Müllerian agenesis

Müllerian agenesis
Classification and external resources
Specialty
ICD-10	Q51.0, Q52.0
ICD-9-CM	626.0
OMIM	158330
DiseasesDB	8390
Patient UK	Müllerian agenesis

Müllerian agenesis, also called Mayer-Rokitansky-Küster-Hauser syndrome or MRKH, named after August Franz Joseph Karl Mayer, Carl Freiherr von Rokitansky, Hermann Kuster, and G. A. Hauser, is a congenital malformation characterized by a failure of the Müllerian duct to develop, resulting in a missing uterus and variable degrees of vaginal hypoplasia of its upper portion. Müllerian agenesis (including absence of the uterus, cervix and/or vagina) is the etiology in 15% of cases of primary amenorrhoea.

Signs and symptoms

An individual with this condition is hormonally normal; that is, they will enter puberty with development of secondary sexual characteristics including thelarche and adrenarche (pubic hair). Their chromosome constellation will be 46,XX. Ovaries are intact and ovulation usually occurs. Typically, the vagina is shortened and intercourse may, in some cases, be difficult and painful. Medical examination supported by gynecologic ultrasonography demonstrates a complete or partial absence of the cervix, uterus, and vagina.

If there is no uterus, people with MRKH cannot carry a pregnancy. However, it is possible for them to have genetic offspring by in vitro fertilization (IVF) and surrogacy. Treatment by uterine transplantation is still in its infancy.

People with MRKH typically discover the condition when, during puberty years, the menstrual cycle does not start (primary amenorrhoea). Some find out earlier through surgeries for other conditions, such as a hernia.

Classification

• Typical MRKH – Isolated uterovaginal aplasia/hypoplasia
  • Prevalence – 64 percent
• Atypical MRKH – Uterovaginal aplasia/hypoplasia with renal malformation or uterovaginal aplasia/hypoplasia with ovarian dysfunction
  • Prevalence – 24 percent
• MURCS syndrome – Uterovaginal aplasia/hypoplasia with renal malformation, skeletal malformation, and cardiac malformation
  • Prevalence – 12 percent

Causes

Woman with MRKH, in this case exhibiting vaginal agenesis.

WNT4 has been clearly implicated in the atypical version of this disorder. A genetic mutation causes a leucine to proline residue substitution at amino acid position 12. This occurrence reduces the intranuclear levels of β catenin. In addition, it removes the inhibition of steroidogenic enzymes like 3β-hydroxysteriod dehydrogenase and 17α-hydroxylase. Patients therefore have androgen excess. Furthermore, without WNT4, the Müllerian duct is either deformed or absent. Female reproductive organs, such as the cervix, fallopian tubes, ovaries, and much of the vagina, are hence affected.

An association with a deletion mutation in chromosome 17 (17q12) has been reported. The gene LHX1 is located in this region and may be the cause of a number of these cases.

Prevalence

The estimated prevalence is 1 in 12000 females with XX chromosomes. Queen Amalia of Greece was found post mortem to have had the syndrome. Her inability to provide an heir contributed to the overthrow of her husband, King Otto.

Treatment

A number of treatments have become available to create a functioning vagina, yet in the absence of a uterus currently no surgery is available to make pregnancy possible. Standard approaches use vaginal dilators and/or surgery to develop a functioning vagina to allow for penetrative sexual intercourse. A number of surgical approaches have been used. In the McIndoe procedure, a skin graft is applied to form an artificial vagina. After the surgery, dilators are still necessary to prevent vaginal stenosis. The Vecchietti procedure has been shown to result in a vagina that is comparable to a normal vagina in patients. In the Vecchietti procedure, a small plastic “olive” is threaded against the vaginal area, and the threads are drawn through the vaginal skin, up through the abdomen and through the navel using laparoscopic surgery. There the threads are attached to a traction device. The operation takes about 45 minutes. The traction device is then tightened daily so the olive is pulled inwards and stretches the vagina by approximately 1 cm per day, creating a vagina approximately 7 cm deep in 7 days, although it can be more than this. Another approach is the use of an autotransplant of a resected sigmoid colon using laparoscopic surgery; results are reported to be very good with the transplant becoming a functional vagina.

Uterine transplantation has been performed in a number of people with MRKH, but the surgery is still in the experimental stage. Since ovaries are present, people with this condition can have genetic children through IVF with embryo transfer to a gestational carrier. Some also choose to adopt. In October 2014 it was reported that a month earlier a 36-year-old Swedish woman became the first person with a transplanted uterus to give birth to a healthy baby. She was born without a uterus, but had functioning ovaries. She and the father went through IVF to produce 11 embryos, which were then frozen. Doctors at the University of Gothenburg then performed the uterus transplant, the donor being a 61-year-old family friend. One of the frozen embryos was implanted a year after the transplant, and the baby boy was born prematurely at 31 weeks after the mother developed pre-eclampsia.

Promising research include the use of laboratory-grown structures, which are less subject to the complications of non-vaginal tissue, and may be grown using the person's own cells as a culture source. The recent development of engineered vaginas using the patient's own cells has resulted in fully functioning vaginas capable of menstruation and orgasm in a number of patients showing promise of fully correcting this condition in some of the sufferers.

See also

• Cervical agenesis
• Vaginal hypoplasia
• MURCS association
• Regenerative medicine

Further reading

Original publications

• Mayer CAJ: Über Verdoppelungen des Uterus und ihre Arten, nebst Bemerkungen über Hasenscharte und Wolfsrachen. J Chir Auger 1829; 13:525-565.
• Rokitansky K: Über die sogenannten Verdoppelungen des Uterus. Med Jahrb Ost Staat 1838; 26:39-77.
• Küster H: Uterus bipartitus solidus rudimentarius cum vagina solida. Z Geb Gyn 1910; 67:692.
• Hauser GA, Schreiner WE: Mayer-Rokitansky-Küster syndrome: rudimentary solid bipartite uterus with solid vagina. Schweiz Med Wochenschr 1961; 91:381-384

External links

• Online 'Mendelian Inheritance in Man' (OMIM) 277000
• MRKH Organization
• MRKH UK
• The National Centre for Adolescent and Adult Females with Congenital Abnormalities of the Genital Tract (UK)
• MRKH Support at askaboutMRKH
• Mayer-Rokitansky-Küster-Hauser Syndrome on WebMD