Müllerian agenesis, also known as Müllerian aplasia, vaginal agenesis, or Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome), is a

congenital malformation A birth defect, also known as a congenital disorder, is an abnormal condition that is present at childbirth, birth regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellect ...

characterized by a failure of the

Müllerian duct Paramesonephric ducts (or Müllerian ducts) are paired ducts of the embryo that run down the lateral sides of the genital ridge and terminate at the sinus tubercle in the primitive urogenital sinus. In the female, they will develop to form the fal ...

s to develop, resulting in a missing

uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...

and variable degrees of

vaginal hypoplasia Vaginal hypoplasia is the underdevelopment or incomplete development of the vagina. It is a birth defect or congenital abnormality of the female genitourinary system. Signs and symptoms Vaginal hypoplasia can vary in severity from being smaller t ...

of its upper portion. Müllerian agenesis (including absence of the uterus, cervix and/or

vagina In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hymen ...

) is the cause in 15% of cases of primary

amenorrhoea Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of mense ...

. Because most of the vagina does not develop from the Müllerian duct, instead developing from the

urogenital sinus The urogenital sinus is a part of the human body only present in the development of the urinary and reproductive organs. It is the ventral part of the cloaca, formed after the cloaca separates from the anal canal during the fourth to seventh w ...

, along with the

bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...

and

urethra The urethra (from Greek οὐρήθρα – ''ourḗthrā'') is a tube that connects the urinary bladder to the urinary meatus for the removal of urine from the body of both females and males. In human females and other primates, the urethra c ...

, it is present even when the Müllerian duct is completely absent. Because

ovaries The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...

do not develop from the Müllerian ducts, affected people might have normal secondary sexual characteristics but are infertile due to the lack of a functional uterus. However, parenthood is possible through use of gestational surrogates. Müllerian agenesis is hypothesized to be a result of autosomal dominant inheritance with incomplete

penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...

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, Müllerian agenesis 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. Type 2 includes MURCS (Müllerian Renal Cervical Somite). The majority of Müllerian agenesis cases are characterized as sporadic, but familial cases have provided evidence that, at least for some patients, it is an inherited disorder. The underlying causes are 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, but thus far, only ''

WNT4 WNT4 is a secreted protein that in humans is encoded by the ''Wnt4'' gene, found on chromosome 1. It promotes female sex development and represses male sex development. Loss of function can have serious consequences, such as female to male sex rev ...

'' has been associated with Müllerian agenesis with

hyperandrogenism Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea (inflamed skin), hair loss on the scalp, increased body or facia ...

. Reports of Müllerian agenesis can be traced back to Hippocrates (460 B.C.–377 B.C.). The

medical eponym Medical eponyms are terms used in medicine which are named after people (and occasionally places or things). In 1975, the Canadian National Institutes of Health held a conference that discussed the naming of diseases and conditions. This was repo ...

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

A female with this condition is hormonally normal; that is, the woman will enter

puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a bo ...

with development of secondary sexual characteristics including

thelarche Thelarche, also known as breast budding, is the onset of secondary breast development, often representing the beginning of pubertal development. It is the stage at which male and female breasts differentiate due to variance in hormone levels; howe ...

and pubarche (pubic hair). The woman's karyotype will be 46,XX. At least one ovary is intact, if not both, and

ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...

usually occurs. Typically, the

is shortened and intercourse may, in some cases, be difficult and painful. Medical examination supported by

gynecologic ultrasonography Gynecologic ultrasonography or gynecologic sonography refers to the application of medical ultrasonography to the female pelvic organs (specifically the uterus, the ovaries, and the fallopian tubes) as well as the bladder, the adnexa, and the rec ...

demonstrates a complete or partial absence of the cervix,

, and vagina. If there is no uterus, a woman with Müllerian agenesis cannot carry a pregnancy without intervention. It is possible for the woman to have genetic offspring by

in vitro fertilization In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...

(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. A woman with Müllerian agenesis typically discovers the condition when, during puberty years, the menstrual cycle does not start (primary

). Some find out earlier through surgeries for other conditions, such as a

hernia A hernia is the abnormal exit of tissue or an organ, such as the bowel, through the wall of the cavity in which it normally resides. Various types of hernias can occur, most commonly involving the abdomen, and specifically the groin. Groin herni ...

