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Phenotypic and clinical aspects of Mayer-Rokitansky-Küster-Hauser syndrome in a Chinese population: an analysis of 594 patients

      Objective

      To analyze the phenotypic and clinical aspects of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome.

      Design

      Cross-sectional study.

      Setting

      University hospital.

      Patient(s)

      Five hundred and ninety-four patients with MRKH syndrome.

      Intervention(s)

      Clinical examination, abdominal or perineal/rectal ultrasound, magnetic resonance imaging, hormonal profile, karyotype, and laparoscopy.

      Main Outcome Measure(s)

      Clinicopathologic data, VCUAM (vagina cervix uterus adnex-associated malformation) classification, types with cycle phase, and karyotype.

      Result(s)

      We identified associated malformations in 43 out of 594 (7.2%) cases of MRKH. The 594 patients could be grouped into hormone phases: 53.7% follicular, 35.2% luteal, and 11.1% ovulatory. The major karyotype of MRKH patients was 46,XX; abnormal karyotypes were found in two cases.

      Conclusion(s)

      A lower proportion of associated malformations were found when compared with those provided in the current literature. Renal anomalies were the most frequent associated malformations, and most of the patients presented with a normal karyotype. Given the large cohort of this study, the lower malformation rates might be related to geographic or referral patterns, so further investigation is warranted.

      Key Words

      Mayer-Rokitansky-Küster-Hauser syndrome (MRKH; OMIM 27700), also known as Rokitansky syndrome, is characterized by congenital aplasia of the uterus, cervix, and upper two-thirds of the vagina during fetal development. The incidence of the syndrome is 1 in 4,500 female newborns (
      • Capraro V.J.
      • Gallego M.B.
      Vaginal agenesis.
      ,
      • Folch M.
      • Pigem I.
      • Konje J.C.
      Müllerian agenesis: etiology, diagnosis, and management.
      ). Women with MRKH syndrome typically have normal ovarian function and a 46,XX karyotype; thus, these patients typically present with primary amenorrhea (
      • Wottgen M.
      • Brucker S.
      • Renner S.P.
      • Strissel P.L.
      • Strick R.
      • Kellermann A.
      • et al.
      Higher incidence of linked malformations in siblings of Mayer-Rokitansky-Kuster-Hauser-syndrome patients.
      ). The association of malformations in müllerian duct development with other organ systems suggests that crucial genes involved in fetal development and sex differentiation are potential candidates for these congenital malformations. However, the etiology of MRKH syndrome remains unknown (
      • Kobayashi A.
      • Behringer R.R.
      Developmental genetics of the female reproductive tract in mammals.
      ).
      The patient's history, clinical examination, ultrasound, magnetic resonance imaging, and laparoscopy can assist in the initial diagnosis of MRKH (
      • Lermann J.
      • Mueller A.
      • Wiesinger E.
      • Haberle L.
      • Brucker S.
      • Wallwiener D.
      • et al.
      Comparison of different diagnostic procedures for the staging of malformations associated with Mayer-Rokitansky-Kuster-Hauser syndrome.
      ,
      • Pompili G.
      • Munari A.
      • Franceschelli G.
      • Flor N.
      • Meroni R.
      • Frontino G.
      • et al.
      Magnetic resonance imaging in the preoperative assessment of Mayer-Rokitansky-Kuster-Hauser syndrome.
      ,
      • Preibsch H.
      • Rall K.
      • Wietek B.M.
      • Brucker S.Y.
      • Staebler A.
      • Claussen C.D.
      • et al.
      Clinical value of magnetic resonance imaging in patients with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome: diagnosis of associated malformations, uterine rudiments and intrauterine endometrium.
      ). The syndrome can be classified into type I (isolated) or Rokitansky syndrome, and type II (associated with malformations of organs of the renal, skeletal, cardiovascular, and other systems) (
      • Oppelt P.
      • von Have M.
      • Paulsen M.
      • Strissel P.L.
      • Strick R.
      • Brucker S.
      • et al.
      Female genital malformations and their associated abnormalities.
      ). Patients with MRKH syndrome can also be classified by the vagina cervix uterus adnex-associated malformation (VCUAM) genital classification system according to phenotypes associated with each of these anatomic structures. The VCUAM system, developed in 2005, aids in providing an accurate description of the phenotypes of female genital malformations (
      • Oppelt P.
      • Renner S.P.
      • Brucker S.
      • Strissel P.L.
      • Strick R.
      • Oppelt P.G.
      • et al.
      The VCUAM (vagina cervix uterus adnex-associated malformation) classification: a new classification for genital malformations.
      ). Recent publications have described patients with MRKH syndrome using the VCUAM classification system, but there are few detailed descriptions of the expected findings in patients within a large cohort.
      Single case studies and small cohort investigations indicate that steroid and pituitary hormone levels in individuals with MRKH fall within the normal limits (
      • Ylikorkala O.
      • Viinikka L.
      Pituitary and ovarian function in women with congenitally absent uterus.
      ,
      • Carranza-Lira S.
      • Forbin K.
      • Martinez-Chequer J.C.
      Rokitansky syndrome and MURCS association—clinical features and basis for diagnosis.
      ). However, some studies have revealed that hormone deregulation could exist in some MRKH patients, as hyperprolactinemia, high progesterone levels, dysregulation of antimüllerian hormone levels, differences in luteal phase estrogens, and hypergonadotrophic hypogonadism have been observed (
      • Carranza-Lira S.
      • Forbin K.
      • Martinez-Chequer J.C.
      Rokitansky syndrome and MURCS association—clinical features and basis for diagnosis.
      ,
      • Kebaili S.
      • Chaabane K.
      • Mnif M.F.
      • Kamoun M.
      • Kacem F.H.
      • Guesmi N.
      • et al.
      Gonadal dysgenesis and the Mayer-Rokitansky-Kuster-Hauser Syndrome in a girl with a 46,XX karyotype: a case report and review of literature.
      ,
      • Bousfiha N.
      • Errarhay S.
      • Saadi H.
      • Ouldim K.
      • Bouchikhi C.
      • Banani A.
      Gonadal dysgenesis 46,XX associated with Mayer-Rokitansky-Kuster-Hauser syndrome: one case report.
      ,
      • Ozekinci M.
      • Erman Akar M.
      • Senol Y.
      • Ozdem S.
      • Uzun G.
      • Daloglu A.
      • et al.
      Comparison of markers of ovarian reserve between patients with complete müllerian agenesis and age-matched fertile and infertile controls.
      ). Our study used the VCUAM classification system to describe the spectrum of congenital malformations in a large cohort of 623 patients with MRKH syndrome.

