Mayer-Rokitansky-Kuster-Hauser_Syndrome

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Classifications

Harrison's Part

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Inheritance

2

Sporadic HP:0003745

Most cases occur with no family history of MRKH syndrome or of the associated renal and uterovaginal anomalies, and monozygotic twin pairs discordant for the syndrome have been reported repeatedly. Sporadic occurrence is therefore the rule rather than the exception. It is important not to read this as evidence against a genetic cause: absolute uterine factor infertility blocks mother-to-daughter transmission, so a dominant allele cannot accumulate in pedigrees the way it would in a fertile disorder, and the familial signal is structurally suppressed.

Sporadic occurrence

Show evidence (2 references)

PMID:38699388 SUPPORT Human Clinical

"several reports of discordant monozygotic twin pairs"

Monozygotic discordance is the observation that most directly supports non-inherited causation in at least some patients.

PMID:38699388 SUPPORT Human Clinical

"the disease nature of MRKH syndrome implies absolute infertility, hindering mother-to-offspring inheritance of a genetic cause, which may cause an underestimation of the genetic component of MRKH syndrome from family histories"

Supports the caveat that apparent sporadicity is partly an artefact of the disease blocking its own vertical transmission.

Autosomal dominant with incomplete penetrance HP:0000006

In the minority of families with recurrence, the pattern is autosomal dominant with incomplete penetrance and sex-limited expressivity: male carriers may show isolated renal agenesis, or nothing, while female carriers may show uterovaginal aplasia, an isolated renal anomaly, or no phenotype at all. This is the pattern the older literature called hereditary urogenital adysplasia, and GREB1L is the gene that has since been shown to segregate in it. Sex-limited expressivity has also been demonstrated directly for PAX8, where paternal transmission was confirmed in three cases.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (2 references)

PMID:38699388 SUPPORT Human Clinical

"Whole-exome sequencing analysis in this family identified a segregating missense variant in GREB1L, supporting GREB1L variants as a novel monogenic cause of MRKH syndrome associated with incomplete penetrance and sex-limited expressivity"

Three-generation pedigree evidence for the dominant, incompletely penetrant, sex-limited pattern this block records.

PMID:38699388 SUPPORT Human Clinical

"In three cases with available parental DNA, paternal inheritance was confirmed, showing a sex-limited expressivity of infertility."

Independent demonstration of sex-limited expressivity, at a second locus.

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Subtypes

2

Type 1 (isolated uterovaginal aplasia) MONDO:0010173

Uterovaginal aplasia with no extragenital malformation. This is the form the four original describing authors reported, and the more common of the two. Rudimentary uterine buds on the pelvic sidewalls, joined by a midline fibrous band, are the typical anatomy.

Show evidence (1 reference)

PMID:38699388 SUPPORT Human Clinical

"MRKH syndrome may present as an isolated anomaly (type I) or in association with extragenital malformations (type II), typically involving the kidneys, skeleton, and heart"

States the two-way clinical classification that these subtypes encode.

Type 2 (with extragenital malformations; MURCS association) MONDO:0010989

GREB1L hgnc:31042 HNF1B hgnc:11630

Uterovaginal aplasia together with at least one extragenital malformation — most often renal, next most often axial skeletal, and less commonly cardiac or auditory. The MURCS acronym (Müllerian duct aplasia, renal aplasia, cervicothoracic somite dysplasia) names the severe end of this subtype and is subsumed within it rather than being curated separately. Complete absence of one Müllerian duct with ipsilateral renal agenesis is the characteristic anatomy, which is the anatomical signature of a shared lineage failure rather than of two independent malformations.

Show evidence (1 reference)

PMID:27609979 SUPPORT Human Clinical

"Typical MRKH syndrome and atypical MRKH syndrome/Müllerian duct aplasia, Renal aplasia, and Cervicothoracic Somite dysplasia association were present in 56.5% and 43.5% of the patients, respectively."

Nationwide registry-validated cohort quantifying the type 1 / type 2 split and naming MURCS as part of the type 2 group.

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Mechanistic Hypotheses

4

Failure of paramesonephric duct formation, elongation or fusion between weeks 5 and 8

md_developmental_arrest CANONICAL

Evidence balance 2 support

The accepted account, and the only one that is not in dispute. The paramesonephric ducts form at about the fifth week as bilateral invaginations of the coelomic epithelium of the urogenital ridge, elongate caudally along the Wolffian ducts to reach the urogenital sinus, and from week 8 fuse caudally to build the uterus, cervix and upper vagina. MRKH syndrome is the failure of that sequence — either the ducts never form, or they form and do not complete elongation and fusion. Everything downstream is anatomical absence rather than tissue damage, which is why the syndrome has no progressive course and no active lesion to treat.

Show evidence (2 references)

PMID:38699388 SUPPORT Human Clinical

"At 5 weeks post gestation, bilateral invaginations of the coelomic epithelium of the urogenital ridges begin to form the MDs which extend caudally, guided by the Wolffian ducts, to reach the urogenital sinus in the midline"

Establishes the normal developmental sequence and its timing, which is the process this hypothesis says fails.

PMID:29266078 SUPPORT Human Clinical

"Müllerian agenesis is caused by embryologic underdevelopment of the müllerian duct, with resultant agenesis or atresia of the vagina, uterus, or both."

Professional-society statement of the same causal claim.

Heterogeneous monogenic loss of a shared intermediate/paraxial mesoderm transcriptional program

mesodermal_transcriptional_program EMERGING

Evidence balance 3 support

The genetic account with the strongest current support. Rather than one MRKH gene, a set of transcriptional regulators of intermediate and paraxial mesoderm — GREB1L, PAX8, HNF1B, LHX1, TBX6 — each account for a small share of patients, with the same haploinsufficiency-like dosage logic and the same dominant, incompletely penetrant, sex-limited pattern. The hypothesis predicts the observed comorbidity structure directly: these are kidney development genes, so type II with renal malformation is what a lesion in them looks like, and TBX6 in paraxial mesoderm is the axial-skeletal arm. It is curated EMERGING rather than CANONICAL because recurrent copy-number variants explain only about 10% of patients and the sequence-variant genes together explain a further minority, so the program is demonstrated but nowhere near complete.

Pathograph links

Loss of Mesodermal Developmental Transcription Factor Dosage -> Failure of Müllerian Duct Epithelial Proliferation and Elongation DIRECT Reduced regulator dosage in the urogenital ridge epithelium is what the mouse models translate into a duct that does not elongate.

Loss of Mesodermal Developmental Transcription Factor Dosage -> Shared Intermediate Mesoderm Lineage Failure DIRECT The same regulators drive nephric duct and kidney development, so a single lesion reaches both organ systems.

Loss of Mesodermal Developmental Transcription Factor Dosage -> Paraxial Mesoderm and Somite Patterning Failure INDIRECT UNKNOWN INTERMEDIATES TBX6 acts in paraxial mesoderm rather than in the duct, which is the lineage route to the axial skeletal anomalies of MURCS. Drawn as indirect because no mechanism has been established for monoallelic TBX6 variants in this disease.

Show evidence (3 references)

PMID:38699388 SUPPORT Human Clinical

"Therefore, genes involved in the development of mesoderm and its derived structures are relevant candidates in the etiology of MRKH syndrome."

States the lineage-based reasoning on which this hypothesis rests.

PMID:38699388 SUPPORT Human Clinical

"epidemiological evidence of rare variant enrichment in larger cohorts, and functional evidence from knock-out mice, suggest GREB1L as a major causative gene in MRKH syndrome."

The single best-supported gene in the program, with pedigree, cohort and mouse evidence converging.

