Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. This syndrome is subdivided in two types: type I (isolated) or Rokitansky sequence (OMIM 277000), and type II or MURCS association (MÜllerian duct aplasia, Renal dysplasia and Cervical Somite anomalies) (OMIM 601076). The MRKH syndrome is also referred to as CAUV (Congenital Absence of the Uterus and Vagina), MA (Müllerian Aplasia) or GRES (Genital Renal Ear Syndrome). It would thus be preferable that all entries (MRKH type I and type II, MURCS association, CAUV, MA and GRES) refer to the unique OMIM number 601076.

The 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.

Other associated malformations include (type II or MURCS association):

- Renal (unilateral agenesis, ectopia of kidneys or horseshoe kidney)

- Skeletal and, in particular, vertebral (Klippel-Feil anomaly; fused vertebrae, mainly cervical; scoliosis)

- Hearing defects

- More rarely, cardiac and digital anomalies (syndactyly, polydactyly)

Isolated utero-vaginal aplasia is referred to as Rokitansky sequence or to type I (isolated) MRKH syndrome. Incomplete aplasia and/or associated with other malformations, is generally referred to as MURCS association (or type II MRKH syndrome). In this case, the term GRES (Genital Renal Ear Syndrome) can also be used.

The incidence of MRKH syndrome has been estimated as 1 in 4500 female births 123. The majority of cases appears to be sporadic 4, however family cases have also been described 1567. The mode of inheritance seems to be autosomal dominant with an incomplete degree of penetrance and variable expressivity 189, suggesting that the prevalence of the syndrome may probably be underestimated. Type I (isolated) MRKH is less frequent than MURCS association 10.

The MRKH syndrome was initially considered to be of sporadic occurrence, suggesting the involvement of non-genetic or environmental factors 56 such as gestational diabetes 57 or thalidomide-like teratogens 1133058. However, studies analyzing available pregnancy histories failed to identify any association with drug use, illness, or exposure to known teratogens 57596061. Another explanation of the sporadic occurrence of the syndrome was the hypothesizes of a polygenic/multifactorial inheritance 4385662, characterized by a low recurrence risk for first-degree relatives. The most plausible explanation actually relies on the description of significant and increasing number of familial aggregates based on accurate delineation of the syndrome in the probands as well as in their relatives. Indeed, utero-vaginal aplasia is often found associated with other malformations, mainly renal and skeletal, these two latter being sometimes observed in combination with the first and interestingly, occurring in more distant relatives as well as mothers of MRKH patients 168963. Utero-vaginal aplasia can thus represent only one manifestation of a variably expressed genetic defect. This latter appears to be transmitted as an autosomal dominant trait with incomplete penetrance coupled with variable expressivity of a single mutant gene, as previously hypothesized 18964, or of a limited chromosomal imbalance undetectable in standard karyotypes.

The etiology of MRKH syndrome has remained quite unclear until now 6465, although the spectrum of malformations encountered suggests a developmental field defect 1319, involving organ systems which are closely related during embryogenesis. More precisely, MRKH syndrome may be attributed to an initial affection of the intermediate mesoderm, consequently leading (by the end of the fourth week of fetal life) to an alteration of the blastema of the cervicothoracic somites and the pronephric ducts 13. These latter subsequently induce the differentiation of the mesonephroi and then the Wolffian and Müllerian ducts.

The lack of families with informative genetic histories has initially led to a candidate gene approach for determination of the underlying etiology of the syndrome based either on association with other genetic diseases or on involvement during embryogenesis. As a result, the genetic association of MRKH with galactosemia 66 or with cystic fibrosis 67 was analyzed, but neither the gene for galactose-1-phosphate uridyl transferase (GALT) 68 nor the gene encoding the cystic fibrosis transmembrane regulator (CFTR) chloride channel 67 showed any mutation or polymorphism associated with the disorder. Aberrant expression of anti-Müllerian hormone (AMH) or its receptor, both involved in Müllerian duct regression 69 was hypothesized as a cause of MRKH syndrome 270; however, this theory was later discounted as a result of contradictory findings from a study of 32 patients 71. Moreover, incomplete aplasia of Müllerian structures is often observed in MRKH syndrome, showing that Müllerian differentiation does take place but is incomplete.