      Material and methods

       Patients

      The cohort included 623 patients who presented initially with primary amenorrhea before MRKH syndrome was diagnosed. The women, who came from all areas of the People's Republic of China, presented between July 2006 and November 2014 in the Department of Obstetrics and Gynecology at the University Hospital of Shenzhen (People's Republic of China).
      The majority of the patients had data collected, including personal and family history, gynecologic examination, abdominal ultrasonography, X-rays, hormone profiling, karyotype testing, magnetic resonance imaging of the pelvis, and surgical reports. All serum samples of hormones were collected at the time of initial diagnosis and were analyzed using DxI800 analyzers (Beckman Coulter). The same operator evaluated all 623 patients according to the VCUAM classification using laparoscopy, as a part of an improved laparoscopic peritoneal vaginoplasty (
      • Huang Z.
      • Liu P.
      • Luo G.
      Comparison of improved laparoscopic peritoneal vaginoplasty and gasless laparoscopic ileal vaginoplasty in treatment of androgen insensitivity syndrome.
      ,
      • Luo G.
      Vaginoplasty.
      ,
      • Zhang J.J.
      • Liao S.
      • Du M.
      • Qin C.L.
      • Li B.Y.
      • Luo G.N.
      Laparoscopy-insisted vaginoplasty with peritoneum in patients with androgen insensitivity syndrome.
      ). The final classification of each malformation was performed using the new VCUAM classification. This classification makes it possible to descriptively record the pathologic anatomy of genital developmental disturbances.
      All the patients were informed that the data were to be analyzed in the context of a research study outlining the key objectives and research outcomes. All participants provided written consent upon request. Approval for the study was obtained from the ethics committee at the University of Shenzhen.

