Exome and copy number variation analyses of Mayer-Rokitansky-Kuster- Hauser syndrome.
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ABSTRACT:
SUBMITTER: Takahashi K
PROVIDER: S-EPMC6160444 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Exome and copy number variation analyses of Mayer-Rokitansky-Küster- Hauser syndrome.
Takahashi Kazumi K Hayano Takahide T Sugimoto Ryota R Kashiwagi Hirofumi H Shinoda Mari M Nishijima Yoshihiro Y Suzuki Takahiro T Suzuki Shingo S Ohnuki Yuko Y Kondo Akane A Shiina Takashi T Nakaoka Hirofumi H Inoue Ituro I Izumi Shun-Ichiro SI
Human genome variation 20180927
Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital absence of the vagina and uterus. We conducted genome-wide SNP analyses and exome sequencing to detect the causes of MRKH syndrome. We identified de novo variants of <i>MYCBP2</i>, <i>NAV3</i>, and <i>PTPN3</i> in three families and a variant of <i>MYCBP2</i> in a sporadic case. Here, we demonstrated the partial genetic makeup of Japanese MRKH syndrome. ...[more]
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Project description:The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. It affects at least 1 out of 4500 women. MRKH may be isolated (type I) but it is more frequently associated with renal, vertebral, and, to a lesser extent, auditory and cardiac defects (MRKH type II or MURCS association). The first sign of MRKH syndrome is a primary amenorrhea in young women presenting otherwise with normal development of secondary sexual characteristics and normal external genitalia, with normal and functional ovaries, and karyotype 46, XX without visible chromosomal anomaly. The phenotypic manifestations of MRKH syndrome overlap with various other syndromes or associations and thus require accurate delineation. For a long time the syndrome has been considered as a sporadic anomaly, but increasing number of familial cases now support the hypothesis of a genetic cause. In familial cases, the syndrome appears to be transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity. This suggests the involvement of either mutations in a major developmental gene or a limited chromosomal imbalance. However, the etiology of MRKH syndrome still remains unclear. Treatment of vaginal aplasia, which consists in creation of a neovagina, can be offered to allow sexual intercourse. As psychological distress is very important in young women with MRKH, it is essential for the patients and their families to attend counseling before and throughout treatment.
| S-EPMC1832178 | biostudies-literature
Project description:BACKGROUND:Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also referred to as Müllerian aplasia, is a congenital disorder characterized by aplasia of the uterus and upper part of the vagina in females with normal secondary sex characteristics and a normal female karyotype (46,XX). MAIN BODY:The diagnosis is often made during adolescence following investigations for primary amenorrhea and has an estimated prevalence of 1 in 5000 live female births. MRKH syndrome is classified as type I (isolated uterovaginal aplasia) or type II (associated with extragenital manifestations). Extragenital anomalies typically include renal, skeletal, ear, or cardiac malformations. The etiology of MRKH syndrome still remains elusive, however increasing reports of familial clustering point towards genetic causes and the use of various genomic techniques has allowed the identification of promising recurrent genetic abnormalities in some patients. The psychosexual impact of having MRKH syndrome should not be underestimated and the clinical care foremost involves thorough counselling and support in careful dialogue with the patient. Vaginal agenesis therapy is available for mature patients following therapeutical counselling and education with non-invasive vaginal dilations recommended as first-line therapy or by surgery. MRKH syndrome involves absolute uterine factor infertility and until recently, the only option for the patients to achieve biological motherhood was through gestational surrogacy, which is prohibited in most countries. However, the successful clinical trial of uterus transplantation (UTx) by a Swedish team followed by the first live-birth in September, 2014 in Gothenburg, proofed the first available fertility treatment in MRKH syndrome and UTx is now being performed in other countries around the world allowing women with MRKH syndrome to carry their own child and achieve biological motherhood. CONCLUSION:Several advances in research across multiple disciplines have been made in the recent years and this kaleidoscopic review provides a current status of various key aspects in MRKH syndrome and provides perspectives for future research and improved clinical care.
| S-EPMC7439721 | biostudies-literature
Project description:Mayer-Rokitansky-Kuster-Hauser (MRKH) is a malformation complex comprising absent vagina and absent or rudimentary uterus. MRKH syndrome may be attributed to an initial affection of the intermediate mesoderm consequently leading (by the end of the 4(th) week of fetal life) to an alteration of the blastema of the cervicothoracicsomites and the pronephricducts. These latter subsequently induce the differentiation of the mesonephric and then the Wolffian and Mullerian ducts. There are very sparse such cases reported. We present a case of type II MRKH or Mullerian renal cervical somite association (i.e., Mullerian duct aplasia, renal dysplasia, and cervical somite anomalies).
| S-EPMC3722622 | biostudies-literature
Project description: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.
| S-EPMC5838123 | biostudies-literature
Project description:BackgroundMayer-Rokitansky-Küster-Hauser (MRKH) syndrome (Online Mendelian Inheritance in Man [OMIM] #277000) is a congenital condition characterized by the total or partial agenesis of vagina and uterus. Agenesis can be isolated (MRKH 1) or associated with other renal, vertebral or cardiac defects (MRKH 2).Case presentationIn this paper, we report a case of a Caucasian patient showing the clinical signs associated with MRKH. Array-based comparative genomic hybridization (a-CGH) analysis revealed a microduplication of approximately 3.01 megabases (Mb) located on the long arm of chromosome 22 (22q11.21). Microduplications affecting the 22q11.21 region have been shown to be associated with MRKH syndrome and Müllerian aplasia. The phenotype of patients with 22q11.2 duplication (OMIM #608363) appears extremely variable, ranging from apparently normal to mild learning difficulties or with multiple defects, sharing features with DiGeorge/velocardiofacial (DGS/VCFS) syndrome.ConclusionsThe altered gene expression together with other genetic, nongenetic, epigenetic or environmental factors can cause the extremely variable phenotype in patients carrying such duplication. Therefore, we can consider MRKH syndrome to be one of the clinical features of DGS/VCFS syndrome.
