Clinical and genetic aspects of Mayer–Rokitansky–Küster–Hauser syndrome

Abstract

The Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome [MIM 277000] is characterised by the absence of a uterus and vagina in otherwise phenotypically normal women with karyotype 46,XX. Clinically, the MRKH can be subdivided into two subtypes: an isolated or type I form can be delineated from a type II form, which is characterised by extragenital malformations. The so-called Müllerian hypoplasia, renal agenesis, cervicothoracic somite dysplasia (MURCS) association can be seen as the most severe phenotypic outcome.The MRKH syndrome affects at least 1 in 4000 to 5000 female new-borns. Although most of the cases are sporadic, familial clustering has also been described, indicating a genetic cause of the disease. However, the mode of inheritance is autosomal-dominant inheritance with reduced penetrance. High-resolution array-CGH and MLPA analysis revealed recurrent aberrations in different chromosomal regions such as TAR susceptibility locus in 1q21.1, chromosomal regions 16p11.2, and 17q12 and 22q11.21 microduplication and -deletion regions in patients with MRKH. Sequential analysis of the genes LHX1, TBX6 and RBM8A, which are located in chromosomal regions 17q12, 16p11.2 and 1q21.1, yielded in the detection of MRKH-associated mutations. In a subgroup of patients with signs of hyperandrogenaemia mutations of WNT4 have been found to be causative. Analysis of another member of the WNT family, WNT9B, resulted in the detection of some causative mutations in MRKH patients.

The endometrial transcription landscape of MRKH syndrome

“…4C, Supplementary Fig. 8), all of which have been associated with MRKH (7). In addition, TWIST2 identified as one of the genes with the most significant expression change (Fig.…”

“…The combined approach of differential and co-expression analyses highlighted candidate genes that can explain large parts of the altered expression landscape in context of the MRKH syndrome. These novel candidates together with previously associated genes like FOXO1 (22) and pathways like WNT signaling (7) share direct links into the TGFB1 regulatory neighborhood (23) and reach into disease-associated co-expression modules. Intriguingly, many interactors are not only targets of TGFB1, but often also upstream regulators, hence, forming regulatory loops (Fig.…”

“…Specifically, chromosomal aberrations in 1q21.1, 16p11.2, 17q12, and 22q11 as well as mutations in LHX1, TBX6, RBM8A, and WNT9B have been linked to MRKH. Additionally, mutations of WNT4 cause an atypical form of the syndrome characterized by hyperandrogenism (7). LHX1, WNT4, and WNT9B play important roles in the formation of the Müllerian Ducts (MD) from the coelomic epithelium in gestational week six (8,9).…”

Genome-wide association identifies seven loci for pelvic organ prolapse in Iceland and the UK Biobank

“…The most significant POP association is with rs3820282-T (P = 3.3 × 10 −21 , OR = 0.85), located in intron 1 of WNT4, which encodes a protein involved in development of the female reproductive tract 35 . Loss of WNT4 function in humans leads to underdevelopment and sometimes absence of the uterus and vagina 36 . Variants correlated (r 2 > 0.8) with the POP-protecting allele rs3820282-T have been associated with increased risk of endometriosis 37 , leiomyoma 38 , increased gestational duration 39 and with decreased bone mineral density 40 (Supplementary Data 10), all of which we replicate (Supplementary Data 9).…”

A young girl with right ovarian torsion and left ovarian ectopy

“…Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) refers to congenital hypoplasia/aplasia of the uterus, the cervix and the upper 2/3 of the vagina, in females with normal ovaries and fallopian tubes, secondary sexual characteristics and 46 XX karyotype [1]. It is reported to have an incidence of 1:4500 women [2]. This condition (also known as müllerian agenesis), originates from abnormal development of Müller's paramesonephric ducts in the early stages of embryonic development.…”