Mayer–Rokitansky–Küster–Hauser Syndrome and Müllerian Aplasia

Congenital aplasia of the uterus and upper two-thirds of the vagina in 46,XX women with functioning ovaries and normal secondary sexual characteristics: isolated form (type I), form with extragenital malformations (type II), MURCS association as the extreme of type II, and the distinct entity of WNT4-related Müllerian aplasia with hyperandrogenism.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Historical overview and eponyms

Mayer–Rokitansky–Küster–Hauser syndrome is named after four authors who, over approximately 130 years, described complementary aspects of the same malformation. The first known description predates all four and is attributed to Realdo Colombo, who in De Re Anatomica (1562) mentioned a woman without a uterus or vagina who complained of pain during intercourse. The German anatomist August Franz Josef Karl Mayer (1829) and Austrian anatomist Carl von Rokitansky (1838) independently observed solid rudimentary uterine buds at autopsy, which Rokitansky termed uterus bipartitus solidus cum vagina solida; Rokitansky's original illustration shows a short blind-ending vagina and two rudimentary uterine remnants (Figure 1A in Herlin et al., 2020, https://pmc.ncbi.nlm.nih.gov/articles/PMC7439721/figure/Fig1/). The German gynaecologist Hermann Küster (1910) described the first case in a living patient, from whom he removed painful remnants, and the Swiss gynaecologist Georges André Hauser, with Schreiner, completed the current definition in 1961, combining uterovaginal agenesis, normal secondary sexual characteristics and a normal female karyotype, in a series of 21 cases; Hauser already used sex chromatin testing to distinguish these patients from women with Turner syndrome [3, 13, 15].

In 1977, Schmid-Tannwald and Hauser described seven patients with associated renal malformations, which they termed atypical MRKH [3]. In 1979, Duncan and colleagues brought together two of their own patients and 28 literature cases with congenital vaginal agenesis and cervicothoracic somite malformations and defined MURCS association (MÜllerian duct aplasia, Renal aplasia, Cervicothoracic Somite dysplasia): Müllerian aplasia or hypoplasia in 96%, renal agenesis or ectopia in 80% and two to four abnormal vertebrae between C5 and T1 in 80%. They proposed that the association resulted from a disturbance of the lower cervical and upper thoracic somite blastemas, upper-limb buds and pronephric ducts, structures in close spatial proximity at the end of the fourth gestational week, and considered a teratogenic cause because of the absence of familial transmission, normal chromosomes and analogy with thalidomide embryopathy [15, 25].

Subsequent decades brought milestones of different kinds. In 1997, Petrozza and colleagues showed that daughters born through gestational surrogacy using oocytes from women with MRKH did not have the malformation, arguing against frequent dominant transmission [26]. In 2004, Biason-Lauber and colleagues described the first WNT4 variant in a woman with Müllerian aplasia and androgen excess, an entity now considered distinct from MRKH [3, 27]. From 2008, recurrent CNVs were identified, particularly 17q12 deletion, first described in MRKH by Cheroki in 2008, and 16p11.2 deletion [13, 28, 29]. In 2014, the first child after uterine transplantation was born in Gothenburg, carried by a 35-year-old woman with MRKH [30]. In 2019 and 2020, family studies established GREB1L as the first gene strongly associated with type II MRKH with renal abnormalities [13, 31, 32].

1.2. Nomenclature and reclassifications

“Type II” now encompasses the atypical MRKH of Schmid-Tannwald and Hauser and MURCS association, namely any uterovaginal aplasia accompanied by extragenital abnormalities; type I accounts for 56–72% of cases and type II for 28–44%, depending on the series [3]. An Erlangen and Tübingen clinical classification distinguished three subtypes, typical, atypical and MURCS, with proportions of 47%, 21% and 32% in 53 patients [33]. Anatomical classifications of female genital tract anomalies evolved from the 1988 American Fertility Society (AFS) classification to the VCUAM system (vagina, cervix, uterus, adnexa and associated malformations, Oppelt, 2005), the 2013 ESHRE/ESGE consensus and the 2021 ASRM classification [11, 12]. In the ESHRE/ESGE (European Society of Human Reproduction and Embryology and European Society for Gynaecological Endoscopy) classification, typical MRKH is coded as aplastic uterus U5a (with a functional rudimentary horn) or U5b (without a functional cavity or with complete aplasia), cervix C4 (aplasia) and vagina V4 (aplasia) [11]. The OMIM codes %277000 and %601076, with a percentage symbol, indicate phenotypes of unknown molecular basis; code #158330 corresponds to Müllerian aplasia with hyperandrogenism, with a molecular basis in WNT4 [3, 34]. Herlin's 2024 review anticipates that classification may eventually become molecular rather than based on types I and II [13].

1.3. Definition of entities within scope

MRKH is defined as congenital absence of the uterus and at least the upper two-thirds of the vagina in a woman with a 46,XX karyotype, normal secondary sexual characteristics and normal ovarian function in the great majority of cases [1, 20]. Type I is isolated uterovaginal aplasia; type II is associated with at least one other malformation, primarily renal or vertebral and, less frequently, auditory, cardiac or gonadal [5, 20]. MURCS association is the most severe form of type II, combining Müllerian aplasia, renal agenesis or ectopia and cervicothoracic somite dysplasia [7, 25]. The Orphanet Müllerian aplasia group (ORPHA:73217) encompasses all Müllerian duct aplasias and hypoplasias, covered together with MRKH in this article because definition, diagnosis and management coincide [6]. Müllerian aplasia with hyperandrogenism is a 46,XX difference of sex development with Müllerian hypoplasia or agenesis and clinical and biochemical evidence of androgen excess, caused by heterozygous WNT4 variants; the reference review considers it a separate entity rather than a cause of MRKH [3, 8]. Presentations in which Müllerian aplasia forms part of a CNV syndrome (17q12 deletion, 22q11.2 deletion, 16p11.2 deletion) are described here only regarding the genital phenotype [13, 16].

2. Molecular Genetics and Pathophysiology

2.1. Müllerian duct embryology

Until the seventh gestational week, embryos of both sexes have Wolffian (mesonephric) and Müllerian (paramesonephric) ducts. Müllerian ducts form from weeks 5–6 by invagination of the coelomic epithelium of the urogenital ridges and grow caudally, guided by the Wolffian ducts, towards the urogenital sinus; their caudal portions fuse to form the uterus, cervix and upper vagina, while the unfused cranial portions form the fallopian tubes. In males, the fetal testis produces anti-Müllerian hormone (AMH, also termed Müllerian inhibiting factor), causing Müllerian duct regression; in females, Wolffian ducts regress in the absence of testosterone [3, 35]. The lower vagina derives from an evagination of the urogenital sinus and is therefore usually present in MRKH as a blind-ending pouch; the ovaries have a distinct embryological origin in the genital ridge and are normal in structure and function [15, 17]. MRKH results from Müllerian duct agenesis or aplasia [3].

The dependence of the Müllerian duct on the Wolffian duct explains the frequent association with renal malformations: the Wolffian duct also induces the ureteric bud and metanephros, and absence of a Müllerian duct often accompanies ipsilateral renal agenesis [3]. The spatial relationship at the end of the fourth week between the cervicothoracic somite blastemas, upper-limb buds and pronephric ducts underlies the pathogenic hypothesis for MURCS association [25].

2.2. Aetiological architecture

The aetiology of MRKH remains uncertain and is probably heterogeneous: monogenic, oligogenic, polygenic, multifactorial, environmental and epigenetic mechanisms and somatic events are considered [2, 3, 13]. Familial cases, approximately 4% of the total, support a genetic component, with most pedigrees suggesting autosomal dominant inheritance with incomplete penetrance, particularly in families with Müllerian aplasia and renal abnormalities, previously termed “hereditary renal adysplasia” by Buchta in 1973 and “hereditary urogenital adysplasia” by Schimke and King [13, 15]. The predominance of sporadic cases, absence of recurrence in daughters born through gestational surrogacy and existence of discordant monozygotic twins argue against a simple genetic cause. Absolute uterine factor infertility historically prevented vertical transmission, so the genetic contribution is probably underestimated [3].

Several non-genetic hypotheses have been tested. Fetal exposure to thalidomide, diethylstilbestrol (DES), organotin compounds and phthalates has been proposed without firm evidence; a French study reported a high incidence of MRKH in third-generation DES-exposed women, but only the title was read in this review [13, 36]. The freemartin hypothesis, whereby AMH from a vanished male cotwin would cause Müllerian duct regression, was tested in the Netherlands: male microchimerism was present in 5.3% of 95 women with MRKH and 17.2% of 99 never-pregnant controls (p = 0.009), with equal frequency in typical and atypical types, which does not support the hypothesis [37]. There is no evidence of involvement of AMH or its receptors, and an extensive list of historically tested candidate genes yielded negative results (GALT, WT1, AMH, AMHR2, CFTR, WNT7A, HOXA7–13, PBX1, RARG, RXRA, CTNNB1, PAX2, among others) [3, 13].

Studies of discordant monozygotic twins provided mosaicism data. In five pairs studied by sequencing blood and rudimentary uterine tissue, an ACTR3B mosaic variant had a high allele fraction in affected tissue, a low fraction in the affected twin's blood and an almost zero fraction in the unaffected twin; in another pair, a pathogenic GREB1L variant was present in both twins and the unaffected mother, an example of reduced penetrance [38]. In one Chinese pair, blood genome sequencing (66–68x) and exome sequencing (95–127x) identified neither validated postzygotic variants nor pathogenic CNVs, and the authors hypothesised mosaicism restricted to Müllerian tissue or epigenetic dysregulation [39]. Epigenetic studies produced variable results without a consistent pattern [14].

The largest gene burden analysis brought together exome or genome data from 727 Chinese probands (476 isolated and 251 with multiple congenital abnormalities; 716 after quality control) and 2402 female controls, considering ultrarare variants (gnomAD frequency ≤0.01%) and excluding probands with a likely pathogenic CNV beforehand. Previously known genes PAX8, BMP7 and GREB1L and new candidates PAN2 and AGPAT2 reached exome-wide significance; enriched processes were apoptosis and mesenchymal-to-epithelial transition, and single-cell RNA sequencing showed expression of associated genes in uterine epithelium at eight weeks and Wolffian duct epithelium at 11 weeks. There were 992 digenic combinations identified, three with exome-wide significance, findings that remain within the research setting [40]. The 2026 systematic review (97 studies) concluded that known genetic alterations explain the phenotype only in a subgroup and that variable expressivity and epigenetic and environmental factors complicate counselling [14].

2.3. Recurrent copy-number variations

Recurrent CNVs explain approximately 10% of patients with MRKH [13]. Table 2.1 summarises the regions described, according to the 2024 review.

Table 2.1. Recurrent CNVs in MRKH (GRCh38 coordinates) [13]

17q12 deletion. This is the CNV with the most consistent evidence. The recurrent deletion, typically 1.4 Mb and mediated by segmental duplications, contains 15 genes, including HNF1B and LHX1, and is highly penetrant, with variable expressivity (renal abnormalities, neurodevelopmental changes, HNF1B-related MODY5 diabetes, genital and hepatic malformations) [13, 16]. In 282 carriers from 42 studies, genital abnormalities affected approximately one-third of women, with partial or complete absence of the upper vagina, cervix and uterus being the most frequent finding [16]. Bernardini and colleagues described two patients with the same 1.5 Mb deletion, one with complete absence of the uterus and vagina and the other with agenesis of the upper vagina, a right unicornuate uterus, a left rudimentary horn and multicystic kidneys; sequencing of HNF1B and LHX1 in 20 patients without a deletion was negative [28]. The 17q12 deletion was estimated to account for approximately 6% of patients in a large German cohort [41]. A family studied by Ledig showed a mother and sister carrying the same deletion with other uterovaginal abnormalities [13].

