Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) is characterized by utero-vaginal 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 ... Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) is characterized by utero-vaginal 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).
The features, in addition to congenital absence of the vagina, are normal female secondary sexual characteristics, rudimentary uterus in the form of bilateral and noncanaliculated muscular buds, normal tubes and ovaries and normal endocrine and cytogenetic evaluations. Anger ... The features, in addition to congenital absence of the vagina, are normal female secondary sexual characteristics, rudimentary uterus in the form of bilateral and noncanaliculated muscular buds, normal tubes and ovaries and normal endocrine and cytogenetic evaluations. Anger et al. (1966) reported 3 affected sisters. Phaneuf (1947) described the malformation in 2 pairs of sisters whose mothers were sisters. Bryan et al. (1949) mentioned that in one of their 100 cases a sister had congenital absence of the vagina and 2 had a sister with primary amenorrhea. Jones and Mermut (1972) concluded that most of the earlier reported cases, except those of Anger et al. (1966), were instances of testicular feminization (300068). They reported 2 affected sisters. Karyotype was normal. Las Casas dos Santos (1888) reported familial cases and referred to a report by Squarey of 3 sisters who had a maternal aunt with no menstruation and 3 other sterile aunts; to a report by Phillips of 2 sisters with congenital absence of the uterus and vagina (with no supporting information) and to a report by Hauff of a person with no uterus, tubes or ovaries, whose sister had 2 daughters with the same condition. The last is clearly testicular feminization, because the author had an opportunity to look for the ovaries (Jones, 1972). Wulfsberg and Grigbsy (1990) reported the Rokitansky sequence in association with facioauriculovertebral sequence (Goldenhar syndrome; 164210) and found reports of 3 other such cases (Rapin and Ruben, 1976; Willemsen, 1982; Winer-Muram et al., 1984). Shokeir (1978) described 18 unrelated females, aged 15 to 28, with aplasia of the mullerian duct derivatives. Their complaints were amenorrhea and difficulty or pain on attempting sexual intercourse; absence of the vagina and failure to palpate the uterus rectally were features in all. Female sexual identification, libido, and female secondary sexual characteristics, as well as stature, intellect, hearing, and vision, were normal. Laparoscopy showed absent uterus, absent or rudimentary tubes, and normal ovaries. Of the eighteen, 14 had affected relatives. The pedigree pattern was consistent with female-limited autosomal dominant inheritance. The disorder was transmitted through normal males. Because of the observation that female rats showed delayed vaginal opening and reduced oocyte number when born to mothers fed on a high-galactose diet (Chen et al., 1981), Cramer et al. (1987) analyzed blood for transferase in 4 mother-daughter pairs in which the daughter had mullerian aplasia. In 2 of the mother-daughter pairs, they found deficiency of transferase. One was a Duarte heterozygote (both mother and daughter); a sister did not have mullerian aplasia, but had premature menopause. In the second pair, the Los Angeles type of transferase deficiency was found in heterozygous state in the mother and daughter. In that instance, the mother was a very heavy milk consumer. See galactosemia (230400). Bau et al. (1994) reported the case of a 32-year-old woman with the Rokitansky sequence in association with bilateral femoral hypoplasia (proximal femoral focal deficiency). She had a short vagina and by ultrasound absence of the uterus with normal kidneys. Guerrier et al. (2006) reviewed the clinical features of the MRKH syndrome and MURCS association phenotypes and discussed genetic hypotheses. Morcel et al. (2007) reviewed the clinical features and management of MRKH syndrome. Drummond et al. (2008) studied 6 Brazilian 46,XX patients with the MRKH defect, 2 of whom were sisters. All had normal secondary sexual characteristics, no clinical signs of hyperandrogenism, and rudimentary uterus and upper vaginal atresia on pelvic ultrasound; 2 patients also had unilateral renal agenesis, but none had skeletal or other associated malformations. Androgen levels were unremarkable in all but 1 patient, who had an elevated basal 17-hydroxyprogesterone level; ACTH-stimulated 17-hydroxyprogesterone levels in that patient were within normal limits, excluding congenital adrenal hyperplasia.