       Statistical Analysis

      The data captured followed a full patient record-review process using a standardized score form, recorded on an Excel database (Microsoft). Where necessary, patients with incomplete data were excluded from the study to ensure that the statistics were accurate and consistent with our identified hypothesis.

      Results

       Clinicopathologic Data

      The patient files of 623 patients with diagnosed MRKH syndrome who were treated during the study period were analyzed. We deemed 594 cases eligible for inclusion in the analysis. Twenty-nine patients were excluded from this study due to undetermined abdominal or perineal/rectal ultrasound, magnetic resonance imaging, hormone profile, and karyotype data.
      All 594 patients were Chinese; all the patients underwent a clinical examination as well as ultrasound and laparoscopy examinations. Patients with skeletal, neuronal, or cardiac malformations were further examined using thoracic X-ray, echocardiography, audiometry, or visual tests. All cases in our research group were sporadic. The mean age at the time of the diagnosis was 24.7 ± 4.5 years (range: 12–43 years). Table 1 gives the characteristics of the study participants. The mean interval between the diagnosis of malformation and surgical treatment was 6.35 ± 3.86 years (range: 12–43 years), with a range of 0 to 21 years. The mean preoperative vaginal length was 2.2 ± 1.1 cm, with a range of 0 to 3 cm. Surgical vaginoplasty was successfully completed in all cases.
      Table 1Sociodemographic data of patients with Mayer-Rokitansky-Küster-Hauser syndrome (N = 594).
      CharacteristicPatients, n (%)
      Marital status
       Married80 (13.5)
       Single362 (60.9)
       Partnership152 (25.6)
      Education level
       Compulsory school
      Compulsory school denotes the first 9 y of education.
      138 (23.3)
       High school267 (44.9)
       University189 (31.8)
      Employment status
       Employed351 (59.1)
       Unemployed87 (14.6)
       Student156 (26.3)
      a Compulsory school denotes the first 9 y of education.

       VCUAM Classifications

       Vagina (V) and cervix (C)

      We found that 594 patients (100%) showed stage V5b (complete atresia) development of the vagina and stage C2b (bilateral atresia/aplasia) of the cervix.

       Uterus (U)

      We found that 585 patients (98.5%) showed stage 4b (bilateral rudimentary or aplastic) uterine development, 3 patients (0.5%) showed stage 4a (unilateral rudimentary or aplastic), five patients (0.8%) showed “other,” and one patient (0.2%) showed stage 3 (hypoplastic uterus).

       Adnexa (A)

      We found that 571 patients (96.1%) showed stage 0 (normal adnexa) development, six patients (1%) showed other malformations, five patients (0.8%) showed stage 3a (unilateral aplasia), four (0.7%) were not classifiable, three patients (0.5%) showed stage 3b (bilateral aplasia), two (0.3%) showed stage 2a (unilateral hypoplasia), two patients (0.3%) stage 1a (unilateral tubal malformation), and one (0.2%) showed 1b (bilateral tubal malformation). Moreover, ovarian mature cystic teratomas were found in four patients.

       Associated malformations (M)