Within the 17q12 region, three genes have been specifically studied. HNF1B, a homeodomain transcription factor, causes the renal, urogenital and endocrine abnormalities of the deletion through haploinsufficiency; intragenic variants cause cystic kidney disease, MODY5 diabetes, hypomagnesaemia, hyperuricaemia, pancreatic atrophy and genital tract malformations in approximately 20% of women [2, 16, 42]. In a Norwegian family with MODY5 and autosomal dominant renal disease due to a 75 bp in-frame deletion in HNF1B exon 2, two of four female carriers had uterovaginal agenesis; an approximately 59 kb HNF1B deletion in a 9-year-old girl with precocious puberty led through reverse phenotyping to confirmation of uterine agenesis; in mice, conditional Hnf1b ablation produces a hypoplastic uterus with renal abnormalities, resembling type II [13]. LHX1, a LIM-domain transcription factor essential for renal and urogenital development, has been proposed as a candidate: the Lim1-null mouse lacks Müllerian derivatives and loss of Lhx1 in Müllerian epithelium eliminates the entire endometrium [3, 43, 44]. Six LHX1 SNVs have been described in MRKH, including a frameshift variant in a German cohort, but larger cohorts found no variants, so LHX1 SNVs are not a major cause [13, 41, 45]. In 2026, a US cohort of 134 patients identified heterozygous intragenic LHX1 deletions in three (2.2%), with allele fractions of 1%, 3.4% and 6.2%, consistent with low-level mosaicism; the 1864 bp genomic deletion (intron 3, exon 4 and intron 4) translates at cDNA level to c.676_841del, p.(Val226Ilefs*120), and disrupts the DNA-binding domain [46]. The same group described truncating ZNHIT3 variants, also in the 17q12 region, in 6 of 132 patients (4.5%), five with type II MRKH, with reduced protein expression in vitro [47].

16p11.2 deletion and TBX6. In a cohort of 63 patients from the United Kingdom and Germany, Nik-Zainal and colleagues found recurrent CNVs in 9 (14%): 16p11.2 microdeletion in four, 17q12 in four and distal 22q11.2 in one; the frequency was 4/38 (10.5%) in isolated forms and 5/25 (20%) in syndromic forms [29]. The proximal 16p11.2 deletion contains TBX6, a T-box factor that patterns the paraxial mesoderm and somites [13, 48]. In congenital scoliosis, the disease results from a dosage model with compound inheritance: a rare null allele (16p11.2 deletion or point variant) in trans with a common hypomorphic haplotype defined by the polymorphisms rs2289292, rs3809624 and rs3809627; among 161 Han Chinese patients, 17 (11%) had a null allele and all had the risk haplotype on the other allele [48–50]. In MRKH, however, no second risk alleles were found, and the monoallelic mechanism remains to be established [13]. In the Finnish cohort of 112 Müllerian aplasias, a TBX6 splicing variant was identified in two patients and two TBX6 variants were more frequent than in controls (8% and 5% versus 2%) [51]. In a multi-ethnic cohort of 622 probands, the burden of rare TBX6 variants was greater in Chinese patients than in 1038 controls (p = 0.0004; odds ratio 5.25), and 7 of 15 variants of uncertain effect showed loss of function in vitro, with incomplete penetrance and variable expressivity within families [52]. The 16p11.2 deletion also has its own phenotype outside the genital tract.

22q11.2 and 1q21.1 regions. The 22q11.2 CNVs described in MRKH share no common region and some do not include TBX1, so the evidence is weak; 22q11.2 duplication also occurs in other uterovaginal malformations [13]. The genitourinary abnormalities of 22q11.2 deletion syndrome include uterus didelphys, vaginal agenesis and absence of the uterus [53]. The 1q21.1 deletion has been described in at least two women with MRKH; RBM8A is located at 1q21.1, and its deletion together with a non-coding polymorphism in trans causes thrombocytopenia-absent radius (TAR) syndrome, also described in a case with MRKH, but causality remains uncertain [13, 54, 55].

2q13q14 deletion and PAX8. Two overlapping 2q13–q14 deletions (10.79 Mb in a 12-year-old girl with global delay, Müllerian agenesis and hypothyroidism; and 2q12.1q14.1 with congenital hypothyroidism, atrial septal defect, intellectual disability, Müllerian agenesis and an anteriorly placed anus) share 4.3 Mb and include PAX8, a gene expressed in the thyroid, kidney and Müllerian derivatives [13, 56]. An exome study of 442 cases and 941 controls with replication identified 11 PAX8 variants, with confirmed paternal inheritance in three cases (sex-limited expressivity) and loss of function in two of five missense variants; reverse phenotyping of five women with PAX8-related congenital hypothyroidism revealed uterovaginal aplasia in one, prompting a proposed congenital hypothyroidism–MRKH spectrum [13]. Since no uterine malformation had been reported in more than 30 published cases of PAX8-related hypothyroidism, penetrance of the uterine phenotype is reduced [40].

2.4. Genes with recurrent variants

Table 2.2 presents genes with recurrent variants in the 2024 review. More than 20 genes outside the 17q12 region have been described in two or more patients, but many of these variants remain classified as variants of uncertain significance [13, 16].

Table 2.2. Genes with recurrent variants in MRKH [13]

GREB1L. This is the gene with the most robust evidence in type II MRKH with renal abnormalities. GREB1L is a retinoic acid receptor coactivator required for metanephric, genital tract and inner ear development; the Greb1l-null mouse lacks kidneys and Wolffian and Müllerian ducts [13, 57]. In 2017, three studies established GREB1L as an autosomal dominant cause of renal hypoplasia or agenesis (RHDA3, OMIM #617805), with female fetuses showing bilateral renal agenesis and uterine aplasia [13, 57]. In a three-generation Danish family (two female cousins with MRKH and unilateral renal agenesis and two deceased men with renal agenesis), Herlin and colleagues identified the cosegregating missense variant c.705G>T, with incomplete penetrance dependent on parental origin [31]. Jacquinet and colleagues found causal heterozygous variants in 4 of 9 multiplex families with uterine and renal malformations and six variants of uncertain significance in 68 predominantly sporadic patients [32]; the 2024 review cites a frequency of 5/63 (7.9%) in sporadic patients from the same study [13]. In an exome study of 148 probands from North America, Europe and South America, with replication in 442 Han Chinese probands, likely deleterious GREB1L variants were present in 16 of 590 probands (2.7%), eight of each type [34]. Penetrance is markedly incomplete: among 49 published variants, half of those with tested relatives showed reduced penetrance and 71% of inherited variants were maternal; 14% were associated with ear abnormalities, and profound deafness with cochlear aplasia (DFNA80, OMIM #619274) is allelic [57]. A nonsense variant was transmitted from an unaffected grandfather and mother to two fetuses with bilateral renal agenesis [57].

WNT9B. In 226 women with Müllerian anomalies (109 with MRKH) and 135 controls, one likely pathogenic nonsense and five likely pathogenic missense variants were identified; five occurred in MRKH (4.6%), all type I (8.5% of this type), and none in controls (p = 0.017). Two patients also had an LHX1 deletion or a TBX6 missense variant, suggesting a digenic model [58]. Other studies were negative, and WNT9B acts upstream of WNT4 [3, 13].

Other genes. Partial SHOX duplications were described in 5 of 30 patients (Gervasini, 2010; including a pair of sisters) and none of 53 controls, but not in 101 Finnish patients, so causality is not established; the same applies to LRP10 (585 kb duplication in an affected twin and five missense variants) [13]. In Turkey, among 19 patients, 4 (21%) had CNVs and 14 (74%) were daughters of parents related in the third degree or closer, with 42 shared regions of homozygosity, raising the possibility of autosomal recessive inheritance in consanguineous populations [59]. Genome sequencing of nine Chinese trios with type I MRKH identified de novo variants in candidate genes (PIK3CD, SLC4A10, TNK2) without validation, and exomes from seven Taiwanese patients proposed candidates (OR4M2, PDE11A) and deletions at 15q11.2, 19q13.31, 1p36.21 and 1q44, also without validation [60, 61]. In the US and Turkish cohort of 147 probands, WNT4, HNF1B and LHX1 sequencing in 100 patients identified no point variants [45].

2.5. WNT4: Müllerian aplasia with hyperandrogenism and SERKAL syndrome

WNT4 (1p36.12; MANE transcript NM_030761.5) encodes a WNT ligand required for Müllerian duct formation, mesenchymal-to-epithelial transition in the developing kidney and repression of ovarian 3β-hydroxysteroid dehydrogenase; its absence explains the combination of Müllerian aplasia, renal malformation and excessive ovarian androgen production [9, 27]. The index case, published in 2004, was an 18-year-old 46,XX woman with primary amenorrhoea, absent Müllerian structures, unilateral renal agenesis and clinical signs of androgen excess, with a loss-of-function WNT4 variant and a phenotype resembling that of the female Wnt4-knockout mouse [27]. In 2007, among six 46,XX patients with Müllerian anomalies, only one, aged 19, had unequivocal androgen excess (acne, hirsutism and repeatedly elevated testosterone); she carried a variant described as “R83C”, with loss of function and a dominant-negative effect in cellular studies. The authors concluded that absence of the uterus with androgen excess, rather than Müllerian anomalies in general, points to WNT4 deficiency [62]. In a French collaborative study of 28 adolescents with primary amenorrhoea and a Müllerian anomaly, a single novel variant (L12P), absent in 100 controls, was found in a patient with severe acne, testosterone of 1.8 nmol/L (versus 1.2 nmol/L in controls), uterine hypoplasia and follicular depletion; the variant increased 3β-HSD and 17α-hydroxylase expression [63]. A fourth variant (A233T) was described in four adolescents with MRKH and hyperandrogenism, with abnormal CYP17A1 re-expression [64]. Herlin and colleagues consider this entity separate from MRKH, and a woman with typical MRKH without hyperandrogenism is very unlikely to have a WNT4 defect [3, 9]. WNT4 missense variants have also been described in Herlyn-Werner-Wunderlich syndrome [13].

SERKAL syndrome (SEx Reversal with dysgenesis of Kidneys, Adrenals and Lungs) is the autosomal recessive allelic WNT4 disorder: a single consanguineous family with a homozygous missense variant that reduced WNT4 mRNA and abolished WNT4-dependent inhibition of β-catenin degradation, with 46,XX female→male sex reversal, renal, adrenal and pulmonary dysgenesis and fetal lethality [9, 10]. Orphanet records three cases, all from this family [9]. The practical difference is substantial: a dominant-negative heterozygous allele produces an adult woman with absent uterus and hyperandrogenism and a 50% transmission risk, whereas biallelic loss of function produces a lethal fetal syndrome with a 25% recurrence risk for a consanguineous couple [9].

