Introduction

Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a condition characterized by the absence of a functioning uterus, a short or absent vagina, normal secondary sexual characteristics, normal ovarian function, and a female karyotype [1]. The syndrome is one of the commonest disorders of sex development (DSD) [2] and accounts for just under 3 percent of Müllerian abnormalities [3]. Following the first descriptions by Mayer (1829) and Rokitansky (1838), Kuster (1910) reviewed cases with absent uteri from the literature in 1910. Hauser added his name to this syndrome calling it Mayer-Rokitansky-Kuster-Hauser in 1961 [4]. The incidence of this condition has been quoted to be 1 in 4, 500 to 5, 000 female births [1].

The MRKH syndrome predominantly exists in three types (Table 8C.1). Renal, skeletal, hearing, or rarely cardiac congenital anomalies are associated with MRKH [6]. Typical MRKH exists with no other genital malformation. Atypical MRKH is associated with malformations in the renal system and Müllerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia or MURCS when associated with renal and skeletal abnormalities [5]. In a study of 283 women with MRKH, Oppelt et al. [7] found the following frequencies: typical MRKH 54.9 percent, atypical MRKH 26 percent, and MURCS 13.4 percent.

Embryology of the Female Reproductive System

A brief synopsis of the embryological development of the reproductive structures and the renal system is presented to understand MRKH syndrome. In females, the Müllerian (paramesonephric) ducts arise from the mesoderm lateral to the mesonephric ducts at the 7th week of gestation (Figure 8C.1). Normal development of the Müllerian system depends on the completion of three phases: organogenesis, fusion, and septal resorption. The Müllerian ducts grow caudally, lateral to the urogenital ridges. They subsequently fuse to form a confluence that is a precursor to the upper two-thirds of the vagina, the cervix, the body of the uterus, and the Fallopian tubes. The unfused cranial ends of the Müllerian ducts form the Fallopian tubes, which open into the coelomic cavity (Figure 8C.1). The renal system develops in three stages: pronephros, mesonephros, and metanephros. The paired pronephros involute by the 5th week. The mesonephros forms in the 4th week. The Wollfian (mesonephric) ducts drain the mesonephros into the cloaca ventrally and nephrogenic cords laterally. The mesonephros and Wollfian ducts regress by the 3rd month and the metanephros eventually becomes the kidney. Arrested development and failed fusion of the Müllerian ducts lead to MRKH syndrome. Due to the close association of the Müllerian and caudal parts of the mesonephric duct, renal agenesis or ectopia can be associated with MRKH. Gonadal differentiation takes place at 7 weeks of fetal life. The primitive germ cells migrate to the genital ridge from the primitive yolk sac leading to the formation of the ovaries. Due to a separate embryological origin of the ovaries, they are spared in MRKH syndrome [1].

Figure 8C.1 Embryology of the female reproductive system

There are several classifications of Müllerian anomalies. According to the American Fertility Society classification (1988), MRKH falls into the first class of anomalies. In the CONUTA classification, MRKH is incorporated into class U5 of anomalies [9]. The U5 group of anomalies is further subdivided depending on the presence or absence of a functional cavity within a rudimentary uterus. Class U5a is characterized by the presence of a bi- or unilateral functional horn and class U5b by the presence of uterine tissue without a functional cavity and complete absence of any uterine tissue.

Diagnosis of MRKH Syndrome

The MRKH syndrome is usually identified when the individual presents with primary amenorrhea. Patients may report to primary care at age 13 or 14; however, due to the presence of normal secondary sexual characteristics, investigations or referral to secondary care may not take place until age 16. Some patients may present with unsuccessful attempts at coitus. Cyclical recurrent lower abdominal pain may result from endometrial proliferation within uterine buds (anlagan) if they contain active endometrium or from endometriosis, adenomyosis and myomas, which have been described in 6-10 percent of patients with MRKH syndrome [10]. History will reveal pubarche and thelarche at the usual time. In a study by Michala et al. [11], 53 percent of women with MRKH were found to have urinary symptoms. Therefore, a history of urinary function should be taken and any recurrent urinary problems need to be monitored.

Examination reveals normal female external genitalia. A small dimple or a short vagina may be seen. An examination under anesthesia is rarely required to make a diagnosis of MRKH. An ultrasound examination of the abdomen and pelvis or an MRI will usually provide adequate information [12].

Women with MRKH usually have a 46XX karyotype, normal gonadotrophins, and normal serum estrogen and testosterone levels [1]. Some patients with MRKH may also have clinical and biochemical hyperandrogenism along with polycystic ovary morphology [16]. A very low concentration of gonadotrophins with low estrogen suggests hypogonadotrophic hypogonadism (HH), and elevated gonadotrophins with low estradiol points toward premature ovarian insufficiency (POI) as the cause of primary amenorrhea. Both these conditions may inhibit development of the uterus leading to the suggestion of absent uterus on imaging studies and an incorrect diagnosis of MRKH syndrome. Michala and colleagues demonstrated the difficulty of diagnosing the absence of uteri before puberty and recommended that the diagnosis of an absent uterus should only be made after puberty or after estrogen supplementation in HH and POI [14]. A state of hypoestrogenism (HH, POI) may sometimes be confused with MRKH due to the presence of a small prepubertal uterus. Low or elevated gonadotrophins will help in diagnosis and estrogen supplementation will usually lead to the development of the uterus in POI and HH. Figure 8C.2 presents a flow chart showing the algorithm for diagnosis of MRKH.

