Mayer-Rokitansky-Kuster-Hauser Syndrome (MRKH)

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Disease Ontology 12 DOID:0112177 OMIM® 57 277000 KEGG 36 H00600 MESH via Orphanet 45 C537371 ICD10 via Orphanet 33 Q51.8

UMLS via Orphanet 71 C0431637 C0431648 C1698581 Orphanet 58 ORPHA247775 ORPHA3109 ORPHA73217 MedGen 41 C1698581 SNOMED-CT via HPO 68 16507009 248871003 248942000 253836009 258211005 263681008 35850006 41729002 55726006 87380008 more UMLS 70 C1698581

GARD : ²⁰ The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 3109 Definition Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome describes a spectrum of Mullerian duct anomalies characterized by congenital aplasia of the uterus and upper 2/3 of the vagina in otherwise phenotypically normal females. It can be classified as either MRKH syndrome type 1 (corresponding to isolated utero-vaginal aplasia) or MRKH syndrome type 2 (utero-vaginal aplasia associated with other malformations) (see these terms). Epidemiology MRKH syndrome has a worldwide incidence of 1/4500 live female births. Clinical description MRKH syndrome is most often diagnosed in adolescence as the first symptom is usually a primary amenorrhea in young women presenting otherwise with normal development of secondary sexual characteristics and normal external genitalia. MRKH syndrome type 1 and 2 patients lack the uterus and the upper 2/3 of the vagina leading to difficulties with sexual intercourse in some. Pelvic pain can be reported in those with uterine remnants. As the uterus is missing or not functional, women cannot bear children, but ovaries are normal and functional. Other associated malformations seen in MRKH type 2 include kidney abnormalities (40% of cases), skeletal abnormalities (20-25%), hearing impairment (10%), and, more rarely, heart defects. Etiology The exact etiology is largely unknown, even if the spectrum of malformations encountered suggests a developmental defect of the intermediate mesoderm during embryogenesis (by the end of the 4th week of fetal life), leading to an alteration of the blastema of the cervicothoracic somites and the pronephric ducts. It is now clear that MRKH syndrome has a genetic origin through increasing family descriptions and numerous genetic studies already completed. These latter have led to reveal several chromosomal abnormalities associated with the disease and several putative candidate genes have been described. Diagnostic methods The karyotype of MRKH patients is always 46, XX. Hormone levels are normal, showing normal and functional ovaries without hyperandrogenism. Transabdominal ultrasonography must be the first investigation in evaluating patients with suspected utero-vaginal aplasia. MRI can be performed to clearly visualize the malformation. A full check-up (renal ultrasonography, spine radiography, heart echography, audiogram) must be undertaken to search for any associated malformations. Differential diagnosis Differential diagnosis includes isolated vaginal atresia, which is found in various syndromes such as McKusick-Kaufman syndrome, androgen insensitivity syndrome, Mullerian aplasia and hyperandrogenism, and renal-genital-middle ear anomalies (see these terms). Genetic counseling MRKH syndrome was thought to be purely sporadic but familial cases seem to be inherited autosomal dominantly with incomplete penetrance and variable expressivity, and in these cases genetic counseling can be beneficial. Management and treatment The medical care of MRKH patients requires the coordinated efforts of pediatricians, gynecologists, surgeons, endocrinologists and psychologists. Treatment consisting in creating a neovagina must be offered to patients only when they are ready to start sexual activity and when emotionally mature (around 17-21 years). Frank's (nonsurgical) method requires the application of vaginal dilators on the vaginal dimple for at least 20 minutes/day for several months. If unsuccessful, various surgical procedures can be performed to create a neovagina. Clinical follow-up and regular intercourse are essential components to a successful outcome. Psychological support and counseling is strongly recommended for affected women and should provide patients with future fertility options ( in vitro fertilization of one's own oocytes followed by surrogate pregnancy or adoption). For the associated malformations in MRKH type 2, specific medical care is directed toward the anomalies. Prognosis MRKH syndrome is not a life threatening disease. With treatment, sexual relationships are possible and fertility options are available.

MalaCards based summary : Mayer-Rokitansky-Kuster-Hauser Syndrome, also known as mrkh syndrome, is related to ureterocele and mullerian aplasia and hyperandrogenism. An important gene associated with Mayer-Rokitansky-Kuster-Hauser Syndrome is GREB1L (GREB1 Like Retinoic Acid Receptor Coactivator), and among its related pathways/superpathways are Wnt signaling pathway and PI3K-Akt signaling pathway. The drugs Tacrolimus and Immunologic Factors have been mentioned in the context of this disorder. Affiliated tissues include uterus, cervix and heart, and related phenotypes are aplasia of the uterus and hypoplasia of the vagina

Disease Ontology : ¹² A syndrome characterized by aplasia of the uterus and upper part of the vagina in patients with normal secondary sex characteristics and a 46,XX karyotype.