2.6. Variant nomenclature

Table 2.3 standardises historically relevant variants on the MANE Select transcript, with the corresponding historical nomenclature. The variant published as “R83C” by Biason-Lauber and colleagues is registered in ClinVar, citing the same article, as NM_030761.5:c.247C>T, which produces p.(Arg83Trp) on the MANE transcript; the sources consulted do not clarify the discrepancy between the published protein designation and ClinVar, so the variant is specified by the record's genomic and cDNA descriptions [62, 65, 66]. Transcripts in the 2020 tables (NM_004608.3 for TBX6, NM_005568.3 for LHX1, NM_003396.1 for WNT9B, NM_001142966.2 for GREB1L) have been replaced by newer versions; the c. positions of the table variants remain unchanged in the MANE versions [3, 66].

Table 2.3. Standardised variants (GRCh38) [3, 65, 66]

In the 2020 table, most TBX6, LHX1 and WNT9B SNVs were of uncertain significance [3]. TBX6 variants with loss of function in vitro in the 2022 cohort (for example c.423G>A, synonymous with a splicing effect, and c.839+5G>A) were published without a transcript in the abstract consulted [52].

2.7. Penetrance, expressivity and genotype–phenotype correlations

In families with an identified cause, the dominant pattern combines incomplete penetrance with sex-limited expressivity: the same allele causes Müllerian aplasia in women and renal agenesis, or no phenotype, in men and some female carriers [13, 31, 32]. Known correlations are partial. GREB1L is mainly associated with type II with renal malformations (22 of 30 variants) and sometimes ear abnormalities; PAX8 is associated with type I and congenital hypothyroidism; WNT9B occurs mainly in type I; 17q12 deletion is accompanied by renal disease, diabetes and neurodevelopmental abnormalities [13, 57]. The 16p11.2 and 17q12 deletions have incomplete penetrance for developmental abnormalities (46.8% and 34.4%, respectively, in a Rosenfeld and Coe case–control analysis cited by the Oxford Desk Reference), data that do not refer to MRKH [67]. Genes shared between MRKH and other uterovaginal malformations (17q12 deletion, EMX2, GREB1L, HNF1B, HOXA10, SPECC1L, WNT4, WNT9B) suggest a spectrum of abnormalities with common causes [13].

3. Clinical Spectrum and Manifestations by System

3.1. Genital anatomy

The malformation affects the uterus, cervix and upper vagina, sparing the vulva, vestibule and ovaries. The vaginal canal is markedly shortened, measuring 0 to 3 cm without a cervix at its apex, or may be reduced to a depression below the urethra [3, 17]. The French protocol describes three introital appearances: a normal hymenal rim with a vaginal dome of variable length, often under 2 cm; absence of the rim when vaginal aplasia is complete; and a sometimes more posterior, round and partially open urethra, which should not be mistaken for the vaginal opening [20]. Uterine remnants exist in 48–95% of patients, and MRI identifies rudimentary Müllerian structures in approximately 90% [3, 17]. Two presentations are described: two aplastic uterine buds on the lateral pelvic wall, connected by a midline remnant or fibrous band, more frequent in type I; or complete absence of one or both ducts, more frequent in type II with ipsilateral renal malformation [3]. The fallopian tubes may be normal and connected caudally to two small muscular buds [2]. Buds may contain functional endometrium (a cavitated rudimentary horn, class U5a), occurring in 2–31% depending on the series and causing cyclical pain, haematometra due to cryptomenorrhoea, adenomyosis and endometriosis [3, 11, 20].

The ovaries are present and functional but frequently located more cranially and laterally, near the external iliac arteries, probably because of absent normal tubal development [3]. In a Chinese MRI series, 23 of 83 patients (28%; 37 of 166 ovaries) had an abnormally located ovary, versus 3 of 60 controls (5%; p < 0.001), without differences in volume or follicle count; location is relevant to oocyte retrieval, interpretation of pelvic pain and surgical planning [68]. Ovarian anomalies themselves (unilateral agenesis, ectopia, polycystic or streak ovaries and, rarely, tumours) occur in approximately 5–10% [3]. Inguinal hernias containing an ovary or Müllerian remnant are frequent, with 27 cases in the review of 512 patients and 54 among 284 German patients [3].

3.2. Associated malformations

Renal malformations are the most frequent extragenital anomalies. ACOG cites frequencies of 27–29%, the PNDS approximately 30% and the 2020 review 30–40% in European cohorts; unilateral renal agenesis accounts for approximately half, frequently with complete absence of the ipsilateral Müllerian duct, followed by pelvic or ectopic kidney, duplex kidney and horseshoe kidney [3, 17, 20]. In the Danish registry, 38 of 111 patients with renal examination (34.2%) had a renal malformation, and 57 of 168 (33.9%) had never undergone urinary tract imaging [18]. Reported frequencies in China are lower (13% and 5%), possibly reflecting interethnic variation or incomplete assessment [3].

Skeletal anomalies occur in approximately 10–40% (8–32% according to ACOG): scoliosis, Klippel-Feil sequence, hemivertebrae, vertebral arch abnormalities, rib aplasia, wrist hypoplasia and, rarely, limb anomalies [3, 17]. Sensorineural or conductive hearing loss (external auditory canal atresia, stapes ankylosis) and heart disease (pulmonary valve stenosis, atrial septal defect) each occur in fewer than 5%; systematic otorhinolaryngological evaluation found ear anomalies in 11% [3, 17]. Müllerian agenesis may form part of VACTERL association (vertebral anomalies, anal atresia, cardiac anomalies, tracheo-oesophageal fistula, renal and limb anomalies) and, more rarely, occurs with an isolated anorectal malformation [3, 17]. Up to 53% of patients have some concomitant malformation [17].

Table 3.1. Associated malformations in cohorts with more than 100 patients [3]

Denominators and assessment methods differ between studies: many cohorts did not systematically investigate the skeleton, hearing or heart, and lower frequencies may reflect underassessment. In the Oppelt cohort (2006), inguinal hernia occurred in 27 patients and neurological abnormalities in 7; anal atresia and VACTERL were recorded in some patients in the German and Danish cohorts [3].

3.3. MURCS association

MURCS association is the most severe form of type II. In the original description and the Smith's Recognizable Patterns summary, which acknowledges ascertainment bias, the main findings are short stature (adult height usually below 152 cm), cervicothoracic vertebral defects primarily between C5 and T1 (80%), sometimes with Klippel-Feil sequence, absence of the proximal two-thirds of the vagina with absent or hypoplastic uterus (96%), and renal agenesis or ectopia (88%) [15]. Occasional anomalies include rib abnormalities, occipitoatlantoaxial junction malformation, early-onset ankylosing vertebral hyperostosis, upper-limb reduction anomalies (a duplicated thumb described) and Sprengel deformity; more rarely deafness, cerebellar cyst, auricular defects, facial asymmetry, heart disease, cleft lip or palate, micrognathia, gastrointestinal and anorectal malformations, laterality defects, abnormal pulmonary lobation and occipital encephalocele [15]. Figure 1 in Smith (p. 927) shows a child with a short neck due to cervical vertebral defects and the corresponding radiograph with partial to complete cervical vertebral fusion [15].

The Brazilian textbook Síndromes Genéticas: Reconhecer para Tratar (SGRT) presents the following frequencies in MURCS association, without specifying denominators or the primary source [7]:

Table 3.2. Frequencies in MURCS association according to SGRT [7]

The same textbook illustrates the cervical vertebral abnormality in figure 10.2.1, reproduced from Saldarriaga and colleagues (2015) [7]. The designation “somatic colon dysplasia” appearing there should read “somite dysplasia”. The frequencies of 96% and 80–88% derive from Duncan's series, enriched for syndromic cases, and do not represent the frequency of these anomalies in MRKH overall, which is shown in Table 3.1 [3, 25].

3.4. Gynaecological, urological and pelvic floor manifestations

Cyclical or chronic pelvic pain results from active endometrium in remnants, ovulation or endometriosis and may improve with hormonal suppression [17]. A meta-analysis of 102 studies (666 patients with documented presence or absence of functional endometrium, 1980–2024) estimated endometriosis prevalence at 10.7% (95% CI 8.5–13.2), with 8.6% in series and 27.4% in case reports, and 3.4% in series with at least 10 patients (41 of 1219). Endometriosis occurred in 32.0% (64/200) of patients with functional endometrium in remnants and 1.5% (7/466) of the remainder (odds ratio 12.0; 95% CI 5.1–28.3); the seven cases without functional endometrium had incomplete assessment, supporting the retrograde menstruation theory [69]. Other described findings are leiomyomas in the rudimentary uterus and adenomyosis [3].

In a 2019 online survey of 615 women from 40 countries (81% white; median age 29 years), 54% had undergone vaginal lengthening (39% of these surgically) and 70% reported at least one urinary symptom, of whom 79% were bothered: incontinence in 34%, frequency and urgency in 40% each, dysuria in 16% and recurrent urinary infection in 29%; lower abdominal pressure occurred in 41%, pelvic heaviness in 29%, vaginal bulging in 11%, constipation in 25% and anal incontinence in 25%. Differences between women with and without lengthening were limited to recent urinary incontinence and anal incontinence, and bulging was greater after intestinal vaginoplasty [19].

3.5. Psychological and sexual impact

Diagnosis in adolescence has a psychological impact that should not be underestimated: anxiety, depression, questioning of female identity, grief over infertility and difficulty sharing the diagnosis with family, peers and partners [17]. Women with MRKH have greater psychological distress than women without the malformation, and studies using the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale–Revised (FSDS-R) document sexual dysfunction and distress; qualitative studies identify themes of independence hindered by maternal involvement, feeling different, difficulty with intimacy and a threat to female identity [3]. The PNDS draws attention to eating disorders, sometimes preceding diagnosis, addictive behaviours such as intensive exercise, maternal guilt, exclusion of the father and a risk of depressive decompensation at any stage [20]. A meta-analysis of 10 studies showed lower total FSFI after vaginoplasty than in healthy women (standardised mean difference −0.233; 95% CI −0.376 to −0.090), with lower lubrication and satisfaction [70]. The best predictor of a good emotional outcome is a good relationship with parents and the ability to share feelings with family and friends [17].

3.6. Features of forms with a known genetic cause

In WNT4-related Müllerian aplasia with hyperandrogenism, the presentation includes a hypoplastic or absent uterus, primary amenorrhoea, acne and hirsutism, sometimes renal anomalies, normal external genitalia and secondary sexual characteristics, and variable elevation of androstenedione, dehydroepiandrosterone and total and free testosterone [8, 62]. The ovaries function, and infertility is due to absence of the uterus rather than gonadal failure [9]. The PNDS notes that clinical hyperandrogenism (acne, hirsutism, abdominal obesity) may accompany MRKH and that moderate hyperandrogenaemia should point towards this subtype; the 2020 review reports biochemical hyperandrogenaemia without clinical expression in approximately half of MRKH patients in a recent study, a finding requiring validation [3, 20].

