Müllerian agenesis, also known as vaginal agenesis and Mayer–Rokitansky–Küster–Hauser syndrome (MRKH syndrome), is a birth defect characterized by a failure of the Müllerian ducts to develop, resulting in a missing uterus and variable degrees of underdevelopment of the upper vagina. It is the cause of 15% of primary amenorrhoea. 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 remains present. Because ovaries 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, biological motherhood is possible through uterus transplantation or use of gestational surrogates. It is believed to be of autosomal dominant inheritance with incomplete penetrance and variable expressivity, which has made it difficult to determine the underlying mechanisms. It 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 other body systems, most often the kidneys and bones, have additional malformations. Type 2 includes MURCS (Müllerian renal cervical somite). The majority of cases are sporadic, but familial cases have provided evidence that, at least for some, it is an inherited disorder. The underlying causes are being investigated, with several genes possibly associated. Most of these studies have served to rule-out genes as causative factors, but thus far, only WNT4 has been associated with Müllerian agenesis with hyperandrogenism. Reports of the condityion can be traced back to Hippocrates (460–377 BC). 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 A female with this condition is hormonally normal; that is, the woman will enter puberty with development of secondary sexual characteristics including thelarche (breast development) and pubarche (pubic hair). The woman's karyotype 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 most 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 woman with Müllerian agenesis cannot carry a pregnancy without intervention. It is possible for the woman 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. A woman with Müllerian agenesis 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.
Causes The etiology of Müllerian agenesis in many cases remains elusive. However, mutations in a variety of different genes have been implicated in causing MRKH syndrome. The typical and atypical forms of the disorder are presumably caused by mutations in different genes. 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. 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, and much of the vagina, are hence affected. An association with 17q12 microdeletion syndrome, a deletion mutation in the long arm (q) of chromosome 17, has been reported. The gene LHX1 is located in this region and may be the cause of a number of these cases.
Diagnosis
Classification Typical Müllerian agenesis – Isolated uterovaginal aplasia/hypoplasia Prevalence – 64% Atypical Müllerian agenesis – Uterovaginal aplasia/hypoplasia with renal malformation or uterovaginal aplasia/hypoplasia with ovarian dysfunction Prevalence – 24% MURCS syndrome – Uterovaginal aplasia/hypoplasia with renal malformation, skeletal malformation, and cardiac malformation Prevalence – 12%
Treatment
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