Müllerian agenesis

Müllerian agenesis
Synonyms Mayer–Rokitansky–Küster–Hauser syndrome (MRKH), Rokitansky–Küster–Hauser syndrome (RKH or RKHS
Classification and external resources
Specialty medical genetics
ICD-10 Q51.0, Q52.0
ICD-9-CM 626.0
OMIM 158330
DiseasesDB 8390

Müllerian agenesis 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 cause in 15% of cases of primary amenorrhoea.[1] Because most of the vagina does not develop from the Müllerian duct, instead developing from the urogenital sinus along with the bladder and urethra, it is present even when the Müllerian duct is completely absent.

Because ovaries do not develop from the müllerian ducts, affected women might have normal secondary sexual characteristics but are infertile due to the lack of a functional uterus. However, motherhood is possible through use of gestational surrogates. MRKH is hypothesized to be a result of autosomal dominant inheritance with incomplete penetrance and variable expressivity, which contributes to the complexity involved in identifying of the underlying mechanisms causing the condition. Because of the variance in inheritance, penetrance and expressivity patterns, MRKH is subdivided into two types: type 1, in which only the structures developing from the müllerian duct are affected (the upper vagina, cervix, and uterus), and type 2, where the same structures are affected, but is characterized by the additional malformations of other body systems most often including the renal and skeletal systems. MRKH type 2 includes MURCS (Müllerian Renal Cervical Somite). The majority of MRKH syndrome cases are characterized as sporadic, but familial cases have provided evidence that, at least for some patients, MRKH is an inherited disorder. The underlying causes of MRKH syndrome is still being investigated, but several causative genes have been studied for their possible association with the syndrome. Most of these studies have served to rule-out genes as causative factors in MRKH, but thus far, only WNT4 has been associated with MRKH with hyperandrogenism.[2][3]

The medical eponym honors August Franz Josef Karl Mayer (1787–1865), Carl Freiherr von Rokitansky (1804–1878), Hermann Küster (1879–1964), and Georges Andre Hauser (1921–2009).

Signs and symptoms

An individual with this condition is hormonally normal; that is, the person will enter puberty with development of secondary sexual characteristics including thelarche and adrenarche (pubic hair). The person's chromosome constellation will be 46,XX. At least one ovary is intact, if not both, 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, a person with MRKH cannot carry a pregnancy without intervention. It is possible for the person to have genetic offspring by in vitro fertilization (IVF) and surrogacy. Successful uterine transplant has been performed in limited numbers of patients, resulting in several live births, but the technique is not widespread or accessible to many women.[4]

A person with MRKH typically discovers 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

Causes

Woman with MRKH, in this case exhibiting vaginal agenesis.

WNT4 (found on the short arm (p) of chromosome 1) 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.[5] 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.[5] 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.[6]

An association with a deletion mutation in the long arm (q) of 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.[7]

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,[8] 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.[9][10] 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.[11] 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.[12]

Uterine transplantation has been performed in a number of people with MRKH, but the surgery is still in the experimental stage.[13] 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.[14][15] 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.[16][17] 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.[18][19]

Epidemiology

The prevalence remains sparsely investigated. To date, two population-based nationwide studies have been conducted both estimating a prevalence about 1 in 5000 live female births.[20][21] According to some reports, Queen Amalia of Greece may have had the syndrome, but a 2011 review of the historical evidence concludes that it is not possible to determine the inability of her and her husband to have a child.[22] Her inability to provide an heir contributed to the overthrow of her husband, King Otto.[22]