      In 551 (92.8%) of 594 patients, no associated malformations were diagnosed (stage 0). In 30 patients (5.1%) we found malformations of the renal system (stage R). In 10 patients, (1.7%) malformations of the skeleton (stage S) were found. Among the renal malformations (stage R), we found 22 cases of unilateral renal agenesis, six cases of pelvic kidneys, and two cases of horseshoe kidneys. Within the group of patients with skeletal malformations (stage S), we found six cases of scoliosis, two cases of hemivertebrae deformity, and two cases of rib deformity. Moreover, in two patients we found different combinations of malformations (renal, skeleton, cardiac). The first case included hemivertebrae deformities and a dextrocardia. The second case had a renal agenesis, atrial septal defect, and scoliosis.
      The specification of associated malformations diagnosed in 594 patients with MRKH syndrome is shown in Table 2. In summary, among 594 patients with MRKH syndrome, 571 patients could be classified with complete atresia of the vagina (V5b), bilateral atresia of the cervix (C2b), bilateral aplastic uterus (U4b), and normal adnexa (A0) (96.1%). The most frequent VCUAM classification was V5bC2bU4bA0M0, which was diagnosed in 551 (92.8%) of 594 patients. The spectrum of associated malformations is shown in Table 3.
      Table 2Specification of associated malformations diagnosed in 594 patients with Mayer-Rokitansky-Küster-Hauser syndrome.
      MalformationNo.Combinations of other malformationsNo.
      Renal
       Pelvic kidney6
       Kidney agenesis (left)9Atrial septal defect and scoliosis1
      In one patient different combinations of malformations (renal, skeleton, cardiac) were found; this case had a renal agenesis, atrial septal defect, and scoliosis.
       Kidney agenesis (right)14
       Horseshoe kidney2
      Skeletal
       Scoliosis7Atrial septal defect and kidney agenesis1
      In one patient different combinations of malformations (renal, skeleton, cardiac) were found; this case had a renal agenesis, atrial septal defect, and scoliosis.
       Hemivertebrae deformity3Dextrocardia1
       Ribs deformity2
      Note: The top row represents the number of Mayer-Rokitansky-Küster-Hauser syndrome patients (n = 594) according to associated malformations and combinations of other malformations.
      a In one patient different combinations of malformations (renal, skeleton, cardiac) were found; this case had a renal agenesis, atrial septal defect, and scoliosis.
      Table 3VCUAM (vagina cervix uterus adnex-associated malformation) classification of 594 patients with Mayer-Rokitansky-Küster-Hauser syndrome.
      VaginaCervixUterusAdnexaMalformation
      Typen (%)Typen (%)Typen (%)Typen (%)Typen (%)
      V5b594 (100)C2b594 (100)U31 (0.17)A0571 (96.1)M0551 (92.76)
      U4a3 (0.51)A1a2 (0.34)MR30 (5.05)
      U4b585 (98.5)A1b1 (0.17)MS10 (1.68)
      U+5 (0.84)A2a2 (0.34)MC1 (0.17)
      A3a5 (0.84)MSC1 (0.17)
      A3b3 (0.51)MRSC1 (0.17)
      A+6 (1.01)
      A#4 (0.67)
      Note: The top row represents the clinical characteristics and the number of Mayer-Rokitansky-Küster-Hauser syndrome patients (n = 594) according to the VCUAM classification
      • Oppelt P.
      • Renner S.P.
      • Brucker S.
      • Strissel P.L.
      • Strick R.
      • Oppelt P.G.
      • et al.
      The VCUAM (vagina cervix uterus adnex-associated malformation) classification: a new classification for genital malformations.
      : A# = without clinical data about adnexes; A+ = other malformation of adnexes; A0 = normal adnexes; A1a = unilateral tubal malformation, ovaries normal; A1b = bilateral tubal malformation, ovaries normal; A2a = unilateral hypoplasia/gonadal streak; A2b = bilateral hypoplasia/gonadal streak; A3a = unilateral aplasia of adnexa; A3b = bilateral aplasia of adnexa; C2b = bilateral atresia/aplasia of cervix; M0 = no associated malformations; MC = malformed cardiac system; MR = malformed renal system; MRSC = combines malformations of renal, skeleton, and cardiac system; MS = malformed skeleton; MSC = combines malformations of skeleton and cardiac system; U+ = other uterine malformation; U3 = hypoplastic uterus; U4a = unilaterally rudimentary or aplastic; U4b = bilaterally rudimentary or aplastic uterus; V5b = complete atresia of vagina.

       Pituitary and Steroid Hormones

      According to their individual hormone values, all 594 MRKH patients were grouped into hormone phases representing: 53.7% follicular, 35.2% luteal, and 11.1% ovulatory. Upon further analysis, according to the VCUAM classification 8 of 594 MRKH patients (1.3 %) had gonadal malformations, including unilateral gonadal aplasia and unilateral streak gonads in addition to another presenting characteristics. It is interesting that seven of these eight patients had overall normal hormone levels. One patient (#1947, age 28) was diagnosed with ovarian mature cystic teratoma and demonstrated normal estradiol (22 pg/mL), progesterone (0.4 ng/mL), and luteinizing hormone (6.28 mIU/mL) values, but had high follicle-stimulating hormone (410.34 mIU/mL) levels.