In 17q12 deletion, Müllerian aplasia occurs with renal abnormalities (80–90%), developmental delay (around 50%) and MODY5 diabetes (around 40–45%), with genital abnormalities in around 30% of women; other forms include bicornuate, didelphic or hypoplastic uterus and ovarian cysts [16, 44]. In RCAD (renal cysts and diabetes) due to an intragenic HNF1B variant, genital tract defects affect around 20% of women, and diabetes and gout develop later [2, 71]. In families with GREB1L, uterovaginal aplasia coexists with unilateral or bilateral renal agenesis, and female fetuses with bilateral renal agenesis, usually lethal because of oligohydramnios, may have no uterus [32, 57].

3.7. Natural history

MRKH is a congenital malformation that does not impair ovarian function or pubertal development; the sources consulted present no mortality or life expectancy data for type I [3, 20]. Overall prognosis depends on the extent and severity of renal abnormalities and multisystem involvement in type II and MURCS association, where short adult stature is frequent [7, 15]. Long-term gynaecological morbidity results mainly from remnant-associated pain, endometriosis, pelvic floor symptoms and psychological and sexual effects [3, 19, 69]. The distinction between natural history and treated disease applies mainly to sexual function: without treatment, a normal vulva and clitoris allow genital sexuality and orgasm, and abstinence is a legitimate option; with dilatation or surgery, most achieve functional vaginal length (section 7) [20].

4. Clinical Recognition and Warning Signs

4.1. Adolescence

The typical presentation is primary amenorrhoea in an adolescent with normal growth and puberty, leading to diagnosis in around 85% of cases [17, 20]. The PNDS defines relevant delay as absence of menstruation two to three years after thelarche, and the 2020 review uses absence of menstruation at 16 years with normal puberty [3, 20]. MRKH is the second cause of primary amenorrhoea: in a series cited by the Oxford Desk Reference, gonadal dysgenesis explained 48.5%, congenital absence of the uterus and vagina 16.2%, GnRH deficiency 8.3% and constitutional pubertal delay 6.0% [2, 3]. Amenorrhoea is generally painless, but cyclical pelvic pain suggests a rudimentary uterine horn with functional endometrium [20]. Less frequently, presentation is dyspareunia or inability to achieve penetration (apareunia) [3, 20].

Signs raising suspicion of MRKH with primary amenorrhoea are normal breast development and pubic and axillary hair, a normal vulva and a short or absent vagina on careful examination; scant or absent hair with developed breasts instead points to complete androgen insensitivity, and acne or hirsutism with elevated androgens points to the WNT4-related form [17, 20, 62]. A bluish bulging membrane without a hymenal fringe, with cyclical pain and a pelvic mass, indicates an obstructive malformation with a uterus present, which should not be confused with MRKH because management differs and error has iatrogenic consequences [3, 17].

4.2. Childhood and neonatal period

Before puberty, MRKH should be systematically considered in a multiple-malformation syndrome, particularly with renal or urinary malformations, an abnormal vaginal opening or an inguinal hernia containing an ovary; it may also be discovered incidentally on pelvic imaging [20]. In children, assessment looks for short stature, facial asymmetry, abnormal spinal alignment, limb abnormalities, a cardiac murmur and hearing impairment, without examining the vaginal cavity at this age [20]. Prepubertal imaging is unreliable: ultrasound identifies the uterus in 95–100% of girls without abnormalities when performed by experienced radiologists, but there is a real risk of falsely diagnosing an absent or hypoplastic uterus, so waiting until puberty to confirm uterovaginal aplasia is recommended [3, 16, 20]. A girl carrying a 17q12 deletion or GREB1L or HNF1B variant with primary amenorrhoea should have her uterus and vagina reassessed [13, 16].

4.3. Familial and syndromic contexts

Suspicion should extend to families with unilateral or bilateral renal agenesis, particularly fetuses with bilateral renal agenesis and women with uterovaginal abnormalities, suggesting GREB1L-related hereditary urogenital adysplasia [31, 32]. Congenital hypothyroidism in a woman with primary amenorrhoea suggests PAX8 [13]. Juvenile-onset diabetes without autoimmunity, with renal cysts or hypomagnesaemia, suggests HNF1B or 17q12 deletion [16, 44]. Congenital scoliosis, Klippel–Feil sequence and a short neck suggest MURCS association [2, 15].

4.4. Warning signs and urgent situations

MRKH has no specific emergencies, but some situations require prompt assessment: severe cyclical pelvic pain with haematometra in a rudimentary horn; acute pain with bleeding, urinary symptoms or fever during dilatation (abrasion, urinary infection, dysfunctional voiding or, rarely, urethral dilatation); bleeding from an intestinal neovagina, potentially indicating a polyp or adenocarcinoma; and, in uterine transplant recipients, signs of rejection, graft thrombosis, hypertension or proteinuria during pregnancy [3, 17, 20, 21]. ACOG recommends that every patient have a written clinical summary of concomitant malformations, useful when seen in emergency or surgical settings by professionals less familiar with the condition [17]. There is no newborn screening for MRKH.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no formal scored criteria. Diagnosis rests on four elements: absent uterus and at least the upper two-thirds of the vagina, normal secondary sexual characteristics, 46,XX karyotype and normal ovarian function [3, 20]. Subclassification as type I or type II depends on investigation for extragenital malformations, and MURCS association requires Müllerian aplasia, a renal abnormality and cervicothoracic somite dysplasia [3, 25]. In the ESHRE/ESGE classification, the abnormality is described as U5a or U5b, C4 and V4; subclass U5a, with a functional rudimentary horn, indicates the risk of cyclical pain and a blood-filled cavity potentially requiring treatment [11].

5.2. Clinical examination

Examination should respect the patient's age and motivation and be performed with consent. In adolescents, it includes stature, Tanner stage, inspection of the vulva and introitus and assessment of vaginal vault length and compressibility with a blunt instrument or finger [17, 20]. Vaginal examination should be avoided in children [3, 20]. History includes familial uterovaginal, renal and skeletal malformations, preferably in a three-generation pedigree, and assessment for a short neck or restricted cervical movement [2, 20].

5.3. Imaging

Suprapubic pelvic ultrasound with a full bladder is first-line: it shows an absent vagina between bladder and rectum and an absent uterus, with normal multifollicular ovaries; the inguinal canal should be explored for hernia and examination completed with renal ultrasound. The endovaginal route is inappropriate. Pitfalls include ectopic ovaries and a quadrangular retrovesical vestigial uterovaginal plate without an endometrial line, potentially mistaken for a prepubertal uterus [20]. ACOG allows two- or three-dimensional transabdominal, translabial or transrectal ultrasound [17].

Pelvic MRI is the reference technique for final diagnosis: it identifies Müllerian remnants in around 90%, assesses active endometrium, locates ovaries and detects extragenital malformations, with high concordance with laparoscopy [3, 17]. The PNDS proposes a protocol extending from the iliac crests to the perineum, with 5 mm T2-weighted sequences in three planes, abdominal axial sections if ovaries are not visualised, a heavily T2-weighted coronal MR urography-type sequence if the urinary tract has not been assessed by ultrasound and, optionally, T1 sequences with and without fat saturation and gadolinium to improve detection of rudimentary horns and ovarian pathology; ACOG states that the request should specifically mention assessment for Müllerian remnants, interpreted by an experienced radiologist and usually without contrast [17, 20]. The ESHRE/ESGE Thessaloniki consensus recommends that adolescents with symptoms suggesting genital abnormalities be assessed with two-dimensional ultrasound, three-dimensional ultrasound, MRI and endoscopy, used and interpreted by experts to avoid overdiagnosis and underdiagnosis [22].

Examination under general anaesthesia and laparoscopy are not indicated diagnostically; laparoscopy is reserved for pelvic pain with active endometrium in remnants, where it may serve to excise them [3, 17, 20]. If a child undergoes anaesthesia for another reason, for example urinary or inguinal hernia surgery, the opportunity should be taken to inspect the introitus [20]. Before puberty, MRI has limited reliability and requires general anaesthesia between 6 months and 5–7 years, so is not indicated in practice; in infants, maternal hormonal exposure facilitates ultrasound [20].

5.4. Hormonal assessment

ACOG proposes testosterone, FSH and karyotype as initial laboratory assessment in a patient without a uterus [17]. The PNDS gives FSH, LH, oestradiol, testosterone, androstenedione and 17-hydroxyprogesterone, which should be normal for pubertal stage; very rarely ovarian insufficiency (elevated FSH) or moderate hyperandrogenism occurs, pointing to the WNT4 subtype [20]. If a WNT4 defect is suspected, the panel includes total testosterone, free androgen index, dehydroepiandrosterone sulfate (DHEAS), androstenedione, LH, FSH and oestradiol [9]. AMH has no diagnostic utility but assesses ovarian function and, in children, may confirm ovaries not visualised on imaging [20]. As there is no menstrual cycle, hormone measurements are individual snapshots and cannot be timed relative to the cycle [2].

5.5. Investigation for associated malformations

Guidelines agree on renal and urinary tract ultrasound in all patients, but differ regarding skeletal, hearing and cardiac screening. Table 5.1 summarises their positions.

Table 5.1. Investigation for associated malformations according to guidance sources

Sources: [3, 13, 17, 20]. The Oxford Desk Reference recommends cervical spine radiography in all, and a German study found musculoskeletal malformations 3.27 times more frequent in patients' siblings than in the newborn population, recommending sibling examination [2, 72].

5.6. Genetic investigation

G-banded karyotyping confirms 46,XX and excludes androgen insensitivity (46,XY) and Turner mosaicism or translocations; the PNDS considers it useful particularly in forms with associated malformations, suspected androgen insensitivity (especially before puberty) and abnormal ovarian function [2, 3, 20]. CMA may be considered without being mandatory according to the 2020 review, and some French teams replace karyotyping with high-resolution CGH-array in forms with associated malformations [3, 20]. The Oxford Desk Reference suggests genomic array, exome or genome when there is strong suspicion of a monogenic basis, an associated malformation syndrome or strong family history [2]. A 17q12 deletion is detected by oligonucleotide or SNP CMA; targeted HNF1B deletion or duplication analysis detects gene loss but does not define the extent of the recurrent deletion, whose size may vary with array design because of segmental duplications at breakpoints [16]. Complete HNF1B deletion almost always corresponds to the recurrent 17q12 deletion, whereas an intragenic variant establishes HNF1B-related disease and excludes the deletion syndrome [16].

The yield of genetic studies is modest and estimates vary with population and definition of a positive result. For CNVs, published values are 14% in 63 UK and German patients (10.5% in isolated and 20% in syndromic cases), 16% in 50 Finnish patients studied by aCGH, around 19% in 31 North American patients, 21% in 19 Turkish patients, 7.7% in 78 French fetuses and women with Müllerian abnormalities and around 10% in the 2024 synthesis; the 2020 review summarises the overall imbalance rate as 16–20% [3, 13, 29, 45, 51, 59, 73]. In the Finnish cohort, CNVs or TBX6 and LHX1 variants were present in 30 of 112 patients (26.8%), including rare TBX6 variants in 15 and combinations of two alterations in 4 (3.6%), suggesting oligogenic aetiology [51]. In the French study, exome sequencing, performed in 65 patients, identified variants in 13.8% within an aggregated category: pathogenic or likely pathogenic variants fully explaining the phenotype, variants of uncertain significance of interest and variants unrelated to the Müllerian abnormality but linked to other signs [73]. These values refer to the proportion of CNVs or variants detected, not clinical test sensitivity, and many published alterations remain of uncertain significance; there is no validated estimate of panel or exome sensitivity in MRKH [13, 14].

