neonates with minimal risk of maternal complications.

Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.

Protein\u2013protein interaction network analysis applied to DNA copy number profiling suggests new perspectives on the aetiology of Mayer\u2013Rokitansky\u2013K\xfcster\u2013Hauser syndrome

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare disease, characterised by the aplasia of vagina and uterus in women with a 46,XX karyotype. Most cases are sporadic, but familial recurrence has also been described. Herein, we investigated an Italian cohort of 36 unrelated MRKH patients to explore the presence of pathogenic copy number variations (CNVs) by array-CGH and MLPA assays. On the whole, aberrations were found in 9/36 (25%) patients. Interestingly, one patient showed a novel heterozygous microduplication at Xp22.33, not yet described in MRKH patients, containing the PRKX gene. Moreover, a novel duplication of a specific SHOX enhancer was highlighted by MLPA. To predict the potential significance of CNVs in MRKH pathogenesis, we provided a network analysis for protein-coding genes found in the altered genomic regions. Although not all of these genes taken individually showed a clear clinical significance, their combination in a computational network highlighted that the most relevant biological connections are related to the anatomical structure development. In conclusion, the results described in the present study identified novel genetic alterations and interactions that may be likely involved in MRKH phenotype determination, so adding new insights into the complex puzzle of MRKH disease.

Familial Beckwith-Wiedemann syndrome: Prenatal manifestation and a possible expansion of the phenotype

We describe a case of Beckwith-Wiedemann syndrome (BWS) demonstrating pre- and post-natal intra-familial variability. Our first encounter with the family occurred in the 1990s following the birth of 3 affected offspring. The first two pregnancies presented with exomphalos and elevated second trimester maternal serum alpha-fetoprotein (msAFP, 3.43 and 4.01 MOM, respectively) as well as elevated maternal human chorionic gonadotrophin (mhCG, 4.33 and 8.8 MOM, respectively). The diagnosis of BWS was confirmed postnatally in both cases. The third ongoing pregnancy presented only with elevated mhCG (7.09 MOM) and no malformation. Nonetheless BWS was suspected. The diagnosis was confirmed postnatally with clinical manifestations including macroglossia and cleft palate. Two affected female siblings were also diagnosed with Mullerian agenesis in adulthood.Suspecting a common genetic etiology, sequencing of the CDKN1C gene revealed a maternally inherited, likely pathogenic variant (NM_000076.2: c.367_385del; p.(Ala123Serfs*143)) causative of BWS. Chromosomal microarray and whole exome sequencing did not reveal any other pathogenic variant that would explain the Mullerian agenesis. One of the affected females underwent successful preimplantation genetic testing (PGT) with a surrogate and gave birth to a healthy female.To the best of our knowledge, this is the first report of Mullerian agenesis as a possible rare expansion of the BWS phenotype. In addition, this case highlights the potential role of abnormal second trimester biochemical markers (msAFP, mHCG) as possible indicators of BWS, especially in familial cases.