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Female Reproductive System ORGAN SYSTEMS

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome

Characterized by congenital aplasia of the uterus and the upper ⅔rd of vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype.

Introduction

Characterized by congenital aplasia of the uterus and the upper ⅔rd of vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype.

Also known as also referred to as CAUV (Congenital Absence of the Uterus and Vagina), MA (Müllerian Aplasia) or GRES (Genital Renal Ear Syndrome)

History:

MRKH syndrome is named after the authors of the four original descriptions published over a 130 year period by German anatomist August Franz Josef Karl Mayer (1829), Austrian anatomist Carl von Rokitansky (1838), German gynecologist Hermann Küster (1910) and Swiss gynecologist Georges Andre Hauser (1961). The first description of congenital absence of the uterus and vagina, however, is attributed to the Italian anatomist Realdo Colombo although his descriptions lacked detail. In his main work De Re Anatomica from 1562, he described in volume 15 titled De iis quae raro in anatome reperiuntur (english: Rare findings in anatomy) an entity he named vulva rara in a woman with no womb and vagina who complained of pain upon coitus. Centuries after Mayer and Rokitansky independently reported on autopsies of two deceased women in which they identified rudimentary uterine buds and described what they referred to as uterus bipartitus solidus cum vagina solida. Küster was the first to report this finding in a living patient from whom he removed the pain-causing uterine remnants, whereas Hauser and Schreiner completed the definition of uterovaginal agenesis in women with normal secondary sex characteristics and normal female karyotype based on a series of 21 cases.

a The original illustration by Carl von Rokitansky (1838) showing the uterovaginal morphology in MRKH syndrome with a shortened blind-ending vagina and two rudimentary uterine remnants. b A sagittal T2-weighted MRI showing complete uterovaginal absence in type II MRKH syndrome associated with renal agenesis and a solitary pelvic kidney. c The pelvis of a patient with MRKH syndrome during surgical preparation for uterus transplantation. The forceps is holding the fibrous uterine rudiment in the midline, while it is dissected free from the bladder. On the uterine buds, located on the pelvic sidewalls, small subserosal leiomyomas are seen on both sides. The ovaries are located medially towards the Pouch of Douglas | Herlin, M. K., Petersen, M. B., & Brännström, M. (2020). Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update. Orphanet journal of rare diseases, 15(1), 214. https://doi.org/10.1186/s13023-020-01491-9

These contributions all described isolated uterovaginal agenesis with no associated extragenital malformations, which in contemporary literature is referred to as type I MRKH syndrome. In 1977, Schmid-Tannwald and Hauser described seven cases with renal malformations which was named atypical MRKH syndrome.


Classification

Isolated (type I) MRKH

Less common type

MRKH type II or MURCS (Müllerian duct aplasia–renal agenesis–cervicothoracic somite dysplasia):

Rare developmental disorder with four common malformations
  1. Uterine hypoplasia/aplasia
  2. Renal agenesis/ectopy (30%)
  3. Vertebral anomalies (10–15%)
  4. Short stature (<152 cm)
  • Other less common features (2–3%): Auditory and cardiac defects

Embryology

The female reproductive tract in humans includes the oviducts (Fallopian tubes), uterus, cervix and vagina. The oviducts, uterus, cervix, and upper two-thirds of the vagina origin from the paramesonephric (Müllerian) ducts (PMD), whereas the lower part of the vagina origins from the urogenital sinus.

Paramesonephric (Müllerian) ducts (PMD):

  • Development starts around 5th–6th gestational week as bilateral craniocaudal invaginations of the coelomic epithelium of the urogenital ridges (intermediate mesoderm) growing caudally guided by the mesonephric (Wolffian) ducts to reach the urogenital sinus (endoderm)
  • The caudal part of the two PMDs fuses to form the uterus, cervix and upper vagina, whereas the upper parts of the PMDs form the two oviducts.

MRKH syndrome is caused by either complete agenesis or aplasia of the PMDs to form the uterus and upper vagina.


Clinical features

Primary amenorrhoea:

Absent menstrual periods by 16 years following normal puberty and development of secondary sex characteristics

Other findings:

  • Dyspareunia/apareunia
  • (Cyclic) abdominal pain

Diagnosis

G/Q-banding chromosomal analysis:

To confirm normal female karyotype (46,XX)

Ultrasound

First-line imaging modality revealing the absence of the uterus and presence of ovaries
USG showing the absence of uterine structure between the bladder and rectum. | Nath, K., Boro, B., & Naskar, S. (2016). A Rare Case of Mayer-Rokitansky-Kuster-Hauser Syndrome Presenting with Acute Psychosis. Journal of clinical and diagnostic research : JCDR, 10(4), VD03–VD04. https://doi.org/10.7860/JCDR/2016/18478.7658