Test limitations should be explained to patients. Karyotyping does not detect submicroscopic CNVs; CMA detects neither point variants nor balanced rearrangements, and resolution depends on platform; exome sequencing has limited coverage of intronic and regulatory regions and small CNVs; low-level mosaicism, such as that described in LHX1 at allele fractions of 1–6%, may escape conventional sequencing; and mosaicism potentially restricted to Müllerian tissue is undetectable in blood [38, 39, 46]. A negative result does not exclude a genetic cause. The 2021 PNDS considered molecular studies, then limited to research programmes, unlikely to change management; the 2025 French investigation proposed genetic analysis as an assessment component, particularly in uterine transplant candidates, to estimate transmission risk [20, 73]. A genetic report should give the gene, versioned transcript, HGVS description, zygosity, ACMG/AMP classification (American College of Medical Genetics and Genomics and Association for Molecular Pathology) and, for CNVs, genomic coordinates with reference genome version; with variants of uncertain significance, family segregation studies and reverse phenotyping (looking for subtle renal or uterine abnormalities) aid interpretation [3, 13].

WNT4 sequencing is justified only with an absent uterus and clinical or biochemical hyperandrogenism [9, 62]. In associated congenital scoliosis, the compound TBX6 genotype requires testing of the null allele, including 16p11.2 deletion by CMA, and the risk haplotype, because no imaging examination establishes it [48].

5.7. Practical algorithm

Table 5.2. Assessment algorithm for suspected Müllerian aplasia

5.8. Prenatal and preimplantation diagnosis

Uterine aplasia cannot be reliably detected by prenatal ultrasound, but female fetuses with bilateral renal agenesis or hyperechogenic kidneys may have uterovaginal aplasia in the context of GREB1L variants or 17q12 deletion [16, 57]. Prenatal diagnosis and preimplantation genetic testing (PGT) are possible only when a pathogenic variant or CNV is identified in the family; a prenatal 17q12 deletion result does not predict phenotype [3, 16]. These options are discussed in section 8.

6. Differential Diagnosis

6.1. Comparative table

Table 6.1. Differential diagnosis of Müllerian aplasia and primary amenorrhoea with a short vagina

Sources: [2, 3, 7, 16, 17, 20, 53, 55, 74–79].

6.2. Complete androgen insensitivity

Complete androgen insensitivity (CAIS, Morris syndrome) is the main MRKH differential diagnosis in an adolescent with primary amenorrhoea, a female phenotype and absent uterus. In a Georgian series (2023–2025), among 233 patients assessed for primary amenorrhoea, 26% had a female phenotype with absent uterus, of whom 57.4% had MRKH, 37.7% CAIS and 4.9% ovotesticular difference of sex development [80]. In CAIS, fetal testes produce AMH, causing regression of the tubes, uterus and upper vagina, and the vagina is short and blind-ending; breasts develop through peripheral testosterone aromatisation, but pubic and axillary hair is scant or absent [17, 74]. Testosterone lies in the male range and karyotype is 46,XY, with confirmation by AR sequencing [17, 20, 75]. In childhood, CAIS sometimes presents as an inguinal hernia containing a testis-like gonad: up to 1.1% of female infants with inguinal hernia have CAIS, whose overall incidence is around 1 in 20,000 females [17, 20]. Distinction has practical consequences because germ cell tumour risk in adolescence and young adulthood is around 2% in CAIS, prompting discussion of gonadectomy after puberty [17]. Contrary to the SGRT differential table, CAIS is accompanied by a short blind-ending vagina, so vaginal length does not distinguish the conditions; the Georgian series observed a shorter vagina in CAIS [7, 74, 80].

6.3. Obstructive malformations and false agenesis

Vaginal agenesis may be confused with an imperforate hymen or transverse vaginal septum, with iatrogenic consequences, for example attempted dilatation or incision with a normal uterus and haematocolpos [3, 17]. In obstructive malformations, cyclical pain increases and imaging shows a proximal vaginal canal and haematocolpos or haematometra [20]. “Müllerian agenesis” has been falsely diagnosed in 46,XX and 45,X women with ovarian insufficiency and oestrogen deficiency, where the uterus exists but has not developed; exogenous oestrogen induces uterine growth [3]. In Turner syndrome, FSH is elevated, stature is short and the uterus and vagina are present [17].

6.4. Malformation syndromes with Müllerian abnormalities

Several syndromes include Müllerian or vaginal abnormalities among their findings: 22q11.2 deletion (uterus didelphys, vaginal agenesis, absent uterus), TAR syndrome (absent uterus, cervix and upper vagina rarely described), Silver–Russell syndrome (MRKH described in women, with referral to a differences of sex development centre recommended), Bardet–Biedl syndrome (partial or complete vaginal atresia, septate vagina, double uterus, hydrometrocolpos), Fraser syndrome (bicornuate uterus, vaginal atresia, clitoromegaly, renal agenesis), Pallister–Hall syndrome (hydrometrocolpos or vaginal atresia), Robinow syndrome (vaginal atresia with haematocolpos), OEIS complex (unfused Müllerian structures, short, duplicated or atretic vagina) and urorectal septum malformation sequence [53, 55, 76, 77, 79, 81–85]. McKusick–Kaufman syndrome manifests as hydrometrocolpos, that is, obstruction with a uterus present, differing from MRKH [78]. In the differential diagnosis of renal abnormalities, MURCS association appears alongside RCAD/HNF1B; 5–10% of renal agenesis, hypoplasia or dysplasia cases have a PAX2, HNF1B, DSTYK, SALL1, SIX1 or EYA1 variant and around 10% a major genomic imbalance [86]. The vertebral differential diagnosis includes isolated Klippel–Feil, VACTERL association and TBX6-related spondylocostal dysostoses [49, 50].

6.5. Müllerian aplasia with hyperandrogenism

Absent uterus with acne, hirsutism and elevated androgens distinguishes the WNT4-related form from classical MRKH [8, 62]. The 17-hydroxyprogesterone measurement included in hormonal assessment also enables consideration of non-classical congenital adrenal hyperplasia, part of the amenorrhoea differential diagnosis in which the uterus is present [2, 20].

7. Treatments and Risk Management Strategies

7.1. General principles

MRKH treatment is non-pharmacological and organised around four axes: creating a functional vagina when the patient wishes; managing pain associated with uterine remnants and endometriosis; psychological and sexual support; and plans for parenthood, addressed in section 8 [3, 17, 20]. Both current guidelines agree on four principles. First, diagnosis should be disclosed only after confirmation, in a dedicated setting, with time and often over several consultations, and the patient referred early to a centre with a multidisciplinary team [17, 20]. Second, sufficient time should separate disclosure from any vaginal decision, which belongs exclusively to the adolescent or young adult; dilatation or surgery starts only when she is emotionally mature and wishes to proceed [17, 20]. Third, it should be explained that the vulva and clitoris are normal and allow genital sexuality and orgasm without treatment, that ovaries produce hormones and gametes, that absence of a uterus prevents pregnancy and that, whatever the technique, vaginal patency requires penetrative intercourse or regular dilatation; choosing no treatment is a legitimate option [3, 20]. Fourth, all patients should receive counselling, be encouraged to contact peer support groups and have parenthood options discussed [16, 17].

7.2. Vaginal dilatation

Primary vaginal dilatation is first-line in most patients because it is safer, patient-controlled and more cost-effective; ACOG has recommended it since 2002 [3, 17]. It involves progressive pressure with increasing-diameter dilators on the apex of the vaginal depression (Frank method), lengthening and widening the canal while maintaining its normal mucosal lining [3, 17, 20].

Table 7.1. Technique and follow-up of vaginal dilatation according to guidance sources

Sources: [3, 17, 20].

The 90–96% figure cited by ACOG rests, among other sources, on the series by Edmonds and colleagues: 245 consecutive women treated with dilators in a multidisciplinary programme, of whom 232 (94.9%) achieved a vaginal length above 6 cm and satisfactory sexual function, and all those who completed the programme succeeded; the published percentage does not correspond to 232/245 (94.7%), so the exact denominator is not made explicit [87]. No initial length predicts success, so even a flat depression justifies dilatation as first line [17]. Failure has mainly non-anatomical causes: low motivation, unstable relationships, conflict, parental misunderstanding, sociocultural factors and mental health; limited understanding, young age or learning difficulty; lack of privacy or difficulty travelling [17]. The PNDS adds normative pressure and, on the medical side, lack of conviction or training among professionals, and identifies as success factors an experienced multidisciplinary team, assessment of motivation, a therapeutic education programme with regular follow-up, sharing with other patients and the prospect of sexual activity [20]. A previous “failure” often reflects insufficient training [17]. Dilator sets are not reimbursed in France, and the PNDS calls for exceptional reimbursement [20].

The most common adverse effects are urinary symptoms, bleeding and pain. With bleeding, more lubricant, a wider or softer dilator and pelvic rest are recommended; with pain, a wider or softer dilator and lubricant, assessing dysfunctional voiding and vaginismus; with urinary symptoms, exclude abrasion, voiding dysfunction and urinary infection [17]. The 2020 review notes a low risk of urethral dilatation, alongside poor adherence, particularly in younger patients, time requirements and discomfort [3].

Coital dilatation (d'Alberton method), where regular intercourse replaces dilators, has good outcomes compared with self-dilatation and surgery but requires regular intercourse; the PNDS considers it equivalent to Frank's method and apparently better experienced [3, 20].

7.3. Surgical neovagina creation

Surgery is reserved for unsuccessful dilatation or patient preference after informed consent, should be performed at experienced centres and usually occurs in late adolescence or early adulthood; the first intervention has a greater likelihood of success than subsequent procedures, and initial surgical failure through scarring compromises sexuality [17, 20]. Surgery does not remove the need for dilatation: length and diameter are maintained only by postoperative dilatation or regular intercourse, and poor adherence causes stenosis and contracture, so no technique is recommended if the patient refuses dilatation [17, 20]. Complications are much more frequent than with dilatation: bladder or rectal perforation, graft necrosis, vaginal hair with skin grafts, fistulae, diversion colitis, inflammatory bowel disease and adenocarcinoma in intestinal neovaginas [17]. There is no consensus on which technique best preserves sexual function and satisfaction [17].

Table 7.2. Techniques for surgical neovagina creation

Sources: [3, 7, 17, 20, 88–92].

Technique selection has implications for future uterine transplantation. Methods dilating the vaginal depression (self-dilatation, coital dilatation, Vecchietti) retain normal mucosal lining, favouring normal vaginal microbiota, embryo transfer and cervical biopsy used to grade rejection [3]. In French protocols, a neovagina obtained by dilatation does not contraindicate transplantation, vulvar or peritoneal flap vaginoplasties are accepted and intestinal segment colpoplasties are contraindicated because no uterine transplant has succeeded in that context [20]. In the international registry, 83.5% (66/79) of MRKH recipients had an epithelium-lined neovagina, undilated, self-dilated or obtained by Vecchietti [21]. Postoperative care includes a mould or dilatation, with weekly then monthly consultations until the result is achieved [20].

7.4. Comparative evidence for dilatation and surgery

No randomised trials compare dilatation with surgery; evidence comes from cohorts, series and systematic reviews. Table 7.3 summarises the main studies.

