The Embryological Landscape of Mayer-Rokitansky-Kuster-Hauser Syndrome: Genetics and Environmental Factors

Abstract

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a disorder caused by Müllerian ducts dysgenesis affecting 1 in 5000 women with a typical 46,XX karyotype. The etiology of MRKH syndrome is complex and largely unexplained. Familial clustering suggests a genetic component and the spectrum of clinical presentations seems consistent with an inheritance pattern characterized by incomplete penetrance and variable expressivity. Mutations of several candidate genes have been proposed as possible causes based on genetic analyses of human patients and animal models. In addition, studies of monozygotic twins with discordant phenotypes suggest a role for epigenetic changes following potential exposure to environmental compounds. The spectrum of clinical presentations is consistent with intricate disruptions of shared developmental pathways or signals during early organogenesis. However, the lack of functional validation and translational studies have limited our understanding of the molecular mechanisms involved in this condition. The clinical management of affected women, including early diagnosis, genetic testing of MRKH syndrome, and the implementation of counseling strategies, is significantly impeded by these knowledge gaps. Here, we illustrate the embryonic development of tissues and organs affected by MRKH syndrome, highlighting key pathways that could be involved in its pathogenesis. In addition, we will explore the genetics of this condition, as well as the potential role of environmental factors, and discuss their implications to clinical practice.

Keywords: Disorders of Sex Development; Genetics; MRKH syndrome; Müllerian anomalies; Müllerian ducts; Sex development; Wolffian ducts.

Figure 1

Molecular regulation of mesodermal patterning. β-catenin induces TCF-3, which regulates the expression of transcription factors and regulatory proteins including Pax3,7, Bmp4, and Wnt1,3a). These signals lead to the differentiation of the three main components, lateral mesoderm, intermediate mesoderm, and paraxial mesoderm. Expression of VEGF in the lateral mesoderm (LM) initiates progenitor cell specification for the development of the heart, blood vessels, limbs and mesenchymal cells. BMP4/FGF3 signaling from the LM stimulates TGF-β/Notch signaling, which activates Wnt3a expression in the intermediate mesoderm driving urogenital system and adrenal gland development. Expression of Wnt1,3a from the neural tube upregulates Pax1,3 and MyoD in the paraxial mesoderm. Pax1,3 and MyoD stimulate SHH/NOTCH and RA/FGF-8 signaling to differentiate the paraxial mesoderm into cartilage, tendons, skeletal muscles, and endothelial cells.

Figure 2

Development of the embryonic kidneys. The pronephric ducts are primordial ducts forming from the intermediate mesoderm. They extend caudally forming the Wolffian ducts, which invade the mesonephric mesenchyme and give origin to the mesonephric tubules. In some species, these tubules transiently assume excretory functions until the ureteric buds branch out into the metanephric mesenchyme and develop into the metanephros, or permanent kidneys.

Figure 3

Phases of early development of the Müllerian ducts. During specification, BMP signaling stimulates the expression of Pax2 in coelomic epithelial cells (precursors of MD epithelial cells, (red)). WD-derived inductive signaling stimulates fibroblast growth factor (FGF) signaling in the Pax2-positive cells to activate the expression of LXH1 and commit their fate to Müllerian duct development. During invagination, Pax2/LXH1 positive Müllerian epithelium (ME) invaginates into the mesonephric mesenchyme (MM) by WNT4 signaling from the MM. In the elongation phase, WD-derived WNT9B signaling guides posterior elongation of the nascent MD to the urogenital sinus.

Figure 4

Molecular mechanism of sex differentiation. Before sex determination, embryos have undifferentiated, or bipotential gonads and both MDs and WDs. In the male, the Y-linked SRY protein interacts with steroidogenic factor-1 (SF-1) to increase the expression levels of Sox9. This drives the differentiation of Sertoli cells and Leydig cells within the testes. Sertoli cells produce anti-Müllerian hormone (AMH) to stimulate MD regression, whereas Leydig cells produce testosterone stabilizing WD development through signaling including WNT/β-catenin. In the female, expression of Foxl2 inhibits the expression of Sox9. As the gonads develop into ovaries and male factors are not produced, the WDs degenerates and the MDs develop into the female reproductive tract under the action of several factors including WNT7A, and members of the HOX family.