Magnetic resonance imaging (MRI):

GOLD STANDARD; non-invasive and superior to CT in showing the Müllerian structures in detail (uterine remnants or complete agenesis) including the presence of endometrium in uterine remnants. MRI also shows the ovaries and extragenital malformations, and has high interrater agreement with laparoscopy
MRI of pelvis T2-weighted TSE images: Axial (A; at the level of symphysis pubis, B &C; at lower sacrum), and Mid-sagittal (D) showing absent cervix with interposition of bowel loops in the expected location of cervix (thick arrow in D). Rudimentary uteri (thick arrow in B) are interconnected at midline. The lower vagina is small (arrowhead in A). The vaginal vault is present (asterix in D). Both ovaries are normal (thin arrows in B). | R: Rectum. SP: symphysis pubis. TSE: turbo spin echo U: urethra. UB: urinary bladder. | Al Dandan, O., Hassan, A., Alsaihati, A., Aljawad, L., & Almejhim, F. (2019). A rare form of Mayer-Rokitansky-Küster-Hauser syndrome: Case report and review of literature. Case reports in women’s health, 24, e00137. https://doi.org/10.1016/j.crwh.2019.e00137

Diagnostic laparoscopy:

Rarely indicated for diagnostic purposes only, but may be relevant in patients with pain-causing uterine remnants where surgical removal of the tissue is needed

Differential diagnosis:

The phenotypic manifestations of MRKH syndrome overlap with various other syndromes or associations and thus require accurate delineation.
  • Isolated vaginal atresia
  • Androgen insensitivity syndrome (AIS)
MRKHAIS
Genotype XXGenotype XY
Normal female serum testosterone levelsNormal male testosterone levels
Normal female pubic and axillary hairDecreased pubic and axillary hair
Normal female heightIncreased height compared with female counterparts
Normal ovaries located high on the pelvic side wallIntra-abdominal testicles
No increased risk of gonadal malignancyGonads removal recommended after puberty due to increased risk of malignancy

Management

Neovagina:

Correction of vaginal agenesis in MRKH syndrome with creation of a functional neovagina has been a hallmark in the treatment
  • Surgical methods: Vaginoplasties using various autografts
    • McIndoe vaginoplasty (split-skin graft covering a mold placed in dissected pouch between rectum & bladder)
    • Baldwin vaginoplasty (bowel graft)
    • Davydov vaginoplasty (peritoneal graft)
    • Williams vulvavaginoplasty (labia majora flaps)
  • Non-surgical methods:
    • Frank’s method (self-dilation by progressive dilators manually placed on vaginal apex for 10–30 min 1-3 times/day) (First-line treatment)
    • d’Alberton’s method (dilation by intercourse; good anatomical & functional outcome compared with self-dilation and surgery)

Uterus transplantation (UTx):

First true infertility treatment for women with MRKH syndrome and giving them full (gestational, genetic, legal) motherhood from start.

History: The group in Gothenburg, Sweden, initiated basic UTx research in animal models already in 1999. The idea to this concept, was given by a young woman, with cervical cancer, who would undergo a radical hysterectomy. Through structured animal-based research and continuous ethics discussions within the research group in Sweden the team optimized the surgical technique, immunosuppression for a uterine graft, rejection diagnosis as well as assuring normal development of the offspring from allogeneic UTx. In 2012, the team received permission from the ethics board as well as permission from the hospital board to perform a prospective observational study of live donor UTx, including up to ten procedures. The surgeries, performed in 2013, included eight MRKH syndrome patients and one cervical cancer patient as recipients. The donors were five mothers, one sister, one maternal aunt, one mother-in-law and one family friend. The surgical outcome of the nine UTx procedures was that donor surgery was extremely difficult, with surgical durations of 10–13 h, but that the transplantation procedures in the recipients were simpler, with surgical durations of 4–5 h. Seven out of nine procedures were surgically successful, with viable grafts showing regular menstruations during the first post-transplantation year. 2 out of the 7 grafts had to be surgically removed during the initial months, because of vascular thrombosis in one case and intrauterine infection in the other case.

The proof-of-concept of UTx as an infertility treatment to women with MRKH came with the world’s first livebirth after UTx which took place in September, 2014 in Gothenburg, Sweden. This birth was followed by 7 more live births in Sweden, until the 9th UTx baby in the world was born in USA in December 2017, after a live donor UTx procedure.

A transplanted uterus in the pelvis of a woman with MRKH syndrome. The uterus is seen in the middle. The bladder is seen below the uterus and the rectum is above | Herlin, M. K., Petersen, M. B., & Brännström, M. (2020). Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update. Orphanet journal of rare diseases, 15(1), 214. https://doi.org/10.1186/s13023-020-01491-9

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