PMID:38699388 SUPPORT INDIRECT Human Clinical

"However, recurrent chromosomal imbalances in MRKH syndrome still only apply to a minor fraction of patients (around 10%)."

Bounds how much of the disease this program currently explains, which is why the hypothesis is EMERGING rather than CANONICAL. Cited as indirect because it quantifies the CNV share specifically, not the whole program.

Somatic, mosaic, epigenetic or environmental disruption of duct development

nonmendelian_somatic_or_environmental ALTERNATIVE

Evidence balance 1 support 1 refute

A germline-monogenic account cannot cover the disease as observed: occurrence is overwhelmingly sporadic, monozygotic twins are repeatedly discordant, and recurrence after surrogate pregnancy has generally not been seen. Those observations are what a post-zygotic somatic or mosaic variant, a tissue-restricted epigenetic change, or an environmental insult during the fifth-to-eighth week would predict. Investigators have accordingly looked for somatic variation and differential methylation in surgically removed uterine remnants. The hypothesis is curated ALTERNATIVE rather than EMERGING because it is so far supported by the pattern of inheritance failing to fit, not by a positive finding: reported epigenetic results have been inconsistent, and no environmental exposure has firm evidence.

Show evidence (2 references)

PMID:38699388 SUPPORT INDIRECT Human Clinical

"Most cases of MRKH syndrome appear isolated with no clear indications of a familial/genetic trait (5, 30). In addition, several reports of discordant monozygotic twin pairs (5, 31–35) and patient-reported outcomes of most surrogate pregnancies also support non-Mendelian causes"

The inheritance-pattern argument for this hypothesis. Indirect because it argues from the absence of a Mendelian signal rather than from a demonstrated somatic or environmental lesion.

PMID:41616459 REFUTE Human Clinical

"Findings on epigenetic regulation show variability, with no consistent patterns of specific gene upregulation or downregulation."

A 97-study systematic review finds no reproducible epigenetic signature, which counts against the epigenetic arm of this hypothesis specifically and is the reason it is not curated as EMERGING.

Ectopic anti-Müllerian hormone or AMHR2 activity drives Müllerian regression in a 46,XX fetus

amh_overexpression ⚠ DEPRECATED

⚠ Overturned model — shown for reference, not as current mechanism

DisMech records superseded hypotheses explicitly rather than deleting them, so that claims still circulating in reviews, textbooks and older diagnostic criteria can be checked against an assessment. This model is not part of the disease mechanism DisMech asserts.

Citation volume does not decide standing here. A hypothesis may retain more supporting than refuting citations simply because the supporting literature accumulated for decades before the refutation landed; where the two conflict, DisMech follows the more recent and more direct evidence. Supporting citations below are retained for the historical record.

Evidence balance 1 refute

The first serious etiological hypothesis, and the one question in MRKH syndrome that the field has actually closed. Because anti-Müllerian hormone physiologically regresses the Müllerian ducts in male embryos, ectopic AMH activity or an activating receptor change was an obvious candidate for Müllerian absence in a 46,XX fetus. Candidate-gene studies of AMH and AMHR2 did not support it, and it is retained here as DEPRECATED — with the negative evidence attached — rather than deleted, because it is what distinguishes MRKH syndrome mechanistically from the 46,XY differential diagnoses in which absent Müllerian structures really are AMH-driven.

Show evidence (1 reference)

PMID:38699388 REFUTE Human Clinical

"Most of these studies had negative results and provided limited evidence for genetic factors in MRKH syndrome. This included investigations of AMH and AMHR2, encoding anti-Müllerian hormone and its receptor, respectively, involved in physiological MD regression in males"

Names AMH and AMHR2 among the candidate genes whose investigation returned negative results, which is the basis for deprecating this hypothesis.

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Discussions and Knowledge Gaps

3

What causes MRKH syndrome in the large majority of patients who have no recurrent copy-number variant and no variant in a known candidate gene?

KNOWLEDGE GAP OPEN mrkh_unexplained_etiology

Attached to

pathophysiology#Loss of Mesodermal Developmental Transcription Factor Dosage mechanistic_hypotheses#mesodermal_transcriptional_program

Recurrent chromosomal imbalances account for around 10% of patients, and the sequence-variant genes with real evidence — GREB1L, PAX8, HNF1B — add a further minority. The initiating node of this entry is therefore unpopulated for most patients, which is unusual for a curated dismech entry: the canonical hypothesis about what fails developmentally is secure, while the hypothesis about why it fails covers a small fraction of cases. The gap is not simply "more sequencing needed": sporadic occurrence and repeated monozygotic discordance mean a germline monogenic explanation cannot cover the whole disease however deeply cohorts are sequenced, so the somatic, mosaic, epigenetic and environmental alternatives have to be tested on their own terms. Reported epigenetic findings are so far inconsistent.

Proposed experiments

Somatic variant and methylation profiling of uterine remnant tissue in discordant monozygotic twins

exp_mrkh_discordant_twin_somatic_variation

Deep sequencing and methylation profiling of surgically removed uterine remnant tissue from monozygotic twins discordant for MRKH syndrome, against matched blood from both twins, to test whether a post-zygotic somatic or epigenetic lesion restricted to the affected twin's urogenital tissue explains the discordance. Interpretation is limited by a caveat the field has already identified: gene expression in adult remnant tissue may not represent embryonic expression, so a negative result would not exclude a developmental epigenetic mechanism.

Would support

mechanistic_hypotheses#nonmendelian_somatic_or_environmental

Would refute

mechanistic_hypotheses#mesodermal_transcriptional_program

Supporting outcome

A somatic variant or differentially methylated region present in the affected twin's remnant tissue and absent from both twins' blood and from the unaffected twin.

Refuting outcome

No tissue-restricted somatic or epigenetic difference, with a shared germline variant in a mesodermal developmental regulator found instead in both twins.

Show evidence (1 reference)

PMID:38699388 SUPPORT Human Clinical

"However, recurrent chromosomal imbalances in MRKH syndrome still only apply to a minor fraction of patients (around 10%)."

Quantifies the size of the gap this discussion records.

Does the compound-inheritance gene dosage model established for TBX6 in congenital scoliosis apply to MRKH syndrome, given that no second hypomorphic allele has been found in MRKH patients?

HUMAN MODEL MISMATCH OPEN mrkh_tbx6_monoallelic_mechanism

Attached to

pathophysiology#Paraxial Mesoderm and Somite Patterning Failure genetic#TBX6

This is a model-fidelity problem rather than an absence of evidence, which is why it is recorded as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP. Evidence for TBX6 exists on both sides: rare variants are enriched in a large MRKH cohort and several are loss-of-function in assays, and the 16p11.2 deletion is recurrent. The mechanism borrowed to explain it comes from congenital scoliosis at the same locus, where disease requires a null allele plus a particular hypomorphic allele in trans. That second allele has not been found in MRKH syndrome. So either the Müllerian phenotype has a lower dosage threshold than the axial-skeletal one, or a different modifier is involved, or the monoallelic variants are not causal at all — and the review states plainly that no clear biological mechanism has been established. This entry therefore draws the TBX6 route to the skeletal node as indirect and records the gene as SUSCEPTIBILITY rather than CAUSATIVE.

Show evidence (1 reference)

PMID:38699388 SUPPORT Human Clinical

"As of now, no clear biological mechanism for monoallelic TBX6 variants causing MRKH syndrome has been established, which challenges interpretation and warrants further studies."

States the mismatch this discussion records.

What accounts for endometriosis in the MRKH patients who have no functional endometrium and no uterine remnant at all?