Table 7.3. Studies of vaginal agenesis treatment and psychological intervention

Sources: [70, 87–91, 93–96].

In Cheikhelard's French study, cited by the PNDS as evidence of dilatation non-inferiority, 68% of the surgical group had sigmoid vaginoplasty; 42% of operated patients required postoperative dilatation and half of dilatation-treated patients required maintenance dilatation; quality of life (WHOQOL) did not differ from the general population except in psychosocial health and social relationships, and sexual distress occurred in 71% and dyspareunia in 53%, without differences between groups [20, 94]. Limitations of this evidence matter: comparisons involve non-randomised groups, with technique selection influenced by centre and patient; success definitions vary between vaginal length (≥6 or ≥7 cm), possible intercourse and reported sexual satisfaction; study success rates should not be compared directly; and many centres have experience with only one technique, introducing bias [3, 88]. Failed dilatation does not compromise subsequent vaginoplasty success [88]. First-line dilatation is still not widely accepted by all surgeons, and standardised functional outcome measures are lacking [3].

7.5. Guideline comparison

Table 7.4. Guideline recommendations and divergences

Sources: [11, 17, 20, 22].

The two clinical guidelines agree on the essentials but differ on three points. For screening for lower genital tract neoplasia, ACOG does not recommend routine cytology because the cervix is absent, although it acknowledges the possibility of vulvar and vaginal intraepithelial neoplasia, whereas the PNDS proposes HPV testing every five years because the virus persists in the vulva, vagina and anus [17, 20]. For screening for associated malformations, the PNDS is systematic and includes the spine and hearing, ACOG merely states that radiography may reveal abnormalities and the 2020 review considers these examinations non-routine [3, 17, 20]. For uterine transplantation, ACOG's 2018 position, which considered it experimental and of limited availability, predates the 2024–2026 data from the international registry and North American programmes (section 8), although the document was reaffirmed in 2026 [17, 21, 97]. There is no European scientific society guideline dedicated to the management of MRKH; the ESHRE/ESGE documents address classification and imaging diagnosis [11, 22].

7.6. Pelvic pain, uterine remnants and endometriosis

Cyclical pelvic pain in a patient with MRKH suggests active endometrium in a rudimentary horn, painful ovulation or endometriosis, and new pain warrants repeat imaging because fibroids and endometriosis are possible, particularly with uterine horns [17, 20]. Hormonal suppression may improve pain [17]. If cyclical pain accompanies active endometrium on MRI, laparoscopic excision of endometrium-containing remnants should be considered [3]. The 2025 meta-analysis recommends always describing the presence or absence of functional endometrium and biopsying suspicious lesions [69]. The sources consulted specify neither drugs nor doses for hormonal suppression in this population.

7.7. Psychological and sexual support

Psychological support is central to treatment rather than supplementary. The only available randomised trial showed that a seven-week group CBT intervention reduced psychological symptoms relative to a waiting list in 39 women [93]. Group programmes reduce distress and peer groups should be encouraged, with attention to cultural aspects [3, 17]. Parents may also benefit from counselling, and the PNDS ideally recommends separate psychologists for the young woman and parents; when diagnosed in childhood, the condition should be disclosed progressively by parents with medical support [17, 20]. Maternal guilt, frequently associated with imagined genetic transmission, should be addressed by explaining that the cause is unknown in most cases [20]. Sexuality should be addressed biopsychosocially rather than reduced to penetration; sexual complaints may be organic (stenosis, scar band), psychological (inhibition focused on absent uterus, anticipatory dyspareunia, vaginismus), educational or relational, and sexology consultation has a role in follow-up [3, 20].

7.8. General gynaecological care

Unnecessary routine questions such as the date of the last menstrual period should be avoided because they reduce trust in the team; ask instead about discharge, bleeding, pelvic pain and dyspareunia [17]. Pelvic examination is performed if complications or stenosis are suspected and, if symptomatic, speculum inspection looks for neoplasia, colitis or ulceration, with biopsy of any abnormal lesion; vaginal appearance after dilatation or surgery does not determine function [17]. The PNDS recommends a complete annual gynaecological examination, including breasts, vulva and vagina (diameter, length, mucosa, stenosis, prolapse, pain), and assessment for urinary symptoms [20]. Human papillomavirus (HPV) vaccination is recommended by both guidelines because it may reduce vulvar and vaginal neoplasia and condylomata [17, 20]. Sexually active women should know they risk sexually transmitted infections and use condoms, because use in this population is low owing to inability to become pregnant [17, 20]. In women with a sigmoid neovagina and a family history of inflammatory bowel disease, polyps or colorectal cancer, endoscopic surveillance may be justified, and bleeding should raise suspicion of a polyp or adenocarcinoma [20].

7.9. Particular features of forms with an identified genetic cause

In WNT4-related Müllerian aplasia with hyperandrogenism, vaginal and reproductive management is that of MRKH, and hyperandrogenism is assessed and treated in endocrinology; the PNDS recommends monitoring weight and metabolic profile [9, 20]. No trial, guideline or consensus is dedicated to this entity or to SERKAL syndrome, which has no treatment and is managed through prenatal diagnosis and counselling [9]. In patients with a 17q12 deletion or HNF1B variant, follow-up of renal disease takes place in nephrology or a reference centre and includes surveillance of diabetes, magnesium and neurodevelopment [16, 20]. In MURCS association, vertebral abnormalities and possible hearing loss guide orthopaedic and otorhinolaryngological follow-up, and in TBX6-associated congenital scoliosis the spine and respiratory function should be assessed [15, 48].

7.10. Drugs and regulatory status

No drug is approved for MRKH by either the Food and Drug Administration (FDA) or European Medicines Agency (EMA), and searches performed identified no regulatory applications; it is a malformation without targeted pharmacological therapy, which does not exclude unpublished processes [92]. Uterine transplant immunosuppression follows kidney transplant regimens and is described in section 8 without doses because consulted sources do not give them. The relevant regulatory status concerns devices, procedures and the legal framework for reproduction.

Table 7.5. Regulatory and access framework

Sources: [3, 17, 20, 92, 97–99].

7.11. Registered trials and studies

There are no drug trials. Registered studies concern tissue engineering, surgery, genetics, quality of life and uterine transplantation, and none had published registry results at consultation [92].

Table 7.6. Studies registered on ClinicalTrials.gov (accessed 10 October 2026)

Source: [92].

7.12. Developments in the last twelve months

Between October 2025 and October 2026, developments were as follows, with their respective evidence level. In uterine transplantation, publications included the second International Society of Uterus Transplantation (ISUTx) registry report, with 91 transplants and 44 live births up to 2024 (self-reported observational registry), ten-year outcomes from four North American programmes, with 60 transplants and 48 newborns (prospective multicentre cohort), a report of post-transplant lymphoproliferative disease after uterine transplantation (case report) and the first successful living-donor uterine transplant in Latin America, in Brazil (case report) [21, 97, 100, 101]. In surgery, the largest modified laparoscopic Davydov series (115 patients, retrospective series) and a non-randomised Brazilian comparison of dilatation and surgery, with similar final length at one year, were published [91, 96]. In genetics, publications included the gene burden study in 727 probands (PAX8, BMP7, GREB1L, PAN2, AGPAT2; research evidence), mosaic LHX1 deletions in 3 of 134 patients, a systematic review of 97 studies and a French CMA and exome study in Müllerian abnormalities [14, 40, 46, 73]. A 2026 international consensus involving ERN eUROGEN and the ARM-net network on timing of vaginal replacement in anorectal malformations with vaginal agenesis did not reach agreement on timing and recommended multidisciplinary counselling, structured follow-up and education [24]. An access study in England showed that only 17% of authorities fund IVF for women with MRKH [99]. A phase 1 tissue-engineered vaginal construct trial and a phase 4 postoperative Lactobacillus trial were registered [92]. No regulatory opinions or authorisations were identified; a negative search does not prove that no processes exist.

7.13. Perioperative context, pregnancy and transition

Before any abdominal or pelvic surgery, the surgeon should know the renal malformations and ovarian position, which may be ectopic, and ACOG's recommended written clinical summary serves this purpose [17, 68]. Pregnancy is possible only after uterine transplantation, with specific risks described in section 8; in recipients with a solitary kidney, calcineurin inhibitor nephrotoxicity is an additional concern [3, 102]. Transition from paediatric to adult services occurs between 15 and 20 years according to maturity, with time alone with the young woman, verification of associated abnormality screening and education on HPV, sexually transmitted infections and breast, ovarian, vaginal and vulvar surveillance; MRKH may also be managed directly in an adult service [20].

8. Reproductive Options and Family Counselling

8.1. Ovarian function and medically assisted reproduction

Ovaries in women with MRKH produce hormones and oocytes, making genetic motherhood possible through in vitro fertilisation (IVF) followed by surrogacy or uterine transplantation [2, 20]. Abnormal ovarian location in around 28% of patients may require transabdominal retrieval [68]. In an Israeli series of 102 cycles in 27 patients, women with atypical MRKH required more gonadotrophins (3600 ± 1297 IU over 13 ± 2.3 days versus 2975 ± 967 IU over 11.6 ± 1.6 days) and had fewer follicles, mature oocytes and embryos than women with the typical form, with a similar pregnancy rate per cycle [103]. In the Italian laparoscopic Davydov series, 27 of 115 patients underwent laparoscopic oocyte retrieval during the same intervention [91].

8.2. Surrogacy

Surrogacy, with IVF using oocytes from the woman with MRKH and her partner's sperm, has been used since the mid-1990s and succeeds in Müllerian agenesis [3, 17]. A systematic review of 14 studies (1988–2011) included 140 patients, mainly from the USA and Israel, with 369 cycles and 71 newborns in 125 patients, but reporting is suboptimal, publication bias exists and no national registry has MRKH-specific data [104]. The legal framework varies: surrogacy is commercial or altruistic according to jurisdiction (mainly commercial in California and exclusively altruistic in Canada), prohibited in Nordic countries and France, and commercially illegal in the United Kingdom, generating reproductive tourism [3, 20, 99]. In England in 2023, only 7 of 42 Integrated Care Boards funded IVF and embryo cryopreservation for women with absolute uterine factor infertility, and 30 funded no part of surrogacy [99].

8.3. Uterine transplantation

Uterine transplantation is the only treatment allowing a woman with MRKH to become pregnant. It is a “temporary” transplant: the graft is removed after the desired birth or births, usually within five years, limiting prolonged calcineurin inhibitor exposure, relevant because several patients have a solitary kidney [3, 20].

Historical development. After animal research began in 1999, the Gothenburg team obtained approval in 2012 for a study of up to 10 living-donor transplants and performed nine in 2013 (eight in MRKH); seven had surgical success and two grafts were removed in the first months because of vascular thrombosis and intrauterine infection [3]. The first birth occurred in September 2014: a 35-year-old woman with MRKH and unilateral renal agenesis, with a neovagina obtained by self-dilatation, received the uterus of a 61-year-old family friend who had delivered twice and was seven years postmenopausal; menstruation began 43 days later, single-embryo transfer occurred one year after transplantation under tacrolimus, azathioprine and corticosteroids, with three mild rejection episodes reversed by corticosteroids; she developed pre-eclampsia at 31+5 weeks and underwent caesarean section for abnormal cardiotocography, delivering a boy weighing 1775 g with Apgar scores of 9, 9 and 10 [3, 30]. Before this case, 11 attempts worldwide had produced no live births [30]. In Brazil, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo performed Latin America's first uterine transplant in 2016, from a deceased donor, resulting in December 2017 in the world's first birth after deceased-donor transplantation (indirect attribution from a 2026 Brazilian review) [105]. In 2026, Latin America's first successful living-donor transplant was published, in a 34-year-old Brazilian recipient with MRKH whose donor was her 31-year-old sister [101].