Figure 8C.2 Flowchart for diagnosis of MRKH

MRI examination should ideally be performed to evaluate the pelvis and the urinary system. Ultrasound examination may be inconclusive depending on the experience of the operator. Although imaging usually reports an absent uterus, some rudimentary uterine buds are present in about 90 percent of MRKH patients. Hall-Craggs and coauthors [15] detected single or bipartite rudimentary uteri, which are often bilateral, in 92 percent of women with MRKH (Figure 8C.3). Ectopic ovaries were found either bilaterally or unilaterally. The ectopic ovaries were positioned in the pelvis either antero-laterally or far laterally and high in the pelvis just below the pelvic brim. Information on location of the ovaries is important when the patients wish to undergo fertility treatment. The route of oocyte retrieval will depend on the location of the ovaries.

Figure 8C.3 Variations in Müllerian duct development in MRKH

A study by Rall et al. [16] also revealed uterine rudiments showing a duct-like structure or small cavity, few of which contained endometrium. All rudiments contained an intact myometrial layer. Tubal epithelium and stroma were found in three rudimentary uteri. No significant differences were observed with regard to estrogen receptor (ER) or progesterone receptor (PR) expression in endometrium or myometrium.

Due to association of renal abnormalities with Müllerian anomalies, the assessment of the renal tract forms part of the routine investigation of patients presenting with Müllerian anomalies. In the largest series reporting the incidence of renal anomalies in patients with Müllerian duct anomalies (MDAs), unilateral renal agenesis has been reported in around 30 percent of patients. Other abnormalities are ectopic kidneys and ureters, duplex kidneys and ureters, and horseshoe kidney [17].

Genetics of MRKH Syndrome

The question that parents of girls with MRKH and MRKH patients often ask is the cause of the anomaly and whether the syndrome is genetically inherited. There is no clear evidence about whether MRKH is genetic, environmental, or both. The syndrome was initially considered to be a sporadic anomaly, but more recent literature supports a genetic link although no single gene defect has been identified [1]. The genetic mutations that have been investigated due to their roles in the development and differentiation of the female reproductive and urinary tract are listed in Table 8C.2.

It is safe to say that Müllerian anomalies display multifactorial rather than single gene inheritance. In familial cases, the syndrome appears to be transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity, which suggests the involvement of either mutations in a major developmental gene or a limited chromosomal imbalance [18,19]. Women with MRKH have not been shown to have increased abnormalities in offsprings. In a study of 58 women with MRKH undergoing infertility treatment with gestational surrogates, none of the 17 female infants born exhibited MRKH [20]. However, women with MRKH and other associated anomalies (renal, skeletal) may be more likely to have children with abnormalities [21].

In the light of this evidence or lack thereof, patients with MRKH should be counseled that their genetic offspring are likely to exhibit normal Müllerian anatomy at birth. No single gene defects have been identified to allow for preimplantation genetic diagnosis of the condition. Women in whom MRKH coincides with musculoskeletal, vertebral, or cardiac conditions may be more likely to pass their disorders to their children but this assumption requires more studies to establish this link.

Management of MRKH Syndrome

The management of MRKH syndrome includes three main aspects of care: neovagina creation, fertility issues, and psychological support. To adequately address all of these issues, the care of these patients should be delivered by a multidisciplinary team experienced in the management of these cases. The team should include a gynecologist, psychologist, nurse specialist, fertility specialist, and radiologist.

Creation of Neovagina

A few patients may be sexually active at presentation, having had natural dilation of the vaginal dimple due to repeated coitus. These patients require no further treatment for neovagina, unless they cease sexual activity, in which case dilation will be necessary to maintain the vaginal length. Dilation procedures for vaginal hypoplasia or agenesis in nonsexually experienced women include nonsurgical dilation therapy and surgical vaginoplasty [26].

Vaginal Dilation Therapy

In 1938, Frank described the use of Pyrex^® tubes of gradually increasing sizes (0.8, 1.5, and 2.0 cm in diameter) to stretch the mucous membrane inward into the introital region. For almost 40 years, this technique was only infrequently used. The downsides to this technique were fatigue of manual effort and the inability to engage in any other activities. To avoid the need to manually stretch and elongate the vaginal dimple, Ingram modified the technique in 1981 by inserting dilators into the saddle of a bicycle stool on which patients could sit astride to create pressure [28]. The seat was later modified by Lee [27] and Lankford and Haefner [29]. However these modifications involved bigger contraptions as opposed to the dilators that could be contained in a small box or case and therefore were more portable.

