Summary
Rokitansky syndrome, or Mayer–Rokitansky–Küster–Hauser syndrome (MRKH) also known as Müllerian agenesis results from embryonic underdevelopment of the Müllerian duct, resulting in agenesis or atresia of the uterus, vagina or both. The vagina is shortened and may appear as just a dimple inferior to the urethra. A single midline uterine remnant may be present, or there may be uterine horns (with or without an endometrial cavity) which do not communicate with the vagina. This condition belongs to the most severe (class 5) of the ESHRE/ESGE classification [1].
9.1 Introduction
Rokitansky syndrome, or Mayer–Rokitansky–Küster–Hauser syndrome (MRKH), also known as Müllerian agenesis, results from embryonic underdevelopment of the Müllerian duct, resulting in agenesis or atresia of the uterus, vagina or both. The vagina is shortened and may appear as just a dimple inferior to the urethra. A single midline uterine remnant may be present, or there may be uterine horns (with or without an endometrial cavity) which do not communicate with the vagina. This condition belongs to the most severe (class 5) of the ESHRE/ESGE classification [Reference Grimbizis, Gordts, Di Spiezio Sardo, Brucker, De Angelis and Gergolet1].
9.2 Embryology
At around the fifth week of pregnancy, Müllerian ducts (paramesonephric ducts) appear. The caudal end of the ducts merge and become the superior two-thirds part of the vagina and uterine cervix, the intermediate part becomes the uterine body and the upper portions remain separate and form the fallopian tubes. In the same period the renal system develops, derived from Wolffian ducts (mesonephric ducts) within the mesenchyme of the metanephros.
Around this same period, there is migration of primordial germ cells from the yolk sac leading to the formation of the ovaries. These arise from mesenchyme and from the epithelium of the genital crest of the intermediate mesoderm. These processes are different and separate from those of the mesonephros, therefore anomalies of Müllerian ducts are not associated generally with anomalies of the ovary.
MRKH results due to failure of development between the fifth and sixth weeks of pregnancy and consequent fusion on the median line of Müllerian ducts, linked only to the caudal mesonephric ligament, destined to form the round ligament. The bladder and rudimentary vagina are unaffected as these arise from the Wolffian ducts and Gartner’s duct, respectively [Reference Pizzo, Lagana, Sturlese, Retto, Retto and De Dominici2].
9.3 Diagnosis
Patients with MRKH usually present with primary amenorrhoea with a normal female phenotype. Puberty is normal, with normal thelarche and adrenarche until periods fail to commence. On examination, patients with MRKH are normal in height, have normal breast development, normal pubic and axillary hair and normal female external genitalia. Vaginal examination reveals a shortened vagina, which may appear as a small dimple. There is no cervix at the apex of the vagina. See Figures 9.1 and 9.2.
Figure 9.1 Examination showing normal external female genitalia. Note normal pubic hair distribution.
Figure 9.2 Parting of labia to reveal short blind-ended vagina.
Investigations reveal a normal 46XX female karyotype and normal sex hormone levels. Imaging reveals an absent uterus. There may be Müllerian remnants, either a midline uterine remnant or uterine horns, which may contain endometrium. The ovaries are, in the vast majority of cases, normal in structure and function, although they may be in atypical locations. Although a pelvic ultrasound scan is appropriate for initial imaging, magnetic resonance imaging (MRI) is the recommended imaging modality. Rudimentary Müllerian structures are found in 90% of patients with MRKH by MRI and this modality can also assess the presence or absence of endometrial tissue within the Müllerian structures. Due to the accuracy of MRI, there is no role for routine laparoscopy in the diagnosis of MRKH. Some clinicians are content to use ultrasound as the primary imaging modality, reserving MRI for cases in which there is diagnostic uncertainty or pelvic pain. See Figure 9.3.
The differential diagnosis of MRKH includes obstructive uterine or vaginal anomalies and 46XY differences in sex development (e.g. complete androgen insensitivity syndrome). The former usually presents with painful primary amenorrhoea and a pelvic mass due to retained menses and the latter have sparse axillary and pubic hair and a 46XY karyotype.