OPEN QUESTION OPEN mrkh_endometriosis_without_functional_endometrium

Attached to

pathophysiology#Retained Cycling Endometrium in Uterine Remnants phenotypes#Endometriosis

The meta-analysis that ties endometriosis in this syndrome to functional endometrium in a remnant is strong — 32.0% versus 1.5%, odds ratio 12.0 — and it substantially rehabilitates retrograde menstruation as the mechanism in a population long cited as the counter-example to it. But it does not go to zero. Seven of 71 patients with endometriosis had no demonstrable functional endometrium and no remnant. Those cases cannot be explained by retrograde menstruation from a remnant, and they are the residue that keeps coelomic metaplasia or embryonic-remnant origins in play. The question is worth keeping open rather than treating the meta-analysis as settling the theory, because this population is one of the few in which the two competing origins can be separated by ascertaining a single anatomical variable.

Show evidence (1 reference)

PMID:40246293 SUPPORT Human Clinical

"Among the 71 MRKHS patients with endometriosis, 64 had coexisting FE, and only seven had no evidence of FE within UR or did not have UR."

The residual cases that motivate this question.

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Pathophysiology

10

Loss of Mesodermal Developmental Transcription Factor Dosage

In the genetically explained minority of patients, the initiating lesion is reduced dosage or activity of a transcriptional regulator of intermediate and paraxial mesoderm. The recurrently deleted 17q12 interval removes both LHX1 and HNF1B; 16p11.2 removes TBX6; sequence variants have been reported in GREB1L, PAX8, HNF1B, LHX1 and TBX6. These are not a pathway in the signalling sense but a set of regulators acting on the same embryonic lineage, which is why loss of any one of them can reach the same anatomical endpoint. GREB1L is thought to act in retinoic acid signalling, though its protein is poorly characterised, and for the monoallelic missense variants that dominate the human reports the molecular consequence is still unknown.

Heterogeneous monogenic loss of a shared intermediate/paraxial mesoderm transcriptional program

GREB1L hgnc:31042 PAX8 hgnc:8622 HNF1B hgnc:11630 LHX1 hgnc:6593 TBX6 hgnc:11605

transcriptional control of urogenital and somitic development GO:0006355 ↓ DECREASED retinoic acid signalling (GREB1L) GO:0048384 ↓ DECREASED

developmental transcription factor activity GO:0003700 ↓ DECREASED

Downstream

Failure of Müllerian Duct Epithelial Proliferation and Elongation Reduced regulator dosage in the urogenital ridge epithelium is what the mouse models translate into a duct that does not elongate.

Shared Intermediate Mesoderm Lineage Failure The same regulators drive nephric duct and kidney development, so a single lesion reaches both organ systems.

Paraxial Mesoderm and Somite Patterning Failure TBX6 acts in paraxial mesoderm rather than in the duct, which is the lineage route to the axial skeletal anomalies of MURCS. Drawn as indirect because no mechanism has been established for monoallelic TBX6 variants in this disease.

Show evidence (3 references)

PMID:38699388 SUPPORT Human Clinical

"Two candidate genes for MRKH syndrome, LHX1 and HNF1B, are located at this locus, both of them being involved in MD development."

Identifies the two developmental regulators removed by the commonest recurrent deletion in this disease.

PMID:38699388 SUPPORT Other

"GREB1L is considered to be involved in retinoic acid signaling, although its protein remains poorly characterized"

Basis for the retinoic acid signalling annotation on this node, and for hedging it.

PMID:38699388 SUPPORT Human Clinical

"the pathogenic mechanism of how these missense variants cause MRKH syndrome is still unknown requiring further functional analysis"

States explicitly that the molecular step between a GREB1L missense variant and this node is not established.

Failure of Müllerian Duct Epithelial Proliferation and Elongation

The cellular step. The Müllerian duct is an epithelial tube that must proliferate, migrate caudally along the Wolffian duct and differentiate on a fixed schedule. Conditional ablation of Hnf1b in Müllerian duct epithelium in mice produces a hypoplastic uterus with renal anomalies — an MRKH type II phenocopy — and single-cell RNA sequencing of the ablated embryonic uterus shows dysregulation of proliferation, migration and differentiation programmes rather than one discrete pathway. Lhx1-null females likewise lack a reproductive tract through a failure of duct elongation and epithelium formation, with normal ovaries, which is exactly the human dissociation.

paramesonephric duct development GO:0061205 ↓ DECREASED epithelial cell proliferation GO:0050673 ↓ DECREASED epithelial cell migration GO:0010631 ↓ DECREASED epithelial cell differentiation GO:0030855 ↓ DECREASED

Müllerian duct epithelium UBERON:0003890

Animal models

Wnt7a-Cre;Hnf1b-floxed Müllerian duct epithelium conditional knockout mouse Mouse recapitulates The lesion is placed in exactly the cell population this node names, and the measured consequence is the cellular failure the node asserts: reduced epithelial proliferation from 13.5 dpc, a shorter uterus, and an epithelium that never organizes into its normal pseudostratified columnar form. The single-cell transcriptomic result is the direct basis for the three cellular processes annotated on this node.

Lim1 (Lhx1)-null mouse Mouse recapitulates The chimera assay is the part that matters for this node: in a mosaic female, Lim1-null cells fail to contribute to Müllerian duct epithelium while wild-type cells in the same animal do, so the requirement is cell-autonomous within the epithelium and not a secondary consequence of the kidney or Wolffian duct phenotype.

Downstream

Müllerian Duct Aplasia An epithelial tube that does not elongate or differentiate leaves no structure behind.

Show evidence (3 references)

PMID:36282544 SUPPORT Model Organism

"We ablated Hnf1b specifically in the epithelium of the Müllerian ducts in mice and found that this caused hypoplastic development of the uterus, as well as kidney anomalies, closely mirroring the MRKH type II phenotype."

Places the lesion in Müllerian duct epithelium specifically, and shows it reproduces the human type II combination.

PMID:36282544 SUPPORT Model Organism

"Using single-cell RNA sequencing of uterine tissue in the Hnf1b-ablated embryos, we analyzed the molecules and pathways downstream of Hnf1b, revealing a dysregulation of processes associated with cell proliferation, migration and differentiation."

Direct basis for the three cellular processes annotated on this node.

PMID:38699388 SUPPORT Model Organism

"Lhx1-null female mice have normal ovaries but lack their reproductive tract, which results from a disruption of MD elongation and epithelium formation"

Second gene reaching the same cellular failure, and the model that reproduces the ovary-spared dissociation seen in patients.

Müllerian Duct Aplasia

The defining lesion: the paramesonephric ducts are absent or aplastic, so the uterus, cervix and upper two-thirds of the vagina are never built. The lower vagina, which derives from the urogenital sinus rather than from the ducts, is present — which is why the anatomy is a short blind-ending pouch rather than complete vaginal absence. The Fallopian tubes, also duct-derived, are correspondingly rudimentary or absent, and their absence is thought to explain the characteristically lateral, more cranial position of the ovaries.

paramesonephric duct development GO:0061205 ∅ ABSENT uterus development GO:0060065 ↓ DECREASED vagina development GO:0060068 ↓ DECREASED

Müllerian duct UBERON:0003890

Animal models

Lim1 (Lhx1)-null mouse Mouse recapitulates Absence of uterus and oviducts in an otherwise female neonate is the tissue-level lesion this node names, arrived at from a single transcription-factor loss.

Downstream

Uterovaginal Aplasia with Rudimentary Uterine Buds What is left in the pelvis when the ducts fail is typically a pair of aplastic buds on the sidewalls joined by a midline fibrous band.

Cervical and Upper Vaginal Atresia with a Blind Vaginal Pouch The caudal, fusion-dependent segment of the duct is the cervix and upper vagina, so its absence leaves the sinus-derived lower vagina ending blindly.