The ACOG [30] in 2002 recommended nonsurgical vaginal dilation as the first-choice treatment, because it is a patient-driven technique that is easy to perform, cost–effective, and safe. Successful neovaginal creation by dilation obviates the need for major surgery in most patients. It is expected that about 85 percent of women will achieve a functional vagina without a surgical approach [31,32]. The same group quoted a 94.9 percent success with creation of neovagina in patients who completed the vaginal dilation program [31]. This study was criticized for taking an arbitrary vaginal length of 6 cm as the outcome measure and not elaborating on how sexual satisfaction was evaluated [22]. Reasons for failure of vaginal self-dilation require further research. Failed vaginal dilation therapy may further jeopardize surgical vaginoplasty as most of these procedures require ongoing vaginal dilation.

Surgical Vaginoplasty

In the UK, surgical vaginoplasty is offered if vaginal dilation therapy fails. In other European countries, this is used as a first line for neovagina creation [34]. Surgical vaginoplasty began with creation of a pouch between the rectum and bladder. This was followed by split thickness skin grafts taken from the thigh or buttock that were inserted over the mold, after dissection of the space between the rectum and bladder. There were proponents of various types of skin grafts (pudendal thigh flaps, free flap graft from the vulvoperineal fasciocutaneous flaps). The drawbacks of most of these techniques were scars and keloid formation, lack of vaginal lubrication, hair regrowth in the Neovagina, and vaginal stenosis. It is rarely performed in the UK for MRKH [36].

Vecchietti Procedure

In 1965, Vecchietti proposed a device that used an upward traction on the vaginal dimple exerted by an acrylic olive in the vagina. The upward traction on the olive was created with the help of a device attached to the anterior abdominal wall into which the threads leading from the olive were connected. These threads were tightened daily for a week leading to the rapid creation of a neovaginal space [37]. This procedure was initially performed via laparotomy. The laparoscopic adaptation proposed in 1992 obviated the need for a large incision, thus improving healing and recovery [38]. The neovaginal epithelium is found to be macroscopically similar to normal vaginal mucosa. The complication rate including bladder and rectal wall injury was reported to be low [34]. A drawback for this procedure is its invasive nature and the pain resulting from the sustained traction that necessitates hospital stay for the duration of traction. Effective analgesia is needed during that time [26]. Vault prolapses have been reported after neovagina creation although not common [39]. This has been successfully treated by sacrospinous ligament suspension.

Davydov’s Procedure

Davydov developed a three-stage operation involving dissection of the rectovesical space with abdominal mobilization of the peritoneum, attachment of the peritoneum to the created introitus, and finally closure of the neovaginal vault with purse-string suture [40]. The claimed advantage of this technique by the authors is the lack of granulation tissue and scar formation. The procedure was modified to a laparoscopic approach, having the advantages of reduced blood loss and postoperative pain in addition to shorter hospital stay, faster recovery, and better cosmetic outcome [41].

Bowel Vaginoplasty

Use of ileal or sigmoid caecum loop for creation of neovagina has been described since the early 1900s. A laparoscopic approach has been carried out since 1996 [42], but the procedure is still most frequently performed through a laparotomy. The main advantages of this operation are said to be the lack of shrinkage with no requirement for long-term vaginal dilation and the natural lubrication provided by the mucous production that obviates the need for artificial lubricants and decreases the risk of dyspareunia [42]. These procedures are associated with greater morbidity than nonsurgical and laparoscopic approaches [2] and are seldom required in MRKH syndrome. Furthermore, many patients describe chronic unpleasant discharge as a consequence of mucosal secretions, which has led to requests for removal of the transposed bowel.

Creatsas Modification of Williams Vaginoplasty

Creatsas modified the Williams vaginoplasty by making a U-shaped incision in the vulva, starting at 4 cm lateral to the external urethral meatus and the medial side of the labia majora, extending down to the perineum and up the other side of the vulva. A layer of sutures is then placed on the inner skin margins to create a pouch. The perineal muscles and subcutaneous tissue are mobilized and approximated, before the external skin is closed. With this technique, vaginal dilation is not necessary and coitus can be commenced once the surgical wounds have healed. Of 200 patients undergoing this procedure, 95.5 percent have a vagina of length 10–12 cm and width 5 cm; 94.5 percent of patients reported a satisfactory quality of sexual life post-procedure. This last assessment, however, was not performed with a validated questionnaire [43].

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Related posts:

1. Chapter 1 – An Introduction to Pediatric and Adolescent Gynecology Practice
2. Chapter 7A – Menstrual Dysfunction in Pediatric and Adolescent Gynecology Practice
3. Chapter 9A – Urinary Problems in Pediatric and Adolescent Gynecology Practice
4. Chapter 9B – Urinary Problems in Pediatric and Adolescent Gynecology Practice

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