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Review
. 2018;30(1):3-11.
doi: 10.1007/s11825-018-0173-7. Epub 2018 Feb 21.

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

Affiliations
Review

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

Susanne Ledig et al. Med Genet. 2018.

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.

Das Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrom [MIM 277000] ist durch einen fehlenden Uterus und eine fehlende Vagina bei phänotypisch unauffälligen Frauen mit dem Karyotyp 46,XX gekennzeichnet. Klinisch werden beim MRKH 2 Subtypen unterteilt: die isolierte oder Typ I Form wird von der Typ II Form, bei der zusätzlich extragenitale Malformationen auftreten, unterschieden. Hierbei kann die sog. MURCS-Assoziation (MURCS: „Müllerian hypoplasia, renal agenesis, cervicothoracic somite dysplasia“) als schwerste phänotypische Ausprägung verstanden werden.Das MRKH tritt bei ca. einem von 4000 bis 5000 weiblichen Neugeborenen auf; die meisten Fälle kommen sporadisch vor. Das Auftreten einiger familiärer Fälle weist auf eine genetische Ursache mit autosomal-dominanter Vererbung und einer reduzierten Penetranz hin.Die Analyse von MRKH-Patientinnen mittels hochauflösender Array-CGH und MLPA führte zur Identifizierung rekurrierender Aberrationen in verschiedenen chromosomalen Regionen wie dem TAR-Suszeptibilitätslokus in 1q21.1, den Regionen 16p11.2 und 17q12 und der Mikroduplikations und –deletionsregion 22q11.21.In den Genen LHX1, TBX6 und RBM8A, die in den chromosomalen Regionen 17q12, 16p11.2, bzw. 1q21.1 lokalisiert sind, wurden zudem MRKH-assoziierte Mutationen nachgewiesen. Hingegen werden Mutationen des Gens WNT4 nur bei einer Subgruppe von Patientinnen mit zusätzlichen Androgenisierungserscheinungen detektiert. Interessanterweise konnten bei der Analyse eines weiteren Mitglieds der WNT-Familie, WNT9B, ebenfalls ursächliche Mutationen bei MRKH-Patientinnen gefunden werden.

Keywords: LHX1; MRKH; TBX6; WNT9B.

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Conflict of interest statement

Compliance with ethical guidelinesS. Ledig and P. Wieacker declare that they have no competing interests. This article does not contain any studies with human participants or animals performed by any of the authors.

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