Show evidence (2 references)

PMID:38699388 SUPPORT Human Clinical

"Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also referred to as Müllerian aplasia, is a congenital disorder characterized by agenesis or aplasia of the uterus and upper part of the vagina."

States the lesion this node represents and its anatomical extent.

PMID:38699388 SUPPORT Human Clinical

"Here, the caudal parts of the two MDs start to fuse to form the uterus and upper vagina starting from week 8."

Establishes which structures are duct-derived, and therefore which are lost and which are spared.

Uterovaginal Aplasia with Rudimentary Uterine Buds

The realised pelvic anatomy. Bilateral rudimentary or aplastic uterine horns are found in the large majority of patients — 84% of a systematically imaged and laparoscoped cohort of 284 — and uterine remnants of some kind are reported across a wide range of series. The buds are not inert: they contain myometrium, which can give rise to leiomyomas, and a variable proportion contain endometrium, which is the origin of the syndrome's only genuinely active pathology.

uterus UBERON:0000995

Downstream

Absolute Uterine Factor Infertility A rudimentary bud cannot implant an embryo or carry a pregnancy.

Primary amenorrhea There is no functional endometrial cavity with an outflow tract, so no menses occur despite normal ovarian cycling.

Aplasia of the uterus The imaging and operative finding that corresponds to this node.

Uterine leiomyoma in rudimentary uterine buds The buds retain myometrium, so the usual leiomyoma biology remains available to them; subserosal leiomyomas on the uterine buds are a described operative finding.

Retained Cycling Endometrium in Uterine Remnants Endometrium present within a bud is the substrate for the syndrome's cyclic pathology.

Show evidence (2 references)

PMID:22906151 SUPPORT Human Clinical

"Complete atresia of Vagina (V5b) and bilateral atresia of Cervix (C2b) were found in 284 patients (100%)."

Establishes that cervical and vaginal atresia are invariant in this cohort, unlike the uterine and adnexal findings which vary.

PMID:32819397 SUPPORT Human Clinical

"Presence of uterine remnants have been reported in 48 – 95% of the patients"

Quantifies how commonly remnant tissue is present, and how widely the reported range varies between series.

Spared Gonadal Ridge Lineage with Normal Ovarian Steroidogenesis

The ovaries do not derive from the Müllerian ducts, so the lesion does not touch them: adnexa are normal in the large majority of patients, and gonadotropins, estradiol and androgens are in the normal female range. Two consequences follow, and between them they account for most of how the syndrome presents. First, puberty is normal — thelarche, pubarche and growth all proceed — so nothing is apparent until menses fail to arrive, which is why the median age at referral is in the late teens rather than at birth. Second, any endometrium retained in a uterine bud is exposed to ordinary cyclic ovarian steroids and therefore cycles. This node is included as a mechanistic mediator rather than as an incidental normal finding precisely because that second consequence is what generates the cyclic pain, haematometra and endometriosis arm of the disease.

Animal models

Wnt7a-Cre;Hnf1b-floxed Müllerian duct epithelium conditional knockout mouse Mouse recapitulates Ovaries were indistinguishable from controls with follicles at every stage of folliculogenesis, and the mutants mated and plugged normally yet never conceived — the dissociation this node exists to record, with the gestational deficit isolated from the gametic one.

Downstream

Retained Cycling Endometrium in Uterine Remnants Cyclic ovarian steroid output is what drives proliferation and shedding in remnant endometrium; without it the remnants would be quiescent.

Show evidence (3 references)

PMID:38699388 SUPPORT Human Clinical

"The patients are characterized by having a normal female karyotype (46,XX), normal external genitalia, and normal pubertal development of secondary sex characteristics (thelarche and pubarche)"

Normal pubertal development is the clinical read-out of preserved ovarian endocrine function.

PMID:22906151 SUPPORT Human Clinical

"Adnexa: normal Adnexa were found in 248 women (87.3%)."

Quantifies adnexal sparing in a systematically evaluated cohort, and shows it is high but not universal.

PMID:29266078 SUPPORT Human Clinical

"Patients with müllerian agenesis usually are identified when they are evaluated for primary amenorrhea with otherwise typical growth and pubertal development."

States the presentation that follows from ovarian sparing: an isolated outflow failure against a normal endocrine background.

Retained Cycling Endometrium in Uterine Remnants

Where a rudimentary bud contains functional endometrium and has no outflow tract, that endometrium proliferates and sheds into a closed cavity. The clinical result is catamenial abdominal pain and, when enough blood accumulates, haematometra. The same cryptic menstruation is the best available explanation for endometriosis in a woman with no uterus: a systematic review and meta-analysis of 666 patients in whom the presence or absence of functional endometrium was actually verified found endometriosis in 32.0% of those with functional endometrium versus 1.5% of those without, an odds ratio of 12.0. That is a strong argument for retrograde menstruation from the remnant, and it is worth noting for what it does to a long-standing objection: MRKH syndrome has often been cited as a case of endometriosis without menstruation, and once functional endometrium is ascertained rather than assumed absent, most of the cases turn out to have a menstruating source. The residual 1.5% is not explained by this mechanism.

uterus UBERON:0000995

Downstream

Cyclic abdominal pain Shedding into an obstructed remnant cavity produces catamenial pain.

Endometriosis Retrograde escape of shed remnant endometrium into the peritoneal cavity, followed by implantation, is the intermediate step.

Show evidence (3 references)

PMID:40246293 SUPPORT Human Clinical

"The proportion of patients with endometriosis was 32.0% in the subgroup with FE (64/200; 95% CI, 25.9-38.8%) and 1.5% (7/466; 95% CI, 0.7-3.1%) in the subgroup without FE within UR/without UR."

The quantitative contrast on which this node rests: endometriosis tracks the presence of functional endometrium in a remnant, not the syndrome itself.

PMID:40246293 SUPPORT Human Clinical

"A significantly increased risk of endometriosis was observed in MRKHSFE+ patients compared with MRKHSFE- patients (overall odds ratio estimate was 12.0; 95% CI, 5.1-28.3%)."

Meta-analytic effect size for the same association.

PMID:40246293 REFUTE Human Clinical

"Among the 71 MRKHS patients with endometriosis, 64 had coexisting FE, and only seven had no evidence of FE within UR or did not have UR."

Seven patients had endometriosis with no demonstrable functional endometrium and no remnant, so retrograde menstruation from a remnant cannot be the whole account of endometriosis in this syndrome.

Shared Intermediate Mesoderm Lineage Failure

The renal arm of type II, and the strongest structural argument that MRKH syndrome is a lineage disorder rather than an organ-specific one. The nephric duct and the Müllerian duct develop side by side out of the intermediate mesoderm, the Müllerian duct elongates guided by the Wolffian duct, and the transcriptional regulators implicated in the syndrome are the regulators of kidney development. Around 30% of patients accordingly have a renal malformation, unilateral renal agenesis being about half of those. The clinching detail is laterality: absence of one Müllerian duct is often accompanied by absence of the ipsilateral kidney, which is what a single unilateral lineage failure predicts and what two independent malformations would not.

intermediate mesoderm development GO:0048389 ⚠ ABNORMAL mesonephric duct development GO:0072177 ⚠ ABNORMAL kidney development GO:0001822 ⚠ ABNORMAL

kidney UBERON:0002113

Animal models

Wnt7a-Cre;Hnf1b-floxed Müllerian duct epithelium conditional knockout mouse Mouse partially recapitulates Unilateral renal agenesis appeared in the mutants and never in controls or heterozygotes, at a frequency close to the human figure — which is the renal arm of type II arising from a lesion targeted at the Müllerian duct.

