Definition and diagnosis criteria
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.
Etiology
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 [
1,
13,
30,
58]. However, studies analyzing available pregnancy histories failed to identify any association with drug use, illness, or exposure to known teratogens [
57,
59‐
61]. Another explanation of the sporadic occurrence of the syndrome was the hypothesizes of a polygenic/multifactorial inheritance [
4,
38,
56,
62], 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 [
1,
6,
8,
9,
63]. 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 [
1,
8,
9,
64], or of a limited chromosomal imbalance undetectable in standard karyotypes.
The etiology of MRKH syndrome has remained quite unclear until now [
64,
65], although the spectrum of malformations encountered suggests a developmental field defect [
13,
19], 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 [
2,
70]; 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 [
64,
74] 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 [
77‐
79]. 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 [
80,
81]. Furthermore, WNT4 appears to be essential for the initial differentiation of the Müllerian ducts [
65,
76,
82]. 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 [
80,
81], 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-1 β) was originally found associated with MODY-type diabetes [
84] and with diabetes mellitus, renal cysts and other renal developmental disorders [
85,
86]. 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.
Unresolved questions
Can an equivalent MRKH syndrome or MURCS manifest in the male? Striking similarities found in male patients have raised the question [
117,
118]. 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 [
9,
119,
120], primary infertility due to azoospermia associated with Klippel-Feil anomaly [
117], and segmentation abnormalities of the cervicothoracic spine and hearing impairment [
121,
122]. 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 [
120,
122] 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 [
121,
122]. 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].
Acknowledgements
We thank all the MRKH patients who participate in our research program and all the physicians and researchers involved in the French PRAM network (Programme de Recherches sur les Aplasies Müllériennes) in various French cities: Angers (D. Bonneau, P. Descamps), Bordeaux (D. Lacombe, C. Hocké), Créteil (C. Louis-Sylvestre, B-J. Paniel), Le Havre (V. Layet), Le Mans (T. Mouchel), Lyon (J. Attia-Sobol, P-H. Communal, G. Lesca, D. Raudrant), Marseille (A. Agostini, S. Sigaudy), Montpellier (P. Philibert, C. Sultan), Nantes (C. Lecaignec, P. Lopes), Nancy (B. Lebon-Labich, B. Leheup, A. Ranke), Paris (M. Gérard-Blanluet, R. Rouzier), Poitiers (B. Gilbert, G. Magnin), Rennes (C. Bendavid, V. David, Y. Deugnier, C. Dubourg, J-Y. Grall, C. Henry, M-C. Laurent, J. Levêque, L. Loeuillet, J. Lucas, S. Odent, D. Pape, L. Pasquier, I. Pellerin, L. Rochard, N. Soriano, T. Watrin), Toulouse (E. Bieth, C. Pienkowski).