9.4 Nomenclature
Rokitansky syndrome was first described by anatomist Bonn and physiologist Mayer in 1829 as a single case. Kussmaul (1859) and Rokitansky (1938) described one case each. Küster (1910) summarised the individual cases in a review paper of the literature, and finally Hauser named the ‘rudimentary solid septate uterus with solid vagina’ the Mayer–Rokitansky–Küster syndrome, to which his name was added, hence the name Mayer–Rokitansky–Küster–Hauser syndrome or MRKH.
9.5 Prevalence
The prevalence of MRKH has been estimated at 1 in 4000–5000 female births. A population-based study in Denmark, the largest to date, concluded that the incidence is 1 in 4962 live female births, in keeping with previous estimates. 168 patients were included, and patient characteristics described [Reference Herlin, Bjorn, Rasmussen, Trolle and Peterson3].
MRKH is divided into two groups: typical/type I (isolated utero-vaginal agenesis) and atypical/type II (associated with extragenital malformations of the kidneys, skeleton, heart and auditory systems). The most frequent of these are renal (34.2%), skeletal (12.5%) and cardiac (3.6%) This is in keeping with previous reports (see Table 9.1). Some cases of type II MRKH can further fulfil the criteria of Müllerian duct aplasia, renal aplasia and cervicothoracic somite dysplasia (MURCS). In this cohort, the distribution of typical MRKH syndrome was 56.5%, and that of atypical MRKH syndrome/MURCS was 43.5%.
| MRKH syndrome | Associated anomalies | Frequency (%) | |
|---|---|---|---|
| Oppeit (2006) | Herlin (2016) | ||
| Typical | Tubes, ovaries, renal system normal | 64 | 56.5 |
| Atypical | Anamolies of ovary or renal system | 24 | 43.5 |
| MURCS | Anomalies in the skeleton and/or heart; muscular weakness, renal malformation | 12 | |
Note. From Oppelt P, Renner SP, Kellermann A, Brucker S, Hauser GA, Ludwig KS, et al. Clinical aspects of Mayer–Rokitansky–Kuester–Hauser syndrome: recommendations for clinical diagnosis and staging. Hum Reprod. 2006;21(3):792–7; Herlin M, Bay Bjorn AM, Rasmussen M, Trolle B, Petersen MB. Prevalence and patient characteristics of Mayer–Rokitansky–Kuester–Hauser syndrome: a nationwide registry-based study. Hum Reprod. 2016;31(10):2384–90.
Many extragenital manifestations have been described. Although not a completely exhaustive list, these are described in Table 9.2.
| System | Frequency (%) | Anomaly |
|---|---|---|
| Renal | 30–40 |
|
| Skeletal – spine | 30–40 |
|
| Skeletal – face and limb | 16 |
|
| Auditory | 10–25 |
|
Note. From Morcel K, Camborieux L. Mayer–Rokitansky–Kuester–Hauser (MRKH) syndrome. Orphanet J Rare Dis. 2007;14(2):13.
9.6 Genetics of MRKH
The aetiology of MRKH remains unclear. It is characterised by a heterogeneous aetiology and inheritance pattern. Familial as well as sporadic cases have been reported. Familial cases support an inherited predisposition, but a clear pattern of inheritance is yet to be described. The most frequent mode of inheritance appears to be autosomal dominant transmission with sex-linked (female) expression and incomplete penetrance. MRKH syndrome is, however, mainly sporadic [Reference Fontana, Gentilin, Fedele, Gernvasini and Miozzo4].
Several gene mutations have been identified in MRKH patients including mutations affecting the following genes: LHX1, TBX6, WNT4, WNT7A, WNT9B.
Genetic counselling for families of patients with MRKH is complicated by the polygenic/multifactorial nature of inheritance. An empirical recurrence risk of 1%–5% has been defined for first-degree relatives. Studies of the biological offspring of patients with MRKH via surrogacy have shown no affected babies reported, and only one male child with a middle ear defect.