See also

References

  1. ↑ Welt, Corinne K.; Barbieri, Robert L. "Etiology, diagnosis, and treatment of primary amenorrhea". Retrieved 19 November 2015.
  2. ↑ Woten, Mary. "Quick Lesson: Mayer-Rokitansky-Kuster-Hauser Syndrome." Ed. Diane Pravikoff. Cinahl Information Systems (n.d.): n. pag. Web.
  3. ↑ Fontana, L., B. Gentilin, L. Fedele, C. Gervasini, and M. Miozzo. "Genetics of Mayer–Rokitansky–Küster–Hauser (MRKH) Syndrome." Clinical Genetics. Blackwell Publishing Ltd, 16 Nov. 2016. Web. 16 Apr. 2017.
  4. ↑ Lewis, Tim. "Uterus transplants: My sister gave me her womb". Retrieved 10 July 2016.
  5. 1 2 3 Sultan, C.; Biason-Lauber, A.; Philibert, P. (2009). "Mayer–Rokitansky–Kuster–Hauser syndrome: Recent clinical and genetic findings". Gynecological Endocrinology. 25 (1): 8–11. PMID 19165657. doi:10.1080/09513590802288291.
  6. ↑ "WNT4 Müllerian aplasia and ovarian dysfunction". Genetics Home Reference. Retrieved 2012-08-18.
  7. ↑ Ledig S, Brucker S, Barresi G, Schomburg J, Rall K, Wieacker P (2012) Frame shift mutation of LHX1 is associated with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Hum Reprod
  8. ↑ S. Saraf; P. Saraf (2007). "McIndoe Vaginoplasty: Revisited". The Internet Journal of Gynecology and Obstetrics. Internet Scientific Publications. 6 (2). ISSN 1528-8439. doi:10.5580/2137. Retrieved 2009-07-17.
  9. ↑ Vecchietti G (1965). "[Creation of an artificial vagina in Rokitansky-Küster-Hauser syndrome]". Attual Ostet Ginecol (in Italian). 11 (2): 131–47. PMID 5319813.
  10. ↑ Fedele L, Bianchi S, Tozzi L, Borruto F, Vignali M (1996). "A new laparoscopic procedure for creation of a neovagina in Mayer-Rokitansky-Kuster-Hauser syndrome". Fertil. Steril. 66 (5): 854–7. PMID 8893702.
  11. ↑ "Vecchietti Procedure" (PDF). University College University Hospitals. Retrieved 2010-04-03..
  12. ↑ Hold MK (2007-01-16). "Modernes Management der angeborenen (Mayer-Rokitansky- Küster-Hauser, MRKH-Syndrom) und erworbenen Vaginalaplasie" (PDF). Frauenheilkunde-Aktuell (in German).
  13. ↑ Ozkan, Omer; Akar, Munire Erman; Ozkan, Ozlenen; Erdogan, Okan; Hadimioglu, Necmiye; Yilmaz, Murat; Gunseren, Filiz; Cincik, Mehmet; Pestereli, Elif; Kocak, Huseyin; Mutlu, Derya; Dinckan, Ayhan; Gecici, Omer; Bektas, Gamze; Suleymanlar, Gultekin (February 2013). "Preliminary results of the first human uterus transplantation from a multiorgan donor". Fertility and Sterility. 99 (2): 470–476.e5. PMID 23084266. doi:10.1016/j.fertnstert.2012.09.035.
  14. ↑ Akhter, Nasreen; Begum, Badrunnesa (3 February 2013). "Evaluation and management of cases of primary amenorrhoea with MRKH syndrome". Bangladesh Medical Journal Khulna. 45 (1–2). doi:10.3329/bmjk.v45i1-2.13626.
  15. ↑ "Rokitansky Syndrome: Information for Parents / Carers" (PDF). St Mary's Hospital, Manchester. Retrieved 11 April 2014.
  16. ↑ "Laboratory-grown vaginas implanted in patients". Retrieved 14 April 2014.
  17. ↑ Atlántida M Raya-Rivera; et al. "Tissue-engineered autologous vaginal organs in patients: a pilot cohort study". The Lancet. Elsevier Ltd. 384: 329–336. doi:10.1016/S0140-6736(14)60542-0. Retrieved 14 April 2014.
  18. ↑ Catherine de Lange (2014). "Engineered vaginas grown in women for the first time". New Scientist.
  19. ↑ Raya-Rivera AM, Esquiliano D, Fierro-Pastrana R, Lopez-Bayghen E, Valencia P, Ordorica-Flores R, Soker S, Yoo JJ, Atala A (2014-04-11). "Tissue-engineered autologous vaginal organs in patients: a pilot cohort study". Lancet. 384: 329–36. PMID 24726478. doi:10.1016/S0140-6736(14)60542-0.
  20. ↑ Aittomäki, K; et al. (2001). "A population-based study of the incidence of Müllerian aplasia in Finland.". Fertility & Sterility. 76 (3).
  21. ↑ Herlin, M; Bjørn, AB; et al. (2016). "Prevalence and patient characteristics of Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide registry-based study". Human Reproduction. 31 (10): 2384–90. doi:10.1093/humrep/dew220.
  22. 1 2 Poulakou-Rebelakou, E; C Tsiamis; N Tompros; G Creatsas (2011). "The lack of a child, the loss of a throne: the infertility of the first royal couple of Greece (1833–62)" (PDF). J R Coll Physicians Edinb. 41 (1): 73–7. PMID 21365071. doi:10.4997/JRCPE.2011.115.

Further reading

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