Downstream

Unilateral renal agenesis The commonest single renal malformation, and typically ipsilateral to the absent Müllerian duct.

Ectopic kidney Failure of normal ascent and positioning within the same lineage.

Horseshoe kidney Midline fusion anomaly reported in the same cohorts.

Duplicated collecting system Nephric-duct-derived collecting system anomaly in the same lineage.

Show evidence (3 references)

PMID:38699388 SUPPORT Human Clinical

"The close relationship between kidney and uterovaginal development is also reflected by the high prevalence (~30%) of kidney malformations in MRKH syndrome"

States the shared-lineage inference and the frequency that motivates it.

PMID:27609979 SUPPORT Human Clinical

"Kidney malformations were the most prevalent extragenital malformations, described in 38 of 111 patients (34.2%)."

Population-based figure for the renal arm; note that the same study reports a third of its cohort had no urinary tract imaging at all, so this is a floor rather than a point estimate.

PMID:36282544 SUPPORT Model Organism

"Thus, we establish that loss of Hnf1b function leads to an MRKH phenotype and generate the first mouse model of MRKH syndrome type II."

A single-gene lesion producing the combined uterine and renal phenotype is what a shared lineage failure predicts.

Paraxial Mesoderm and Somite Patterning Failure

The skeletal arm of type II, and the reason the MURCS acronym names cervicothoracic somite dysplasia alongside Müllerian and renal aplasia. Paraxial mesoderm forms the axial skeleton, TBX6 patterns it, and the 16p11.2 deletion that removes TBX6 is one of the recurrent copy-number variants in this syndrome — the same locus is independently associated with congenital scoliosis. Skeletal anomalies are the second most frequent extragenital finding and involve the axial skeleton preferentially. This node is nonetheless the weakest link in the entry's causal chain: the scoliosis association at this locus follows a compound inheritance dosage model requiring a second hypomorphic allele, no such second allele has been found in MRKH syndrome, and no biological mechanism has been established for the monoallelic TBX6 variants reported here.

paraxial mesoderm development GO:0048339 ⚠ ABNORMAL

Downstream

Scoliosis Axial patterning failure expressed as a curvature deformity.

Cervical vertebral fusion Segmentation failure of the cervicothoracic somites, the Klippel-Feil end of the MURCS phenotype.

Hemivertebrae Failure of formation of one half of a vertebral body from a somite.

Show evidence (3 references)

PMID:38699388 SUPPORT Human Clinical

"Other common extragenital anomalies include the skeleton and heart, which do also develop from the mesoderm, with the paraxial mesoderm forming the axial skeleton"

Establishes the paraxial mesoderm as the lineage linking this syndrome to axial skeletal anomalies.

PMID:38699388 REFUTE Human Clinical

"As of now, no clear biological mechanism for monoallelic TBX6 variants causing MRKH syndrome has been established, which challenges interpretation and warrants further studies."

Directly contradicts a confident mechanistic reading of this node, and is recorded here rather than only in a discussion so the node cannot be quoted as settled.

PMID:38699388 SUPPORT INDIRECT Human Clinical

"requiring one TBX6-null allele and a particular hypomorphic trans allele, as described in the compound inheritance gene dosage model"

The genetic architecture established for TBX6 in congenital scoliosis; indirect here because it describes the scoliosis phenotype, and the second risk allele it requires has not been found in MRKH syndrome.

Absolute Uterine Factor Infertility

The terminal consequence, and the one that defines the therapeutic problem. Absolute uterine factor infertility is infertility from anatomical absence of a uterus or presence of a non-functional one; MRKH syndrome is its congenital form, alongside acquired causes such as hysterectomy for malignancy or obstetric haemorrhage. Ovarian function being intact, the gametes are available and the deficit is purely gestational — which is precisely why uterus transplantation works here and why it was first performed in this disease.

Downstream

Female infertility The clinical phenotype corresponding to this node.

Show evidence (1 reference)

PMID:25301505 SUPPORT Human Clinical

"Uterus transplantation is the first available treatment for absolute uterine infertility, which is caused by absence of the uterus or the presence of a non-functional uterus."

Defines the condition this node names and situates MRKH syndrome within it.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

17

Cardiovascular 1

Atrial septal defect under 5% HP:0001631

Show evidence (1 reference)

PMID:38699388 SUPPORT Human Clinical

"MRKH syndrome may present as an isolated anomaly (type I) or in association with extragenital malformations (type II), typically involving the kidneys, skeleton, and heart"

Names the heart among the typical extragenital systems involved.

Ear 1

Hearing impairment under 5% when not systematically sought, about 11% when it is HP:0000365

Show evidence (1 reference)

PMID:38699388 SUPPORT INDIRECT Human Clinical

"MRKH syndrome may present as an isolated anomaly (type I) or in association with extragenital malformations (type II), typically involving the kidneys, skeleton, and heart"

Cited indirectly: it establishes the extragenital malformation category this phenotype belongs to but lists the three commonest systems rather than the ear.

Genitourinary 11

Primary amenorrhea obligate HP:0000786

Show evidence (2 references)

PMID:32819397 SUPPORT Human Clinical

"MRKH syndrome has been reported in ~ 16% of patients with primary amenorrhea"

Quantifies how large a share of primary amenorrhea this syndrome accounts for.

PMID:29266078 SUPPORT Human Clinical

"Patients with müllerian agenesis usually are identified when they are evaluated for primary amenorrhea with otherwise typical growth and pubertal development."

Establishes primary amenorrhea against normal puberty as the presenting pattern.

Aplasia of the uterus obligate HP:0000151

Show evidence (1 reference)

PMID:38699388 SUPPORT Human Clinical

"Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also referred to as Müllerian aplasia, is a congenital disorder characterized by agenesis or aplasia of the uterus and upper part of the vagina."

Uterine aplasia is definitional for the syndrome.

Female infertility obligate HP:0008222

Show evidence (1 reference)

PMID:25301505 SUPPORT Human Clinical

"Uterus transplantation is the first available treatment for absolute uterine infertility, which is caused by absence of the uterus or the presence of a non-functional uterus."

Names the infertility category this phenotype belongs to.

Dyspareunia common before treatment HP:0030016

Show evidence (1 reference)

PMID:29266078 SUPPORT INDIRECT Human Clinical

"Nonsurgical vaginal elongation by dilation should be the first-line approach. When well-counseled and emotionally prepared, almost all patients (90-96%) will be able to achieve anatomic and functional success by primary vaginal dilation."

Cited indirectly: the existence and success rate of a treatment aimed at anatomic and functional vaginal adequacy evidences the functional deficit it treats, rather than reporting dyspareunia frequency directly.

Endometriosis about 32% with functional endometrium in a remnant versus 1.5% without HP:0030127

Show evidence (1 reference)

PMID:40246293 SUPPORT Human Clinical

"The aggregate prevalence of endometriosis was considerably higher in MRKHS patients with FE (MRKHSFE+) than in those without FE (MRKHSFE-)."

The stratified frequency this phenotype records.

Uterine leiomyoma in rudimentary uterine buds uncommon HP:0000131

Show evidence (1 reference)

PMID:32819397 SUPPORT Human Clinical

"Presence of uterine remnants have been reported in 48 – 95% of the patients"

Establishes that remnant uterine tissue is commonly present, which is the precondition for a leiomyoma arising in it. The leiomyoma finding itself is described in the same review's operative figure legend.

Unilateral renal agenesis about half of the renal malformations HP:0000122

Show evidence (1 reference)

PMID:27609979 SUPPORT Human Clinical

"Kidney malformations were the most prevalent extragenital malformations, described in 38 of 111 patients (34.2%)."

Population-based frequency for renal malformation as a class, of which unilateral agenesis is the largest component.