9.7 Management Principles
The management of MRKH comprises three principles: creation of a vagina for coitus (if desired), fertility issues and psychological support. These management areas are all crucial for successful management of these patients, and therefore management should be within centres experienced in managing MRKH. These centres should possess a fully functioning multidisciplinary team able to offer a vaginal dilation programme, surgical treatment, fertility counselling, psychology and genetic counselling.
9.7.1 Vaginal Creation
Vaginal elongation is usually necessary in patients with MRKH for penetrative coitus to occur. This can be achieved by coital dilation (elongation of the vagina by repeated attempts at coitus), non-surgical vaginal dilation or surgical techniques of vaginal creation.
9.7.1.1 Primary Vaginal Dilation
Primary vaginal dilation is a non-surgical technique of vaginal elongation, originally described by Frank (1938), in which the vagina is lengthened and widened gradually using vaginal dilators of increasing lengths and widths being advanced via sustained, repeated pressure on the vaginal dimple until a vaginal length exceeding 6 cm is achieved. This technique has the advantages of being patient-controlled, safe, less painful and lower cost than operative techniques. This technique was then modified by Ingram (1981) using a variation of the vaginal dilator and a bicycle seat stool. With this technique, the dilator is held in place by a light girdle, and clothing can be worn over this. The pressure is maintained for 2 hours per day by sitting on a specially modified bicycle seat stool. This avoids fatigue on the hands and the necessity to adopt lithotomy, squatting or Sims’ position, and allows the patient to perform other activities during the hours of pressure required. Vaginal dilation via Frank’s technique is still, however, the most frequently used method.
The most commonly reported reasons for discontinuing dilation prior to achieving success are lack of motivation and readiness. These issues should be explored prior to embarking on dilator therapy. The patient should be encouraged to start dilation when she truly feels ready and motivated to do so. Patients who start dilation prior to the age of 18 have lower anatomic success (47% vs 78%) when compared with those 18 and over, but both age ranges report similar functional success (78% in the under 18 group vs 76% of those 18 and over).
Other barriers to successful dilation include psychosocial issues (poor compliance, sociocultural factors, interpersonal conflict), cognitive issues (young age, lack of knowledge of process, underlying learning disability), logistical (lack of privacy, travel distance from clinic) and anatomic (discomfort/pain), scar from prior operation, absence of dimple [Reference Oelschlager, Debiec and Appelbaum5].
9.7.1.1.1 Frequency of Dilation
In terms of achieving anatomical success, frequency may be more important than duration. Patients instructed to dilate for 10 minutes three times per day achieve higher rates of anatomic success when compared with those instructed to dilate once per day for 30 minutes (76% vs 46%, respectively). There is no difference, however, in functional success in these two groups (78% three times daily vs 84% once daily). Starting vaginal length is not correlated with ending vaginal length but may be associated with duration of dilator therapy.
Vaginal dilation can be associated with bleeding, pain or urinary symptoms. These can usually be successfully managed with appropriate support and advice. Thus, ongoing support during the dilation programme is paramount to success. This support is often nurse-led, with psychology input.
9.7.1.2 Surgical Neovagina Creation
The primary aim of surgery in the creation of a neovagina is to allow penetrative intercourse. There have been several techniques described, and no clear consensus exists regarding the best technique.
Regardless of the technique chosen, this should be performed by experienced operators as the first procedure is more likely to succeed than follow-up procedures.
9.7.1.2.1 Modified Abbe–McIndoe Operation
This procedure utilises a vaginal approach. A space between the bladder and rectum is dissected, a stent covered with a split-thickness skin graft is placed into the space, and vaginal dilation is performed postoperatively. There is a high rate of graft take and low rate of prolapse. Postoperative dilation is necessary and there is a high rate of graft contracture and neovaginal stenosis. Other issues include a lack of lubrication and a risk of squamous cell carcinoma. Complication rates are up to 14%. Modifications of this procedure include using allogenic tissue or autologous vaginal mucosa to line the neovagina.
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