Causes

The etiology of Müllerian agenesis in many cases remains elusive. However,

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...

s in a variety of different

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

s have been implicated in causing MRKH syndrome. The typical and atypical forms of the disorder are presumably caused by mutations in different genes.

(found on the short arm (p) of

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...

) 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

, the

is either deformed or absent. Female reproductive organs, such as the cervix,

fallopian tubes The fallopian tubes, also known as uterine tubes, oviducts or salpinges (singular salpinx), are paired tubes in the human female that stretch from the uterus to the ovaries. The fallopian tubes are part of the female reproductive system. In ot ...

, and much of the

, are hence affected. An association with 17q12 microdeletion syndrome, a deletion mutation in the long arm (q) of

chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...

, has been reported. The gene ''

LHX1 LIM homeobox 1 is a protein that in humans is encoded by the LHX1 gene. This gene encodes a member of a large protein family which contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor i ...

'' is located in this region and may be the cause of a number of these cases.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

Diagnosis

Classification

* Typical Müllerian agenesis – Isolated uterovaginal

aplasia Aplasia (; from Greek ''a'', "not", "no" + ''plasis'', "formation") is a birth defect where an organ or tissue is wholly or largely absent. It is caused by a defect in a developmental process. Aplastic anemia is the failure of the body to produc ...

/ hypoplasia ** Prevalence – 64% * Atypical Müllerian agenesis – Uterovaginal

/ hypoplasia with renal malformation or uterovaginal

/ hypoplasia with ovarian dysfunction ** Prevalence – 24% * MURCS syndrome – Uterovaginal

/ hypoplasia with renal malformation, skeletal malformation, and cardiac malformation ** Prevalence – 12%

Treatment

A number of treatments have become available to create a functioning vagina, the first successful uterus transplantation has been done in 2021, giving fertility to the transplant recipient. Standard approaches use vaginal dilators and/or surgery to develop a functioning

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 An artificial vagina is a device designed to imitate the female sex organ. To achieve this, it will generally be made of a soft material, lubricated, and sometimes heated. There are different types of artificial vaginas. They may be designed ...

. After the surgery, dilators are still necessary to prevent vaginal stenosis. The

Vecchietti procedure Vaginoplasty is any surgical procedure that results in the construction or reconstruction of the vagina. It is a type of genitoplasty. Pelvic organ prolapse is often treated with one or more surgeries to repair the vagina. Sometimes a vaginoplas ...

has been shown to result in a

that is comparable to a normal

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 Laparoscopy () is an operation performed in the abdomen or pelvis using small incisions (usually 0.5–1.5 cm) with the aid of a camera. The laparoscope aids diagnosis or therapeutic interventions with a few small cuts in the abdomen.Medli ...

. 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

by approximately 1 cm per day, creating a

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 Müllerian agenesis, but the surgery is still in the experimental stage. Since

are present, people with this condition can have genetic children through

IVF In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...

with

embryo transfer Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus of a female with the intent to establish a pregnancy. This technique (which is often used in connection with in vitro fertilizati ...

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 woman 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 woman'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.

Epidemiology

The prevalence remains sparsely investigated. To date, two population-based nationwide studies have been conducted both estimating a prevalence about 1 in 5,000 live female births. 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. Their inability to conceive an heir contributed to the overthrow of the king King Otto.

People with Müllerian agenesis

* Ben Barres, transgender male scientist * Esther Morris Leidolf, medical sociologist and

intersex Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical bin ...

activist * Stephanie Lum, Australian intersex activist * Shon Klose, Australian intersex activist and musician * Jaclyn Schultz, Miss Michigan

Suspected cases

Eva Braun Eva Anna Paula Hitler (; 6 February 1912 – 30 April 1945) was a German photographer who was the longtime companion and briefly the wife of Adolf Hitler. Braun met Hitler in Munich when she was a 17-year-old assistant and model for his ...

Amalia of Oldenburg Amalia of Oldenburg (; 21 December 181820 May 1875) was a Bavarian princess who became Queen of Greece from 1836 to 1862 as the wife of King Otto Friedrich Ludwig. She was loved widely by the Greeks due to her patriotic love for the country ...

References

External links

*
American College of Obstetricians and Gynecologists, Müllerian Agenesis: Resource Overview
{{DEFAULTSORT:Mullerian Agenesis Congenital disorders of female genital organs Pediatric gynecology Intersex variations Congenital malformations of uterus and cervix