Ectopic kidney uncommon HP:0000086

Show evidence (1 reference)

PMID:22906151 SUPPORT Human Clinical

"associated malformations were found in 126 of 282 evaluable women (44.7%), 84 women (29.6%) had malformations of the renal system"

Frequency of renal malformations as a class in a systematically evaluated cohort; the individual anomaly types are enumerated in the same study.

Horseshoe kidney uncommon HP:0000085

Show evidence (1 reference)

PMID:22906151 SUPPORT Human Clinical

"A variety of associated malformations were present, predominantly of the renal system."

Establishes the renal system as the predominant site of associated malformation, within which this anomaly is reported.

Duplicated collecting system uncommon HP:0000081

Show evidence (1 reference)

PMID:22906151 SUPPORT Human Clinical

"It is therefore recommended that all patients with genital malformations should be evaluated for renal abnormalities."

The cohort's own recommendation, which follows from the breadth of renal anomaly types it found.

Musculoskeletal 3

Scoliosis reported in 10-40% depending on imaging performed HP:0002650

Show evidence (1 reference)

PMID:38699388 SUPPORT Human Clinical

"Other common extragenital anomalies include the skeleton and heart, which do also develop from the mesoderm, with the paraxial mesoderm forming the axial skeleton"

Places skeletal anomalies among the common extragenital findings and assigns them to the paraxial mesoderm lineage.

Cervical vertebral fusion uncommon Fused cervical vertebrae HP:0002949

Show evidence (1 reference)

PMID:27609979 SUPPORT Human Clinical

"Typical MRKH syndrome and atypical MRKH syndrome/Müllerian duct aplasia, Renal aplasia, and Cervicothoracic Somite dysplasia association were present in 56.5% and 43.5% of the patients, respectively."

Names cervicothoracic somite dysplasia as a defining component of the MURCS subgroup, which is what this phenotype records.

Hemivertebrae uncommon HP:0002937

Show evidence (1 reference)

PMID:22906151 SUPPORT INDIRECT Human Clinical

"associated malformations were found in 126 of 282 evaluable women (44.7%), 84 women (29.6%) had malformations of the renal system"

Cited indirectly: it establishes the overall associated-malformation burden and that renal anomalies are only two-thirds of it, leaving the skeletal remainder to which this phenotype belongs.

Constitutional 1

Cyclic abdominal pain subset with functional endometrium in a remnant HP:0002027

Temporal: RECURRENT

Show evidence (1 reference)

PMID:40246293 SUPPORT INDIRECT Human Clinical

"The recent advent of high-resolution ultrasonography and magnetic resonance imaging (MRI) allowed the reliable preoperative identification of FE concealed within UR"

Establishes that functional endometrium concealed within a uterine remnant is a real, now preoperatively detectable entity — the substrate for this phenotype. Indirect because it concerns detection of the substrate rather than the pain itself.

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Genetic Associations

7

GREB1L (Causative)

Gene: GREB1L hgnc:31042 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:38699388 SUPPORT Human Clinical

"epidemiological evidence of rare variant enrichment in larger cohorts, and functional evidence from knock-out mice, suggest GREB1L as a major causative gene in MRKH syndrome."

The review's own summary judgement on this gene, based on pedigree, cohort-enrichment and mouse evidence together.

PMID:38699388 SUPPORT Model Organism

"Homozygous knock-out of Greb1l in mice has been shown to cause absence of the kidneys, Wolffian ducts, and Müllerian ducts"

Mouse loss of function reproduces the combined renal and Müllerian phenotype, which is the functional half of the causality argument.

PMID:38699388 SUPPORT Human Clinical

"the pathogenic mechanism of how these missense variants cause MRKH syndrome is still unknown requiring further functional analysis"

Records the limit of the account: the human allele class is monoallelic missense and its mechanism is unresolved, so the mouse null is not a complete model of it.

PAX8 (Causative)

Gene: PAX8 hgnc:8622 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:38699388 SUPPORT Human Clinical

"Among cases, they found enrichment for predicted loss-of-function variants in PAX8."

Case-control enrichment is the primary evidence for this gene.

PMID:38699388 SUPPORT Human Clinical

"This confirms MRKH syndrome as a part of the PAX8 disease spectrum in females"

States the pleiotropy claim this record encodes.

HNF1B (Causative)

Gene: HNF1B hgnc:11630 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:38699388 SUPPORT Human Clinical

"Notably, two of four female variant carriers also had uterovaginal agenesis, supporting MRKH syndrome as part of the HNF1B disease spectrum"

Human pedigree evidence, from a family ascertained for diabetes rather than for a genital anomaly.

PMID:36282544 SUPPORT Model Organism

"Thus, we establish that loss of Hnf1b function leads to an MRKH phenotype and generate the first mouse model of MRKH syndrome type II."

Tissue-specific ablation establishes causality rather than association for this gene.

LHX1 (Candidate gene at the 17q12 locus; sequence variants disputed)

Gene: LHX1 hgnc:6593 relationship_type: DISPUTED

Show evidence (2 references)

PMID:38699388 SUPPORT Model Organism

"Lhx1-null female mice have normal ovaries but lack their reproductive tract, which results from a disruption of MD elongation and epithelium formation"

The animal evidence in favour of a role for this gene.

PMID:38699388 REFUTE Human Clinical

"LHX1 mutational analysis of larger cohorts did not report any variants, suggesting that sequence variants of LHX1 are no major cause of MRKH syndrome"

Negative cohort evidence against LHX1 sequence variation as a monogenic cause, which is why the relationship is recorded as DISPUTED.

TBX6 (Susceptibility at the recurrent 16p11.2 deletion locus)

Gene: TBX6 hgnc:11605 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:38699388 SUPPORT Human Clinical

"Ma et al. reported 16 rare TBX6 variants enriched in a large MRKH syndrome patient cohort compared to controls."

Case-control enrichment supporting a genuine association with this gene.

PMID:38699388 REFUTE Human Clinical

"However, in contrast to null alleles associated with scoliosis, no second risk alleles were reported in MRKH syndrome"

The compound-inheritance model that explains TBX6 in scoliosis does not transfer, which argues against a simple causative reading here.

WNT9B (Candidate gene; variants of uncertain significance)

Gene: WNT9B hgnc:12779 relationship_type: UNKNOWN

Show evidence (1 reference)

PMID:38699388 SUPPORT Model Organism

"Wnt9b is expressed in the Wolffian duct epithelium providing signals guiding MD elongation"

Establishes the biological candidacy, which is what this record rests on in the absence of settled human genetics.

RBM8A (Proposed candidate gene at the 1q21.1 locus; causality not established)

Gene: RBM8A hgnc:9905 relationship_type: UNKNOWN

Show evidence (1 reference)

PMID:38699388 NO_EVIDENCE Human Clinical

"The possible causal role of 1q21.1 deletions/RBM8A gene variants in MRKH syndrome is, however, still unclear warranting further studies to establish causality."

Graded NO_EVIDENCE because the cited review states the causal question is unresolved: it neither supports nor refutes a gene-disease relationship for RBM8A.

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Medical Actions

7

Progressive Vaginal Dilation

Action: progressive self-dilation of the vaginal dimple (Frank method) Ontology label: Vaginal Dilation Therapy NCIT:C93165

Platform: Behavioral / lifestyle

First-line therapy for vaginal agenesis and has been the ACOG recommendation since 2002. Progressive dilators are applied to the vaginal apex for 10 to 30 minutes, one to three times daily. Anatomic and functional success is reached by 90-96% of patients, at a low complication rate and low cost, and comparative studies generally find dilation non-inferior to surgery. Two points are easy to lose. First, the method works because the residual pouch is lined with native vaginal mucosa, which surgical grafts do not reproduce — and that mucosal lining also supplies a normal vaginal microbiota, which matters if uterus transplantation is later contemplated. Second, success depends on maturity, motivation and supervised therapeutic education rather than on the device; poor compliance is the main mode of failure, and it is a legitimate outcome for a patient to choose no treatment at all.