       Abnormal Karyotypes

      A karyotype analysis was performed routinely for every patient, which returned normal 46,XX results in the majority of cases. Abnormal karyotypes were found in two cases. The first case was that of an 18-year-old patient presenting with uterovaginal aplasia with a symptomatic 10-cm ovarian cyst adjacent to the left uterine rudiment. Her chromosome analysis revealed a 47,XX,+mar[21] karyotype. The parent's karyotypes were normal, as was her family history. The second case was a 29-year-old MRKH type 1 patient who had very rare, coexisting triple X syndrome.

      Discussion

      Our study details the phenotypes of 594 patients with MRKH syndrome in one of the largest cohort studies of affected individuals grouped according to a defined classification system (VCUAM). Ours is the first study to include hormone profiles on all participants.
      Most medical interest in MRKH syndrome has been focused on surgical and nonsurgical techniques to improve sexual intercourse through the creation of a neovagina. With the increasing number of MRKH patients has come a concomitant increase of interest in the clinical aspects of patients with MRKH (
      • Oppelt P.G.
      • Lermann J.
      • Strick R.
      • Dittrich R.
      • Strissel P.
      • Rettig I.
      • et al.
      Malformations in a cohort of 284 women with Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH).
      ,
      • Rall K.
      • Eisenbeis S.
      • Henninger V.
      • Henes M.
      • Wallwiener D.
      • Bonin M.
      • et al.
      Typical and atypical associated findings in a group of 346 patients with Mayer-Rokitansky-Kuester-Hauser syndrome.
      ). The MRKH syndrome phenotype is highly variable; in our study, 100% of patients showed complete vaginal atresia, although 1 to 3 cm of the lower vagina may be present. We found that 100% of patients also showed cervical aplasia.
      Malformations in the ovaries and fallopian tubes are rare in patients with MRKH syndrome and can vary in their severity. Severe changes in these organs, including gonadal dysgenesis or tubo-ovarian agenesis, can impact hormone function. We found that 3.9% of the affected individuals in our cohort had ovary malformations, which concurs with Rokitansky, Rall et al. (
      • Rall K.
      • Eisenbeis S.
      • Henninger V.
      • Henes M.
      • Wallwiener D.
      • Bonin M.
      • et al.
      Typical and atypical associated findings in a group of 346 patients with Mayer-Rokitansky-Kuester-Hauser syndrome.
      ), and Oppelt et al. (
      • Oppelt P.
      • von Have M.
      • Paulsen M.
      • Strissel P.L.
      • Strick R.
      • Brucker S.
      • et al.
      Female genital malformations and their associated abnormalities.
      ,
      • Oppelt P.G.
      • Lermann J.
      • Strick R.
      • Dittrich R.
      • Strissel P.
      • Rettig I.
      • et al.
      Malformations in a cohort of 284 women with Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH).
      ) who delineated that described hypoplastic or aplastic ovaries were limited to a small number of cases.
      Rall et al. (
      • Rall K.
      • Eisenbeis S.
      • Henninger V.
      • Henes M.
      • Wallwiener D.
      • Bonin M.
      • et al.
      Typical and atypical associated findings in a group of 346 patients with Mayer-Rokitansky-Kuester-Hauser syndrome.
      ) reported the spectrum of genital and associated malformations in a cohort of 346 patients with MRKH syndrome. Associated malformations were found in 46.8% of patients, including 26.6% with renal malformations. Within our cohort, we found 7.2% with associated malformations, a rate identified as less than current literature suggests and thus deemed inconsistent with comparable studies (46.8%, 53%, and 64%) (
      • Oppelt P.G.
      • Lermann J.
      • Strick R.
      • Dittrich R.
      • Strissel P.
      • Rettig I.
      • et al.
      Malformations in a cohort of 284 women with Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH).
      ,
      • Rall K.
      • Eisenbeis S.
      • Henninger V.
      • Henes M.
      • Wallwiener D.
      • Bonin M.
      • et al.
      Typical and atypical associated findings in a group of 346 patients with Mayer-Rokitansky-Kuester-Hauser syndrome.
      ). Within the group with associated malformations, we found 71.4% with renal anomalies, confirming this as the most frequent associated malformation with MRKH; the incidence of renal malformations in MRKH patients was higher than that of the general population (
      • Oppelt P.
      • Renner S.P.
      • Kellermann A.
      • Brucker S.
      • Hauser G.A.
      • Ludwig K.S.
      • et al.
