Subject(s)
46, XX Disorders of Sex Development/genetics , Congenital Abnormalities/genetics , Endometriosis/genetics , Epigenesis, Genetic , Genes, Homeobox , Mullerian Ducts/abnormalities , Wnt Signaling Pathway/genetics , 46, XX Disorders of Sex Development/embryology , Congenital Abnormalities/embryology , Endometriosis/embryology , Female , Gene Expression Regulation, Developmental , Humans , Mullerian Ducts/embryology , Organogenesis/geneticsABSTRACT
BACKGROUND: The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is present in at least 1 out of 4,500 female live births and is the second most common cause for primary amenorrhea. It is characterized by vaginal and uterine aplasia in an XX individual with normal secondary characteristics. It has long been considered a sporadic anomaly, but familial clustering occurs. Several candidate genes have been studied although no single factor has yet been identified. Cases of discordant monozygotic twins suggest that the involvement of epigenetic factors is more likely. METHODS: Differences in gene expression and methylation patterns of uterine tissue between eight MRKH patients and eight controls were identified using whole-genome microarray analyses. Results obtained by expression and methylation arrays were confirmed by qRT-PCR and pyrosequencing. RESULTS: We delineated 293 differentially expressed and 194 differentially methylated genes of which nine overlap in both groups. These nine genes are mainly embryologically relevant for the development of the female genital tract. CONCLUSION: Our study used, for the first time, a combined whole-genome expression and methylation approach to reveal the etiology of the MRKH syndrome. The findings suggest that either deficient estrogen receptors or the ectopic expression of certain HOXA genes might lead to abnormal development of the female reproductive tract. In utero exposure to endocrine disruptors or abnormally high maternal hormone levels might cause ectopic expression or anterior transformation of HOXA genes. It is, however, also possible that different factors influence the anti-Mullerian hormone promoter activity during embryological development causing regression of the Müllerian ducts. Thus, our data stimulate new research directions to decipher the pathogenic basis of MRKH syndrome.
Subject(s)
46, XX Disorders of Sex Development/embryology , 46, XX Disorders of Sex Development/genetics , Abnormalities, Multiple/embryology , Abnormalities, Multiple/genetics , DNA Methylation , Gene Expression Profiling , Gene Expression Regulation, Developmental/physiology , Congenital Abnormalities , CpG Islands/genetics , Female , Humans , Kidney/abnormalities , Mullerian Ducts/abnormalities , Oligonucleotide Array Sequence Analysis , Reproducibility of Results , Reverse Transcriptase Polymerase Chain Reaction , Somites/abnormalities , Spine/abnormalities , Uterus/abnormalities , Uterus/embryology , Uterus/metabolism , Vagina/abnormalities , Vagina/embryologyABSTRACT
Mayer-Rokitansky-Kuster-Hauser (MRKH) is a characteristic syndrome in which the mullerian structures are absent or rudimentary. It is also associated with anomalies of the genitourinary and skeletal systems. There are very few cases reported regarding its association with anorectal malformations, particularly perineal fistulas. To the best of our knowledge, there have not been any reported cases of anal canal stenosis in patients with MRKH. We describe a very rare association of MRKH with anal canal stenosis and multiple renal calculi. The patient underwent corrective surgery for the anomalies and removal of renal calculi. She has been under regular follow-up for the last few months and is doing well.