Mechanism Target:

RESTORES Cervical and Upper Vaginal Atresia with a Blind Vaginal Pouch — Mechanical elongation of the sinus-derived pouch addresses the vaginal arm of the lesion. It does nothing for the uterine arm, and does not treat infertility.

Show evidence (1 reference)

PMID:29266078 SUPPORT Human Clinical

"Nonsurgical vaginal elongation by dilation should be the first-line approach. When well-counseled and emotionally prepared, almost all patients (90-96%) will be able to achieve anatomic and functional success by primary vaginal dilation."

Establishes both the first-line status and the success rate quoted here.

Vaginoplasty

Action: vaginoplasty for vaginal agenesis Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Reserved for patients in whom dilation has failed. Several techniques exist — laparoscopic Vecchietti traction, McIndoe split-skin graft, Davydov peritoneal graft, Williams vulvovaginoplasty, bowel graft, and more recently cultured autologous vulvar tissue and tissue-engineered constructs — and no comparative trial establishes one as best; most centres see too few patients to acquire more than one technique, which is itself a source of publication and reporting bias in the outcome literature. The point that most changes patient expectations is that surgery does not remove the need for dilation: post-operative dilation is still required to prevent strictures. NCIT has no clinical-action term for vaginoplasty, so the binding is the generic Surgical Procedure with the specificity carried in the preferred term.

Mechanism Target:

RESTORES Cervical and Upper Vaginal Atresia with a Blind Vaginal Pouch — Surgical creation of a neovaginal canal in the space between bladder and rectum, substituting for the absent duct-derived segment.

Show evidence (1 reference)

PMID:29266078 SUPPORT Human Clinical

"In cases in which surgical intervention is required, referrals to centers with expertise in this area should be considered because few surgeons have extensive experience in construction of the neovagina"

Supports both the second-line positioning and the centre-volume caveat.

Uterus Transplantation

Action: uterus transplantation Ontology label: Organ Transplantation NCIT:C15289

Platform: Surgery

The first and still the only treatment for the infertility itself, as distinct from the anatomy. A living-donor uterus transplant in a 35-year-old woman with MRKH syndrome in Gothenburg in 2013 led to menstruation 43 days after transplantation, pregnancy after a single embryo transfer a year later, and a livebirth in September 2014. Three episodes of mild rejection were reversed with corticosteroids; delivery was by caesarean section at 31 weeks and 5 days for pre-eclampsia. The mechanistic logic is that in this syndrome the deficit is purely gestational — ovaries and oocytes are normal — so replacing the uterus restores gestational, genetic and legal motherhood together, which neither surrogacy nor adoption does. It requires IVF beforehand and immunosuppression throughout pregnancy, so it is a serious intervention rather than a routine option.

Mechanism Target:

RESTORES Absolute Uterine Factor Infertility — Supplies the missing organ, which is the only mechanism by which this node can be addressed.

Show evidence (2 references)

PMID:25301505 SUPPORT Human Clinical

"In 2013, a 35-year-old woman with congenital absence of the uterus (Rokitansky syndrome) underwent transplantation of the uterus in Sahlgrenska University Hospital, Gothenburg, Sweden."

Establishes that the index case of this treatment was a patient with this syndrome.

PMID:25301505 SUPPORT Human Clinical

"We describe the first livebirth after uterus transplantation. This report is a proof-of-concept for uterus transplantation as a treatment for uterine factor infertility."

The outcome that makes this a treatment rather than a proposal.

In Vitro Fertilization with a Gestational Carrier

Action: in vitro fertilization with gestational surrogacy Ontology label: In Vitro Fertilization NCIT:C16580

Platform: Other

IVF using the patient's own oocytes with embryo transfer to a gestational carrier, which yields genetic but not gestational motherhood. It has been the established route to biological parenthood since the mid-1990s and is effective, but it is prohibited in many jurisdictions on ethical, religious or legal grounds, so availability is a matter of geography rather than of medicine. One consequence worth recording: because surrogacy bypasses the infertility that otherwise blocks vertical transmission, mother-to-daughter recurrence of MRKH syndrome after surrogacy has now been reported, which is why recurrence-risk counselling is becoming a real part of care rather than a theoretical one.

Mechanism Target:

BYPASSES Absolute Uterine Factor Infertility — Bypasses rather than corrects the missing organ, by gestating the patient's genetic embryo elsewhere.

Show evidence (1 reference)

PMID:29266078 SUPPORT Human Clinical

"Assisted reproductive techniques with use of a gestational carrier (surrogate) have been shown to be successful for women with müllerian agenesis."

Establishes efficacy of this route in this population.

Psychological Counselling and Peer Support

Action: psychological counselling and support Ontology label: Psychotherapy NCIT:C15308

Platform: Behavioral / lifestyle

Not adjunctive. The diagnosis arrives in adolescence and simultaneously delivers infertility, a threat to female identity, and the prospect of coital difficulty; measured psychological distress is higher than in comparison women, and qualitative work identifies hindered independence, feeling different, difficulty managing intimacy and threatened female identity as the recurring themes. Group programmes reduce distress, and every patient should be offered counselling and encouraged to connect with a peer support group. Counselling also gates the anatomical treatments: dilation depends on maturity and motivation, so counselling precedes it rather than following it.

Mechanism Target:

MODULATES Absolute Uterine Factor Infertility — Addresses the psychological consequences of this node, which no anatomical or reproductive intervention removes.

Show evidence (1 reference)

PMID:29266078 SUPPORT Human Clinical

"The psychologic effect of the diagnosis of müllerian agenesis should not be underestimated. All patients with müllerian agenesis should be offered counseling and encouraged to connect with peer support groups."

Professional-society statement that counselling and peer support are part of standard care here.

Laparoscopic Excision of Symptomatic Uterine Remnants

Action: laparoscopic excision of a uterine remnant Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Indicated where a rudimentary bud contains functional endometrium and is causing catamenial pain or haematometra, and it is the one operation in this syndrome that treats an active lesion rather than an absence. Since MRI now identifies concealed functional endometrium preoperatively, the decision can be made on imaging rather than at diagnostic laparoscopy. Given that endometriosis risk tracks functional endometrium in a remnant at an odds ratio of about 12, removing the symptomatic remnant plausibly addresses the source of that risk as well as the pain — though the entry does not claim a demonstrated reduction in endometriosis incidence, which has not been shown.

Mechanism Target:

INHIBITS Retained Cycling Endometrium in Uterine Remnants — Removes the cycling tissue, which is the substrate of the node.

Show evidence (1 reference)

PMID:40246293 SUPPORT Human Clinical

"A significantly increased risk of endometriosis was observed in MRKHSFE+ patients compared with MRKHSFE- patients (overall odds ratio estimate was 12.0; 95% CI, 5.1-28.3%)."

Quantifies the risk attached to the tissue this operation removes. It does not itself evidence that excision lowers that risk.

Genetic Counselling

Action: genetic counselling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Increasingly relevant rather than routine. A detailed family history covering both MRKH syndrome and associated renal or uterovaginal anomalies in relatives is the single highest-yield step, since subtle anomalies in asymptomatic relatives may need imaging to find. Where a variant in GREB1L, PAX8 or HNF1B is identified, counselling covers recurrence risk with incomplete penetrance and sex-limited expressivity, and at-risk relatives can be tested. Two cautions belong in the same conversation: most reported variants remain of uncertain significance, and the recurrence question is only actionable at all because surrogacy and transplantation have made genetic parenthood possible.