Technique and immunosuppression. The donor uterus is procured without ovaries or tubes and implanted orthotopically, with end-to-end vaginal anastomosis and anastomoses of graft uterine vessels to the recipient's external iliac arteries and veins, in an operation lasting around 5 hours for the recipient [3, 20]. Immunosuppression follows the kidney transplant model: induction with corticosteroids and antithymocyte globulin or basiliximab; maintenance with a calcineurin inhibitor (tacrolimus or ciclosporin), mycophenolic acid and low-dose corticosteroid; teratogenic mycophenolate is replaced by azathioprine at least eight weeks before embryo transfer [20]. In the international registry, tacrolimus was the calcineurin inhibitor in all 43 live-birth pregnancies under immunosuppression, and 67.4% of these recipients received tacrolimus, azathioprine and corticosteroids [21]. The sources consulted give no doses. The first pregnancy requires IVF because there are no tubes, with prior embryo or oocyte cryopreservation and transfer only with a rejection-free graft and stable immunosuppression [20].

Table 8.1. Uterine transplant outcomes

Sources: [21, 97, 106, 107].

In the international registry, live birth rate per embryo transfer fell from 35.8% (data up to 2020: 45 transplants and 19 live births) to 30.3%, and graft survival was higher with premenopausal donors [21]. Mothers were the most frequent living donors (64.2%), and 16 of 67 living donors underwent bilateral oophorectomy. Graft hysterectomy was performed in 65 of 91 recipients, 29 after births and 36 without a live birth, because of hypoperfusion, thrombosis, recurrent miscarriages or implantation failure, infection, rejection, patient request, post-transplant lymphoproliferative disease or irreversible endometrial injury [21]. Registry data are self-reported and unvalidated, at least four centres did not register their cases and ongoing pregnancy outcomes were unknown [21]. The 2020 review gave a take-home baby rate above 80% in recipients with a functional graft for more than six months, but these were unpublished author observations [3]. A 2026 narrative review estimated more than 130 transplants and more than 70 live births worldwide, with graft survival around 74%, vascular thrombosis as the main cause of loss and at least one live birth in around 43% of recipients [108].

Recipient risks include bleeding, graft loss mainly through anastomotic thrombosis, infection, rejection, vesicovaginal fistula, vaginal dehiscence or stenosis, and immunosuppression risks: infection, hyperglycaemia, nephrotoxicity, cytopenias and theoretical cancer risk [20]. A case of post-transplant lymphoproliferative disease has been published [100]. In a study of 22 recipients from the USA and Czech Republic (95.5% with MRKH), estimated glomerular filtration rate fell by a mean of 25.7 mL/min/1.73 m² under postpartum immunosuppression (95% CI 18.7–32.7), partially recovered after withdrawal and remained 10.2 mL/min/1.73 m² below baseline at a median three-year follow-up; recipients continued low-dose aspirin, without a dose given in the text [102]. Children born in the DUETS programme (14 children from 12 recipients; median gestational age 36+6 weeks, median weight 2940 g) had appropriate physical and neurological development through 24 months, without immune abnormalities and with mild transient cognitive deviations [109].

In French protocols, recipients should be healthy, have good ovarian reserve and no previous major surgery; previous cancer is generally a contraindication, and unilateral renal agenesis is no longer a contraindication in most studies. The donor may be the mother and, by exception, other relatives or people with a stable emotional bond for at least two years, or a premenopausal deceased donor with brain death [20]. Among MRKH recipients in the international registry, 88.8% had both kidneys normally positioned [21]. The ISUTx Ethics Committee published recommendations in 2025 on recipient and donor selection, living versus deceased donation, medically assisted reproduction, consent, clinical provision and research [110]. ACOG in 2018 and ASRM in the same year considered uterine transplantation experimental [17, 98].

8.4. Recurrence risk

There is no validated empirical recurrence risk estimate. Table 8.2 summarises data by scenario.

Table 8.2. Recurrence risk by scenario

Sources: [9, 13, 15, 16, 26, 31, 32, 48, 57, 72].

The mother→daughter transmission report is known only through indirect attribution in the 2024 review; the daughter was diagnosed at 14 years with primary amenorrhoea, and the 2q37 deletion was absent in maternal grandparents [13]. A study of incomplete Müllerian fusion abnormalities, excluding aplasia, found a symptomatic uterine abnormality in 1 of 37 sisters (2.7%) and none of 24 mothers, 45 maternal aunts and 50 paternal aunts, compatible with multifactorial aetiology; because it concerns another malformation, it should not be applied directly to MRKH [2, 111]. SGRT describes cases as sporadic with negligible recurrence risk, a more absolute formulation than other sources [7]. Both guidelines state that female offspring usually have a normal reproductive tract, although familial clusters exist [17, 20].

8.5. Cascade testing, prenatal and preimplantation diagnosis

When a CNV or pathogenic variant is identified, parents and, if positive, other at-risk relatives should be tested; reverse phenotyping with renal ultrasound and uterine assessment in women helps clarify variants and identify carriers with subtle expression [3, 13, 16]. The PNDS recommends at least renal ultrasound in parents and siblings of all patients [20]. With uterine transplantation and surrogacy, more women will have biological children and demand for prenatal diagnosis and PGT in pretransplant IVF is expected to increase; these options should be considered only with a robust genetic diagnosis and relevant recurrence risk, after genetic counselling and respecting reproductive autonomy [3, 13]. In 17q12 deletion, prenatal diagnosis and PGT are possible, but the result does not predict phenotype, and hyperechogenic fetal kidneys are strongly associated with the deletion [16]. In GREB1L families, fetal bilateral renal agenesis is the severe manifestation to consider in counselling [32, 57]. Genetic assessment of uterine transplant candidates has been proposed as part of pretransplant assessment to estimate transmission risk [73].

8.6. Counselling content

Counselling should explain that the cause is unknown in most cases and research programmes exist, helping alleviate parental guilt [20]. A genetic diagnosis reduces guilt and the “diagnostic odyssey”, guides investigation for gene-specific associated abnormalities and enables testing of at-risk relatives, but many published variants are of uncertain significance and require cautious interpretation [13]. The geneticist explains the genetic basis and reproductive implications when medically assisted reproduction uses the patient's own oocytes [2]. The sources consulted do not detail reproductive genetic counselling of minors; the PNDS recommends progressive parental disclosure of a childhood diagnosis with medical support [20].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The commonly cited frequency of 1 in 4500 to 5000 female newborns comes from few population studies, all European [3, 17, 112]. Table 9.1 distinguishes what each estimate measures.

Table 9.1. MRKH frequency estimates

Sources: [1–3, 5, 6, 17, 18, 20, 113].

Birth prevalence and point prevalence differ from diagnosis counts because diagnosis occurs in adolescence and some women are never investigated; in the Danish registry, median referral age was 17.5 years [3, 18]. Among primary amenorrhoea causes, MRKH represents around 16% (16.2% in one series) [2, 3]. Müllerian duct abnormalities collectively affect around 5% of infertile women and congenital female genital tract malformations 4–7% of the female population, figures not referring to MRKH [11, 29]. Müllerian aplasia with hyperandrogenism has unknown prevalence; in a series of 28 girls with primary amenorrhoea and a Müllerian abnormality, only one had a WNT4 variant, and MRKH frequency should not be extrapolated to this entity [8, 9, 63].

9.2. Population diversity

Population studies are only European, and whether frequency differs in other populations is unknown [3]. Type II proportion and renal malformation frequency vary between cohorts: in European cohorts, renal malformations occur in 20–45%, whereas 13% and 5% have been described in China, potentially reflecting interethnic variation or incomplete assessment; conversely, Deng's Chinese cohort recorded skeletal abnormalities in 41% and scoliosis in 34% [3]. In Turkey, 74% of 19 patients were daughters of related parents, prompting a proposed autosomal recessive component in consanguineous populations [59]. In Finland, a founder population, the 112-patient cohort contributed to defining the role of TBX6, LHX1 and CNVs, and no SHOX duplications were found in 101 patients [13, 51]. In the international pelvic floor symptom survey, 81% of respondents were white, limiting generalisation [19].

In genetic cohorts, rare TBX6 variant burden was demonstrated in the Chinese cohort and the 2026 gene burden study was based exclusively on Chinese probands; the GREB1L cohort included patients from North America, Europe and South America, with replication in Han Chinese patients [34, 40, 52].

9.3. Brazilian and Portuguese data

In Brazil, a São Paulo university outpatient clinic recorded 67 patients with MRKH among 151 with genital malformations (44.4%) between 2010 and 2020 and compared dilatation with surgery in 49 treated patients [96]. Another prospective São Paulo study compared Frank dilatation with modified McIndoe in 20 women [95]. Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo performed Latin America's first uterine transplant in 2016 and, in 2026, the region's first successful living-donor transplant was published, in an MRKH recipient [101, 105]. The Brazilian SGRT manual presents no original epidemiological data [7]. No Portuguese data were found in the sources consulted, which does not demonstrate their absence.

9.4. Special populations

Third-generation women exposed to diethylstilbestrol were the subject of a French report of elevated MRKH incidence, whose numerical content was not consulted [36]. Discordant monozygotic twins are a group of interest for mosaicism and epigenetic research [38, 39]. Uterine transplant recipients with a solitary kidney, frequent in MRKH, warrant particular renal surveillance [3, 102].

9.5. Reference networks and patient associations

The French PNDS identifies Endo-ERN (European Reference Network on Rare Endocrine Conditions) as the European MRKH reference network, through thematic group 7 dedicated to differences of sex development and maturation; the network comprises more than 100 centres in 27 Member States and Norway [20, 23]. ERN eUROGEN, dedicated to rare and complex urogenital diseases, includes complex genital reconstruction and co-signed the 2026 consensus on vaginal replacement in anorectal malformations; explicit inclusion of MRKH within its scope was not confirmed on an official page [24]. In France, the FIRENDO network organises the coordinating referral centre at Hôpital Necker, with constituent centres in Toulouse and Pitié-Salpêtrière and around 20 competence centres [20]. Patient associations include Beautiful You MRKH Foundation (USA; https://www.beautifulyoumrkh.org/), Association Syndrome de Rokitansky-MRKH (France; https://asso-mrkh.org/), Association MAIA dedicated to parenthood (France; https://maia-asso.org/) and a Dutch association with around 300 members [20, 37]. The Oxford Desk Reference also mentions, using 2017 data, a UK support group for Müllerian aplasia and Infertility Network UK [2].