Genes with a broad spectrum of activity during early development (such as WT1 72, PAX2 73, HOXA7 to HOXA13 6474 and PBX1 74) have also been suggested as candidates, on the basis of phenotypes observed in mutant mice. However, their role in MRKH syndrome has not been subsequently demonstrated. WNT4 is another developmental gene, belonging to the WNT family of genes that regulate cell and tissue growth and differentiation during embryogenesis 75: its homozygotic inactivation in the mouse model leads to a total failure of Müllerian duct formation and numerous lethal defects at birth 76. In addition, WNT4 is known to be critical for successful nephrogenesis 777879. A loss-of-function mutation in the WNT4 gene has been recently described in an 18-year-old woman, in association with absence of Müllerian-derived structures, unilateral renal agenesis, and clinical signs of androgen excess 80. The congenital malformations observed in this patient suggested an MRKH-like phenotype and were similar to those observed in the Wnt4-/-mouse 76, indicating a dominant effect 80. In this pathological case as well as in the mouse model, it seems that loss-of-function of WNT4 which is essential for normal ovarian differentiation 76, has led to a masculinization of the fetal gonads consequently producing androgens. The WNT4 protein is known to repress male-specific genes such as those encoding steroidogenic enzymes CYP17A1 and HSB3B2, which are essential for the synthesis of testosterone 76. Mutated WNT4 may not be able to suppress the expression of androgen-synthesizing enzymes in ovarian cells, therefore leading to the observed hyperandrogenic phenotype 8081. Furthermore, WNT4 appears to be essential for the initial differentiation of the Müllerian ducts 657682. The dominant-negative mutation of WNT4 may then produce two distinct effects, hyperandrogenism and uterine aplasia. The sequencing of the WNT4 gene in 19 MRKH patients has confirmed that this gene is not involved in MRKH syndrome 83. Finally, the very recent report on a second patient bearing another WNT4 mutation has led to the conclusion that WNT4 deficiency is responsible for a clinical phenotype distinct from the classic MRKH syndrome 81. This new syndrome due to WNT4 mutations in XX women and characterized by absence of Müllerian ducts derivatives, hyperandrogenism and kidney optional adysplasia 8081, is close but different from MRKH syndrome; therefore, it should be referred to as a proper name, such as "WNT4 syndrome" or "WNT4 defects" and be consequently recorded under an appropriate OMIM number. This latter could well be 277000 if amended; OMIM 601076 would then be restricted to MRKH type I and II or MURCS.

The TCF2 gene (formerly v-HNF1 or HNF-1β) was originally found associated with MODY-type diabetes 84 and with diabetes mellitus, renal cysts and other renal developmental disorders 8586. Interestingly, genital malformations such as bicornuate uterus 87, uterus didelphys 87 and Müllerian aplasia 88 (OMIM 158330) were occasionally found associated with renal anomalies in some familial aggregates showing mutations within the TCF2 gene. Defects of this later gene can thus account for some rare cases of Müllerian malformations, including aplasia, making this gene one of the candidates for MRKH, but restricted to familial cases with renal and/or diabetes history. Finally the hypothesis of polygenic/multifactorial causes for MRKH syndrome has been reinforced by recent findings, in adults, of interstitial and terminal deletions involving chromosomes 22 89 and 4 90, respectively. However, the large number of genes included in each of these deletions has not allowed yet to precise any specific gene responsible for the syndrome. Only analysis of large cohorts of MRKH patients will certainly help to delineate new candidate genes and to establish phenotype/genotype correlations necessary for the genetic diagnosis of the syndrome.

Differential diagnosis of Müllerian aplasia includes patients presenting with primary amenorrhea and with normal secondary sexual characteristics (Table 1). This should first lead to exclusion of gonadal dysgenesis. The differential diagnosis includes congenital absence of uterus and vagina (aplasia or agenesis), isolated vaginal atresia and androgen insensitivity 9697. Transverse vaginal septum and imperforate hymen, which can be initially misleading, are not included. Indeed, patients with these latter conditions have normal cervix and uterus, both of which are palpable on rectal examination. Ultrasonography can be used to define the Müllerian structures in infrequent cases where palpation is unrevealing.

Young women diagnosed with MRKH syndrome suffer from extreme anxiety and very high psychological distress when they are told they have no uterus and vagina. Thus, it is recommended that the patient and family attend counseling before and throughout treatment. Group programs 106 and/or MRKH patients associations are also of great help. Indeed, psychological adjustment as well as medical attitude will be of great consequence for future decisions of creation of a neo-vagina and management of sterility 270106.

Can an equivalent MRKH syndrome or MURCS manifest in the male? Striking similarities found in male patients have raised the question 117118. Combinations of Wolffian duct agenesis or severe hypoplasia with or without renal and/or skeletal anomalies and/or hearing impairment have been described and include congenital unilateral renal agenesis associated with ipsilateral agenesis of the vas deferens 9119120, primary infertility due to azoospermia associated with Klippel-Feil anomaly 117, and segmentation abnormalities of the cervicothoracic spine and hearing impairment 121122. Interestingly, such male cases were found in families with female patients with MRKH syndrome 9. It is noteworthy that in azoospermic patients, the infertility seems to be attributable to uni- or bilateral defects of vas deferens development, ranging from hypoplasia 117 to agenesis 120122 and leading to a so-called obstructive azoospermia.

Since the designation MURCS association cannot apply to males, it was suggested that the male counterpart ARCS (Azoospermia, Renal anomalies, Cervicothoracic Spine dysplasia) would be a more suitable designation for this condition in males 121122. The acronym GRES (Genital Renal Ear Skeletal), which applies to both sexes 10, would be even more appropriate, especially when MURCS and ARCS are found together in the same family 9.