MedlinePlus Genetics : ⁴³ Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a disorder that occurs in females and mainly affects the reproductive system. This condition causes the vagina and uterus to be underdeveloped or absent, although external genitalia are normal. Affected women usually do not have menstrual periods due to the absent uterus. Often, the first noticeable sign of MRKH syndrome is that menstruation does not begin by age 16 (primary amenorrhea). Women with MRKH syndrome have a female chromosome pattern (46,XX) and normally functioning ovaries. They also have normal breast and pubic hair development. Although women with this condition are usually unable to carry a pregnancy, they may be able to have children through assisted reproduction.When only reproductive organs are affected, the condition is classified as MRKH syndrome type 1. Some women with MRKH syndrome also have abnormalities in other parts of the body; in these cases, the condition is classified as MRKH syndrome type 2. In this form of the condition, the kidneys may be abnormally formed or positioned, or one kidney may fail to develop (unilateral renal agenesis). Affected individuals commonly develop skeletal abnormalities, particularly of the spinal bones (vertebrae). Females with MRKH syndrome type 2 may also have hearing loss or heart defects.

OMIM® : ⁵⁷ Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) is characterized by uterovaginal atresia in an otherwise phenotypically normal female with a normal 46,XX karyotype. Anomalies of the genital tract range from upper vaginal atresia to total mullerian agenesis with urinary tract abnormalities. It has an incidence of approximately 1 in 5,000 newborn girls (Cheroki et al., 2006). The abnormality of sexual development in MRKH syndrome is the same as that in the MURCS association (601076), in which cervicothoracic somite anomalies, unilateral renal agenesis, and conductive deafness are also seen. Mullerian aplasia and hyperandrogenism (158330) is caused by mutation in the WNT4 gene (603490). Familial cases of unilateral or bilateral renal agenesis in combination with mullerian anomalies have also been reported (see urogenital adysplasia, 191830). (277000) (Updated 05-Apr-2021)

KEGG : ³⁶ Mullerian agenesis, also known as Mayer Rokitansky Kuster Hauser (MRKH) syndrome, is characterized by utero-vaginal atresia in an otherwise phenotypically normal female with a normal 46,XX karyotype. It has been reported that Mullerian aplasia and hyperandrogenism is caused by mutations in the WNT4 gene. WNT4, a secreted protein that suppresses male sexual differentiation, is thought to repress the biosynthesis of gonadal androgen in female mammals.

UniProtKB/Swiss-Prot : ⁷² Rokitansky-Kuster-Hauser syndrome: Characterized by utero-vaginal atresia in otherwise phenotypically normal female with a normal 46,XX karyotype. Anomalies of the genital tract range from upper vaginal atresia to total Muellerian agenesis with urinary tract abnormalities. It has an incidence of approximately 1 in 5'000 newborn girls.

Wikipedia : ⁷³ Müllerian agenesis, also known as Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) or vaginal agenesis, is... more...

Clinical features from OMIM®:

277000 (Updated 05-Apr-2021)

#	Description	GenomeRNAi Source Accession	Score	Top Affiliating Genes
1	Increased shRNA abundance (Z-score > 2)	GR00366-A-100	9.64	WT1
2	Increased shRNA abundance (Z-score > 2)	GR00366-A-107	9.64	TBX5
3	Increased shRNA abundance (Z-score > 2)	GR00366-A-119	9.64	HNF1B
4	Increased shRNA abundance (Z-score > 2)	GR00366-A-120	9.64	SHOX
5	Increased shRNA abundance (Z-score > 2)	GR00366-A-122	9.64	WT1
6	Increased shRNA abundance (Z-score > 2)	GR00366-A-145	9.64	WT1
7	Increased shRNA abundance (Z-score > 2)	GR00366-A-147	9.64	SHOX
8	Increased shRNA abundance (Z-score > 2)	GR00366-A-152	9.64	WT1
9	Increased shRNA abundance (Z-score > 2)	GR00366-A-169	9.64	SHOX
10	Increased shRNA abundance (Z-score > 2)	GR00366-A-190	9.64	TBX3
11	Increased shRNA abundance (Z-score > 2)	GR00366-A-214	9.64	SHOX WT1
12	Increased shRNA abundance (Z-score > 2)	GR00366-A-30	9.64	WT1
13	Increased shRNA abundance (Z-score > 2)	GR00366-A-43	9.64	WT1
14	Increased shRNA abundance (Z-score > 2)	GR00366-A-47	9.64	WT1
15	Increased shRNA abundance (Z-score > 2)	GR00366-A-5	9.64	HNF1B
16	Increased shRNA abundance (Z-score > 2)	GR00366-A-67	9.64	TBX5
17	Increased shRNA abundance (Z-score > 2)	GR00366-A-69	9.64	TBX5
18	Increased shRNA abundance (Z-score > 2)	GR00366-A-85	9.64	WT1
19	Increased shRNA abundance (Z-score > 2)	GR00366-A-93	9.64	TBX3
20	Increased shRNA abundance (Z-score > 2)	GR00366-A-98	9.64	TBX5

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