Genetics of Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also referred to as Müllerian agenesis, is the second most common cause of primary amenorrhea. It is characterized by congenital absence of the uterus, cervix, and the upper part of the vagina in otherwise phenotypically normal 46,XX females. MRKH syndrome has an incidence of about 1 in 4,500-5,000 newborn females and it is generally divided into two subtypes: MRKH type 1, in which only the upper vagina, cervix and the uterus are affected, and MRKH type 2, which is associated with additional malformations generally affecting the renal and skeletal systems, and also includes MURCS (MÜllerian Renal Cervical Somite) characterized by cervico-thoracic defects. MRKH syndrome is mainly sporadic; however, familial cases have been described indicating that, at least in a subset of patients, MRKH may be an inherited disorder. The syndrome appears to demonstrate an autosomal dominant inheritance pattern, with incomplete penetrance and variable expressivity. The etiology of MRKH syndrome is still largely unknown, probably because of its intrinsic heterogeneity. Several candidate causative genes have been investigated, but to date only WNT4 has been associated with MRKH with hyperandrogenism. This review summarizes and discusses the clinical features and details progress to date in understanding the genetics of MRKH syndrome.