      Clinical aspects of Mayer-Rokitansky-Kuester-Hauser syndrome: recommendations for clinical diagnosis and staging.
      ). The most frequent renal malformation was renal agenesis. As a consequence, patients with MRKH should be evaluated for renal abnormalities.
      These results made the further identification of malformation subtypes challenging to quantify. Based on the large sample size, the removal of 29 patient samples had no significant effect on the correlation of the overall study. We were aware of the possible relationship of the genetics of anomalies in patients and their families. Given the rare positive family history with MRKH, it was difficult to provide an accurate connection with family factors of probands with MRKH. Based on the sociodemographic data (Table 1), up to 76.7% of the patients had received a good education, indicating that their families had good economic conditions that could support them. Thus, it must be questioned whether the family economic conditions of probands with MRKH played a role in the etiology. It must also be mentioned that the average age at marriage of their parents, the educational level of their parents, the family economic level, and the use of infertility services were not part of this study.
      The difference between the incidences of malformations in this population compared with what has been reported in other studies was evident for several potential sources of bias: our study of the incidence of malformations was single-center case series, which was potentially subject to selection bias; the inconsistent screening process may have determined the infrequency of samples; admission rate bias may have been a factor; and financial and social background may have biased the outcomes of admission rates.
      Mayer-Rokitansky-Küster-Hauser syndrome is often underrepresented in hospital-based series because patients with milder symptoms often present with intent-to-treat of neovagina creation; patients with more complex symptoms tend to be turned away because their expensive medical bills are a heavy burden for public hospitals. Thus, the research team investigated the data collected at the university hospital from our 594 cases in comparison with [1] other demographics and regions, [2] referral analysis of presenting issues within a larger time variance, [3] referral analysis of presenting issues regarding malformations as expanded upon further data collection and investigation, and [4] referral analysis of family factors in the probands with MRKH.
      The necessity of performing a chromosomal analysis as part of screening for MRKH syndrome has been widely accepted (
      • Strissel P.L.
      • Oppelt P.
      • Cupisti S.
      • Stiegler E.
      • Beckmann M.W.
      • Strick R.
      Assessment of pituitary and steroid hormones and members of the TGF-beta superfamily for ovarian function in patients with congenital uterus and vaginal aplasia (MRKH syndrome).
      ). We found normal 46,XX results in 592 cases, and abnormal karyotypes in two patients (0.33%). In our group, one patient had both typical MRKH and triple X syndrome, a combination that is a very rare finding. Goswami et al. (
      • Goswami R.
      • Goswami D.
      • Kabra M.
      • Gupta N.
      • Dubey S.
      • Dadhwal V.
      Prevalence of the triple X syndrome in phenotypically normal women with premature ovarian failure and its association with autoimmune thyroid disorders.
      ) found premature ovarian failure in triple X syndrome patients with autoimmune thyroid disorders. Raziel et al. (
      • Rall K.
      • Eisenbeis S.
      • Henninger V.
      • Henes M.
      • Wallwiener D.
      • Bonin M.
      • et al.
      Typical and atypical associated findings in a group of 346 patients with Mayer-Rokitansky-Kuester-Hauser syndrome.
      ) found familial original hearing loss in triple X syndrome patients. These were absent in our patient. In our group, one patient had a 47,XX,+mar [21] karyotype; the details of the karyotype are still unknown.

      Conclusion

      A lower proportion of associated malformations were found compared with the current literature. Renal anomalies were the most frequent associated malformations. Most of the patients presented with a normal karyotype. Given the large cohort of our study, the lower malformation rates might be due to geographic or referral patterns, so further investigation is warranted.

      Acknowledgments

      The authors thank Alison Hensley and Amy C. Lossie for providing us with constructive comments and suggestions; and all the patients for participating in the present study.

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