Timmreck et al. (2003) examined the relationship between mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR; 602421) and congenital absence of the uterus and vagina (CAUV). CFTR mutations are associated with congenital bilateral absence of the ... Timmreck et al. (2003) examined the relationship between mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR; 602421) and congenital absence of the uterus and vagina (CAUV). CFTR mutations are associated with congenital bilateral absence of the vas deferens (CBAVD; 277180). CBAVD is caused by a disruption in the vas deferens, a wolffian duct derivative. Because the embryologic development of the mullerian ducts depends directly on the prior normal development of the wolffian ducts, the same gene products may be necessary for normal embryologic development of both ductal systems. Timmreck et al. (2003) studied DNA samples from 25 patients with CAUV for the presence of 33 of the most common CFTR mutations. Two patients were heterozygous for CFTR mutations. One was the W1282X mutation (602421.0022) and the other was the delF508 mutation (602421.0001). The incidence of the 33 CFTR mutations found in the patients with CAUV (8%) was twice that found in the general population (4%), but much less than the incidence of CFTR mutations in men with CBAVD (80%). Timmreck et al. (2003) concluded that it is unlikely that CFTR mutations cause CAUV in females but CAUV in females may be the same disorder as CAUVD in males who do not have CFTR mutations. Cheroki et al. (2006) reported a 17-year-old Brazilian girl who had a rudimentary uterus and vaginal agenesis with normal secondary sexual characteristics in whom they identified a 4-Mb deletion at chromosome 22q11. Additional features included mild to moderate learning disabilities, minor craniofacial anomalies with a long face, prominent nose, short philtrum, and high palate, mild dorso-lumbar scoliosis, and slight increase of the aortic arch. She also had hypothyroidism secondary to Hashimoto thyroiditis. Cheroki et al. (2006) noted that the patient's deletion included loci responsible for DiGeorge syndrome (188400) and velocardiofacial syndrome (192430). Cheroki et al. (2008) further mapped the rearrangement in this patient, revealing that the deletion spanned 2.5 Mb but was interrupted by a small chromosome segment with apparently normal copy number, containing the TBX1 gene (602054). The patient was also noted to have agenesis of the right kidney. Cheroki et al. (2008) performed array CGH on 14 female patients with mullerian aplasia and additional features, including urinary tract anomalies, cardiac and skeletal defects, hearing impairment, and mental retardation. Four (29%) of the 14 patients, 1 of whom was previously studied by Cheroki et al. (2006), were found to have submicroscopic copy number alterations affecting chromosomes 1q21.1, 17q12 (see 614527), 22q11.21, and Xq21.31. The alterations were also present in the unaffected mother of 1 patient, suggesting incomplete penetrance and/or variable expressivity. Cheroki et al. (2008) noted that these findings suggest involvement of previously unknown chromosomal regions in mullerian aplasia, specifically pointing to LHX1 (601999) and KLHL4 (300348) as candidate genes. Bernardini et al. (2009) reported 2 female patients with MRKH syndrome who had identical de novo 1.5-Mb deletions at chromosome 17q12. One was a 20-year-old woman with mildly dysmorphic facial features who presented for evaluation of primary amenorrhea and had complete absence of the uterus and vagina; pelvic MRI showed bilaterally normal ovaries and kidneys. The other patient was a 15-year-old girl who had bilateral renal cysts noted on fetal ultrasound and at 5 years of age had small, multicystic kidneys on ultrasound. At 12 years of age, menarche was complicated by hematocolpos due to agenesis of the upper and middle thirds of the vagina, which was surgically corrected. At laparoscopy, mullerian malformations were seen, including right unicornuate uterus, noncavitating rudimentary left horn, and right hematosalpinx. Growth and psychomotor development were normal in both patients, and both had normal blood glucose levels. Nik-Zainal et al. (2011) performed array CGH on DNA samples from a cohort of 63 individuals with mullerian aplasia and found that 9 (14%) had copy number variants, including 4 with microdeletion at 16p11.2, 4 with microdeletion at 17q12, and 1 with a microdeletion at distal 22q11.2. Microdeletions at 16p11.2 or 17q12 were found in 4 of 38 cases (10.5%) with isolated mullerian aplasia, and at 16p11.2, 17q12, or 22q11.2 in 5 of 25 cases (20%) with syndromic mullerian aplasia. - Exclusion Studies Clement-Ziza et al. (2005) analyzed the WNT4 gene but identified no mutations in 19 patients with mullerian aplasia from 15 families, 11 of whom had symmetrical uterus abnormalities that are typical of RKH and 6 of whom had asymmetric uterus and renal anomalies; a full uterine survey was not available in 4 cases. Clement-Ziza et al. (2005) concluded that WNT4 is not a major disease-causing gene in MRKH anomaly. Cheroki et al. (2006) failed to find mutations in the WNT4 gene in 25 women with the MRKH anomaly. Biason-Lauber et al. (2007) found no mutations in the WNT4 gene in 5 patients with varying degrees of mullerian abnormalities, 2 of whom also had renal agenesis and dysplasia, and all of whom were negative for mutation in the TCF2 gene (189907). Philibert et al. (2008) found no mutations in the WNT4 gene in 27 adolescent girls with primary amenorrhea, XX karyotype, and mullerian duct abnormalities, who were negative for mutation in the TCF2 gene. In 6 Brazilian 46,XX patients with the MRKH defect, Drummond et al. (2008) sequenced the WNT4 gene but found no nucleotide variation in the coding exons. Bernardini et al. (2009) performed a focused chromosome 17 array CGH analysis in 20 consecutive MRKH patients but detected no abnormalities; direct sequencing of the candidate genes TCF2 and LHX1 (601999) revealed no pathogenic mutations.