| S-EPMC8058992 | biostudies-literature
Project description:Introduction Mayer-Rokitansky-Kuster-Hauser Syndrome (MRKHS) is a rare congenital disorder with an incidence of 1 in 5000 females. It is characterized by uterovaginal aplasia with normal secondary sexual characteristics and genetic karyotype 46XX. The exact etiology of MRKH syndrome is not known. Case presentation We report a case of type 2 MRKHS with agenesis of left kidney. Discussion The diagnosis of MRKH mainly depends on imaging study. Transabdominal ultrasonography is the first line investigation but abdomino-pelvic MRI gives more precise and clear information than the prior. So, we suggested our patient to do MRI even though she had done ultrasonography earlier. The differential diagnosis includes congenital vaginal agenesis, low transverse vaginal septum, androgen insensitivity, and imperforate hymen. Conclusion This case presents that MRKH syndrome can occur with normal endocrine function and secondary sexual characteristics. Surgical correction by creating a neovagina is a good treatment method in young females for sexual intercourse. Highlights • MRKH syndrome can occur with normal endocrine function and secondary sexual characteristics.• Surgical correction by creating a neovagina is a good treatment method in young females for sexual intercourse.
| S-EPMC9577869 | biostudies-literature
Project description:Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is a disease caused by congenital absence of the uterus and two-thirds of the upper vagina. The pathogenic mechanism of MRKHS may involve gene abnormalities, and there are various case reports associating MRKHS with the Wnt family member 4 (Wnt4) mutation. Analysis of genes mapped to regions in which deletion and duplication are frequently detected in patients with MRKHS has shown involvement of LIM homeobox 1 (LHX1), HNF1 homeobox B (HNF1B) and T-box 6 (TBX6). In addition, there are case reports of MRKHS caused by chromosomal translocation and epigenetic function may be involved in MRKHS onset. Overexpression of HOXA and overexposure to estrogen may contribute to the onset and regulation of expression by methylation as a pathogenic mechanism. Determination of the molecular basis of MRKHS is in progress, but current treatment only includes vaginal enlargement and vaginoplasty for improved quality of life. Clinical application of uterine transplantation to allow childbearing by MRKHS patients is under investigation and clinical trials are underway around the world.
| S-EPMC5526143 | biostudies-literature
Project description:Background and Objectives: The Mayer-Rokitansky-Küster-Hauser syndrome is a congenital condition in which patients are born with vaginal and uterus agenesis, affecting the ability to have a normal sexual life and to bear children. Vaginal reconstruction is a challenging procedure for plastic surgeons. The aim of this study is to report our experience in the management of twelve patients with congenital absence of the vagina due to the MRKH syndrome. Materials and Methods: We performed a retrospective study on 12 patients admitted to the Plastic Surgery Department of the Clinical Emergency Hospital "Prof. Dr. Agrippa Ionescu", Bucharest, Romania, for vaginal reconstruction within a period of eleven years (January 2009-December 2019). All patients were diagnosed by the gynaecologists with vaginal agenesis, as part of the Mayer-Rokitansky-Küster-Hauser syndrome. The Abbe'-McIndoe technique with an autologous skin graft was performed in all cases. Results: The average age of our patients was 20.16 (16-28) years. All patients were 46 XX. The average surgical timing was 3.05 h (range 2.85-4h). Postoperative rectovaginal fistula was encountered in 1 patient. Postoperative average vaginal length was 10.4 cm (range 9.8-12.1 cm). Regular sexual life was achieved in 10 patients. Conclusion: Nowadays, there is no established standard method of vaginal reconstruction. In Romania, the McIndoe technique is the most applied. Unfortunately, even if the MRKH syndrome is not uncommon, less and less surgeons are willing to perform the procedure to create a neovagina.
| S-EPMC7404697 | biostudies-literature
Project description: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.
| S-EPMC8686787 | biostudies-literature
Project description:BackgroundMayer-Rokitansky-Küster-Hauser (MRKH) syndrome is mainly characterized by congenital aplasia of the uterus and the upper two-thirds of the vagina in females with normal secondary sex characteristics and female karyotype (46,XX). MRKH syndrome is typically diagnosed due to primary amenorrhea in adolescence and is very difficult to diagnose in childhood. MRKH syndrome combined with central precocious puberty (CPP) is extremely rare. In this article, we report a case of MRKH syndrome with idiopathic CPP (ICPP).Case descriptionA 7-year-old girl was presented with development of bilateral breasts for 1 year and relatively low body height. Based on her age, clinical signs, and laboratory findings, she was initially diagnosed with ICPP and treated with sustained-release gonadotropin-releasing hormone analog (GnRHa) therapy, and recombinant human growth hormone (rhGH) therapy from the 6th month onwards. During the follow-up, ultrasound and magnetic resonance imaging showed no uterus or uterine neck, an unclear vaginal structure, and normal ovaries. Her chromosome karyotype was 46,XX. A pediatric gynecological examination showed colpatresia. She was finally diagnosed with MRKH syndrome combined with CPP. After the GnRHa and rhGH treatment, her height became normal compared to her peers, and her bone age development was delayed.ConclusionsThe present case suggests the possibility of concomitant CPP in patients with MRKH syndrome. The gonads and sexual organs of children with precocious puberty should be carefully monitored and assessed to exclude any sexual organ disorders.
| S-EPMC10248929 | biostudies-literature