10. Illustrative Clinical Case

10.1. 17q12 deletion with type II MRKH and MODY5 diabetes

Lee and colleagues described in 2024, at a South Korean university hospital, a 14-year-old girl referred for polydipsia and polyuria of around one year's duration [44]. She had been born at 30 weeks, weighing 1.5 kg, after premature rupture of membranes and had global developmental delay; her mother and maternal grandfather had diabetes treated with oral antidiabetic drugs. On examination she measured 141.6 cm (z score −3.3) and weighed 39.1 kg (body mass index 19.5 kg/m²), had low-set ears, hypertelorism and a prominent forehead, and was Tanner stage B4 PH5 A5 without menarche. Glucose was 464 mg/dL and glycated haemoglobin 19.9%, without ketoacidosis; fasting insulin was 3.2 µIU/mL, C-peptide 1.4 ng/mL and autoantibodies negative.

Computed tomography showed dorsal pancreatic agenesis, uterine agenesis, right renal malrotation, chronic left portal vein thrombosis with left hepatic lobe hypotrophy and scoliosis. Karyotype was 46,XX, excluding Turner syndrome. SNP microarray identified a heterozygous 1.5 Mb deletion, arr[hg19] 17q12(34,822,465–36,283,612)x1, including HNF1B, LHX1, ZNHIT3, PIGW, AATF, TADA2A, DUSP14, DDX52, ACACA, SYNRG and GGNBP2, confirming 17q12 deletion syndrome. Gynaecological examination showed a microperforate hymen and an underdeveloped clitoris, and pelvic MRI confirmed absent uterus and upper vagina, with bilateral uterine buds, triangular tissue corresponding to Müllerian remnants and follicle-containing ovaries; LH was 3.5 mIU/mL, FSH 4.2 mIU/mL and oestradiol 39 pg/mL. Diagnosis was type II MRKH in the context of 17q12 deletion [44]. Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC11049139/figure/children-11-00404-f001/) shows (a) dorsal pancreatic agenesis on CT and (b) absent uterus and upper vagina on sagittal MRI.

The patient started multiple daily insulin injections (0.84 IU/kg/day) with continuous glucose monitoring. Complication assessment revealed non-proliferative diabetic retinopathy in the right eye, peripheral polyneuropathy, albumin/creatinine ratio 142.9 mg/g and magnesium 1.32 mg/dL, suggesting renal loss; scoliosis (Cobb angles 20.93° at T12 and 21.32° at L3) was treated with Schroth exercises; brain MRI showed severe diffuse atrophy with enlarged lateral ventricles, intelligence quotient was 85 and thrombophilias were excluded. At 14 years and 8 months, glycated haemoglobin was 6.7%. Vaginal treatment, by dilatation or surgery, was deferred until adulthood, and follow-up was undertaken by an endocrinology, rehabilitation, neurology, gynaecology, ophthalmology and hepatology team [44].

10.2. Lessons from the case

The case illustrates three points of general relevance. First, primary amenorrhoea in an adolescent with non-autoimmune diabetes, a renal abnormality and neurodevelopmental alterations should suggest a 17q12 deletion, and the detection of MRKH in a patient with a 17q12 deletion warrants renal, metabolic and hepatic assessment [16, 44]. Second, the diagnosis of Müllerian aplasia rested on MRI, which identified the remnants, and on confirmation of normal ovarian function, as the guidelines recommend [17, 20]. Third, deferring vaginal treatment until adulthood is consistent with the principle, shared by ACOG and the PNDS, of starting dilatation or surgery only when the patient is mature and wishes it [17, 20]. The metabolic management in this report is that of an individual case and does not replace the specific guidance for MODY5 diabetes.

10.3. Historical and reference images

Figure 1 of Herlin and colleagues' review (https://pmc.ncbi.nlm.nih.gov/articles/PMC7439721/figure/Fig1/) brings together (A) Rokitansky's original illustration (1838), with a short blind-ending vagina and two rudimentary uterine remnants; (B) a sagittal T2-weighted MRI with complete uterovaginal absence in a patient with type II MRKH, renal agenesis and a solitary pelvic kidney; and (C) a patient's pelvis during uterine transplant preparation, with forceps holding the midline fibrous uterine rudiment, subserosal leiomyomas in lateral uterine buds and medially positioned ovaries [3]. Figure 1 in Smith's Recognizable Patterns (p. 927) illustrates MURCS association with a short neck and cervical vertebral fusion [15].

11. Prognosis and Long-Term Follow-Up

11.1. Overall prognosis

Type I MRKH does not impair ovarian function, pubertal development or, according to the sources consulted, life expectancy; these sources provide no specific mortality data [3, 20]. In type II and in MURCS association, prognosis depends on the extent and severity of renal abnormalities and of multisystem involvement, and short adult stature, below 152 cm, is frequent in MURCS association [7, 15]. In forms with an identified genetic cause, prognosis is that of the underlying disease: in the 17q12 deletion, renal disease, MODY5-type diabetes and neurodevelopmental alterations determine morbidity, as illustrated by the case in section 10 [16, 44]; in WNT4-related Müllerian aplasia with hyperandrogenism, the hyperandrogenism and the metabolic profile warrant specific surveillance [9, 20].

11.2. Long-term functional and sexual outcomes

Primary dilatation succeeds in more than 90–96% of patients according to ACOG, and the PNDS reports good anatomical and functional outcomes in more than 85%, generally in under six months with good adherence [17, 20]. In Cheikhelard and colleagues' French multicentre study, assessing 131 women over 18 years at least one year after treatment, median vaginal depth was 9.6 cm after dilatation, 11 cm after surgery and 11 cm after coital dilatation, all within the normal range, and only four women had less than 6.5 cm; overall Female Sexual Function Index (FSFI) scores were similar between groups, differing only in the satisfaction domain, sexual distress measured by FSDS-R (Female Sexual Distress Scale–Revised) affected 71% and dyspareunia 53% [94]. In this study, surgery had complications in 40.5% of patients, with 20 reinterventions in 17 women, 42% of operated patients required postoperative dilatation and half treated by dilatation required maintenance dilatation [94]. Quality of life assessed by WHOQOL (World Health Organization Quality of Life) did not differ from the general population except in psychosocial health and social relationships [94]. A ten-study meta-analysis showed that total FSFI after vaginoplasty is lower than in healthy women, with a standardised mean difference of −0.233 (95% confidence interval −0.376 to −0.090), mainly through lubrication and satisfaction [70]. Comparing laparoscopic Davydov and Vecchietti, length at 12 months was 8.3 cm and 8.7 cm and FSFI 28.9 and 27.5, without sexual dysfunction on average in either group [90]. These data come from heterogeneous observational series without randomisation and cannot predict individual outcomes; the best success criterion is a functional vagina allowing comfortable sexual activity, reported by the patient herself [17].

11.3. Late complications

Neovaginal stenosis and contracture occur particularly when postoperative dilatation is not maintained, and women who stopped dilatation may need to resume before restarting sexual activity [17]. Late-onset pelvic pain should prompt repeat imaging because uterine remnants with functional endometrium may produce leiomyomas, haematometra and endometriosis; in a meta-analysis of 666 patients, endometriosis occurred in 32.0% of those with functional endometrium in remnants and 1.5% of the remainder [20, 69]. Intestinal neovaginas carry risks of diversion colitis, inflammatory bowel disease and adenocarcinoma, and bleeding should raise suspicion of a polyp or neoplasia [17, 20]. Vulvar and vaginal intraepithelial neoplasia is possible despite absent cervix, and sexually transmitted infection risk persists [17, 20]. Psychologically, anxiety, depression, eating disorders and grief over infertility may decompensate at any life stage, so psychological surveillance does not end with vaginal treatment [3, 17, 20].

11.4. Prognosis after uterine transplantation

In the second ISUTx registry report, graft survival at 12 months was 74.7%, and 36 of 76 recipients transplanted before July 2023 (47.4%) had at least one live birth; 61.4% of pregnancies had complications, particularly pre-eclampsia (22.7%), all deliveries were by caesarean section and 75.0% of newborns were preterm, without major malformations [21]. In a cohort of 22 recipients, estimated glomerular filtration rate remained, after immunosuppression withdrawal, a mean of 14.1 mL/min/1.73 m² below baseline, with a persistent reduction of 10.2 mL/min/1.73 m² at a median three-year follow-up, particularly relevant in patients with a solitary kidney [102]. In DUETS, the 13 children followed had appropriate physical and neurological milestones through 24 months, with mild transient cognitive deviations [109]. Graft hysterectomy after desired births limits immunosuppression duration [3].

11.5. Surveillance table

Guidelines set no MRKH-specific surveillance schedule beyond gynaecological follow-up; the table brings together recommendations from consulted sources, with each stated interval.

11.6. Organisation of follow-up

Follow-up preferably occurs at a referral centre with a multidisciplinary team of paediatric and adolescent gynaecology, psychology, radiology, genetics and, according to associated abnormalities, nephrology, orthopaedics and otorhinolaryngology; transition to adult services occurs between 15 and 20 years [20]. ACOG recommends providing patients with a written clinical summary of associated malformations, useful when receiving emergency care or undergoing surgery by a professional unfamiliar with the condition [17].

12. Summary and Final Considerations

Mayer–Rokitansky–Küster–Hauser syndrome is congenital aplasia of the uterus and upper two-thirds of the vagina in a 46,XX woman with functional ovaries and normal secondary sexual characteristics, and the second cause of primary amenorrhoea after ovarian insufficiency [1, 3]. It is divided into type I, isolated, and type II, with extragenital malformations, mainly renal, vertebral, auditory and cardiac, of which MURCS association is the most extensive form; WNT4-related Müllerian aplasia with hyperandrogenism is a distinct entity, and SERKAL syndrome its recessive allelic disease [3, 9, 25].

Aetiology is heterogeneous and unknown in most patients. Recurrent copy-number variations such as 17q12 deletion, 22q11.2 deletion and 16p11.2 rearrangements, and variants in genes such as LHX1, HNF1B, TBX6, GREB1L, PAX8 and WNT4 explain a minority of cases, and inheritance, when identified, is generally autosomal dominant with incomplete penetrance and variable expressivity [3, 13, 14, 40, 112]. Genetic investigation by chromosomal microarray and, in research or syndromic phenotypes, exome sequencing should be interpreted with its limitations, and a negative result does not exclude a genetic cause [13, 73].

Diagnosis rests on clinical examination, ultrasound and MRI without diagnostic laparoscopy, and hormonal confirmation and, if uncertain, a 46,XX karyotype to exclude complete androgen insensitivity; renal malformation screening is universal, whereas skeletal and hearing screening is systematic in the French PNDS and symptom-directed in other sources [3, 17, 20]. Vaginal dilatation is first-line treatment, succeeding in the vast majority of patients, and surgery is reserved for failure or informed preference at experienced centres; decision and timing belong to the patient [17, 20]. Psychological support and peer groups are part of treatment from diagnosis [3, 17].

Reproductively, normal ovarian function allows genetic reproduction through surrogacy where legally permitted, and uterine transplantation has progressed from an experimental procedure to an option with registry outcomes, still associated with surgical, immunological, obstetric and renal risks [21, 97, 102]. Offspring recurrence risk is low in forms without an identified cause but lacks a validated estimate, and is higher in families with a known pathogenic variant [13, 26]. Long-term follow-up includes gynaecological examination, HPV vaccination and screening, intestinal neovagina surveillance, attention to pelvic pain and psychological and sexual health, and syndrome-specific surveillance, linked with the European Endo-ERN network identified by the PNDS and patient associations [20, 23].

13. References

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