Show evidence (1 reference)

PMID:38699388 SUPPORT Human Clinical

"However, in the current state of knowledge, many reported variants associated with MRKH syndrome are still to be considered as variants of uncertain significance, which warrant cautious interpretations and counseling in clinical care."

Supports the caution this record places on genetic counselling in this syndrome.

🔬

Diagnosis

5

Pelvic magnetic resonance imaging

The reference standard. MRI confirms uterovaginal agenesis, distinguishes rudimentary uterine buds from complete absence, and — the clinically decisive part — shows whether a bud contains endometrium, which is what determines the risk of catamenial pain, haematometra and endometriosis and therefore whether the remnant should be removed. It also images the kidneys and can show extragenital anomalies in the same study.

pelvic MRI of the internal genitalia NCIT:C16809

Show evidence (1 reference)

PMID:40246293 SUPPORT Human Clinical

"The recent advent of high-resolution ultrasonography and magnetic resonance imaging (MRI) allowed the reliable preoperative identification of FE concealed within UR"

Establishes that imaging now answers the functional-endometrium question preoperatively, which is the diagnostic value this record claims.

Pelvic ultrasonography

First-line imaging, showing an absent uterus with two present ovaries. It also excludes the mimics that matter most: an imperforate hymen or transverse vaginal septum will show a proximal vaginal canal and often haematocolpos, which uterovaginal agenesis will not — a distinction with real consequences, since operating on the wrong one is harmful.

transabdominal or transperineal pelvic ultrasonography NCIT:C17230

Show evidence (1 reference)

PMID:22906151 SUPPORT Human Clinical

"290 women with MRKH syndrome were clinically evaluated with using clinical examinations, abdominal and perineal/rectal ultrasound, MRI, and laparoscopy."

Documents the diagnostic sequence in which ultrasound is used for this syndrome.

Renal imaging

Screening for renal malformation in every patient, not only the symptomatic ones. A third of patients have a renal anomaly and most are asymptomatic; in the Danish cohort a third of patients had no urinary tract imaging at all, so under-ascertainment is the documented failure mode here.

renal ultrasonography or MRI NCIT:C17230

Show evidence (1 reference)

PMID:22906151 SUPPORT Human Clinical

"It is therefore recommended that all patients with genital malformations should be evaluated for renal abnormalities."

The recommendation this record implements, from the cohort that motivates it.

Karyotype

Confirms 46,XX, and its real purpose is to separate this syndrome from the 46,XY differential diagnoses that share a blind vagina and absent uterus — complete androgen insensitivity syndrome and 17-hydroxylase/17,20-lyase deficiency. It is diagnostically confirmatory rather than aetiologically informative.

karyotyping NCIT:C16768

Show evidence (1 reference)

PMID:38699388 SUPPORT Human Clinical

"The patients are characterized by having a normal female karyotype (46,XX), normal external genitalia, and normal pubertal development of secondary sex characteristics (thelarche and pubarche)"

The karyotype finding this test establishes, which is part of the case definition.

Chromosomal microarray

Optional rather than obligate. It detects the recurrent 17q12, 16p11.2, 22q11 and 1q21.1 imbalances, but those together account for only about 10% of patients and interpreting them is not straightforward — so a negative result excludes very little and a positive one often needs careful counselling rather than delivering a clean answer.

chromosomal microarray analysis NCIT:C18477

Show evidence (1 reference)

PMID:38699388 SUPPORT Human Clinical

"However, recurrent chromosomal imbalances in MRKH syndrome still only apply to a minor fraction of patients (around 10%)."

Quantifies the diagnostic yield, which is the basis for treating this test as optional.

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Prevalence

3

Denmark, live female births 1974-1996

Birth Prevalence 20.1 per 100,000 (17.0–23.7) live births 1–9 per 10,000 (births)

1 in 4982 (95% CI 4216-5887) live female births, from a nationwide registry cohort whose diagnoses were validated against cytogenetic registry data and medical records. The positive predictive value of the registry diagnosis code alone was only 55.3%, which is why the validation step matters and why unvalidated registry counts of this syndrome should be treated with caution. Denominator is live female births.

Show evidence (1 reference)

PMID:27609979 SUPPORT Human Clinical

"The prevalence of MRKH syndrome in Denmark is 1 in 4982 (95% confidence interval (CI): 4216-5887) live female births."

The population-based estimate and interval this record normalises.

Worldwide (conventional estimate)

Birth Prevalence 20.0 per 100,000 live births 1–9 per 10,000 (births)

The figure generally quoted, 1 in 5000 female live births. Note that only two population-based studies exist and both are European, so whether the prevalence differs in other populations is unknown rather than established as equal.

Show evidence (1 reference)

PMID:38699388 SUPPORT Human Clinical

"The estimated birth prevalence of MRKH syndrome is 1 in 5,000 female live births"

The conventional estimate as stated in a current review.

United States clinical estimate

Birth Prevalence 21.1 per 100,000 (20.0–22.2) live births 1–9 per 10,000 (births)

1 per 4,500-5,000 females, as stated by ACOG. Recorded as a range because the source gives one.

Show evidence (1 reference)

PMID:29266078 SUPPORT Human Clinical

"Müllerian agenesis, also referred to as müllerian aplasia, Mayer-Rokitansky-Küster-Hauser syndrome, or vaginal agenesis, has an incidence of 1 per 4,500-5,000 females."

Professional-society frequency statement.

⚖️

Clinical Burden

Moderate

The burden here is almost entirely reproductive and psychological rather than one of organ failure or shortened life: ovarian endocrine function is intact, puberty is normal, and most patients have no systemic illness. What the diagnosis delivers, in adolescence and usually all at once, is irreversible absolute uterine factor infertility, a threat to female identity, and the prospect of coital difficulty — and measured psychological distress is accordingly higher than in comparison women. Against that, treatment is effective on its own terms (dilation achieves a functional vagina in most patients without surgery) and the reproductive deficit is now partly addressable through uterus transplantation and gestational surrogacy, which is why this is MODERATE rather than HIGH. The type 2 renal arm can raise it for an individual patient; a solitary kidney carries its own lifelong surveillance burden that the genital anomaly does not.

Deliberately assessed at the level of the disease concept. Individual phenotypes carry their own severity: catamenial pain from a functional uterine remnant and the renal anomalies of type 2 are the two components that most often move an individual patient's burden above this.

Show evidence (2 references)

PMID:32819397 SUPPORT Human Clinical

"The diagnosis of MRKH syndrome may have profound psychological and/or psychosexual impact"

States the dimension in which the burden of this syndrome principally falls, which is what the MODERATE assessment is weighing.

PMID:29266078 SUPPORT Human Clinical

"The psychologic effect of the diagnosis of müllerian agenesis should not be underestimated. All patients with müllerian agenesis should be offered counseling and encouraged to connect with peer support groups."

A professional society treats the psychological consequence as a routine part of the disease burden requiring its own management, not as an occasional complication.

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Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Mayer-Rokitansky-Kuster-Hauser_Syndrome:

Complete androgen insensitivity syndrome Not Yet Curated MONDO:0021023

Overlapping Features Shares the presentation almost exactly: normal female appearance, breast development, a blind-ending vagina and an absent uterus, presenting as primary amenorrhea. The mechanism is the opposite — a 46,XY individual whose testes produce anti-Müllerian hormone, so the Müllerian structures regress normally rather than failing to form, and whose androgen receptor is non-functional. Sparse pubic hair and karyotype separate them.

Show evidence (1 reference)

PMID:38699388 SUPPORT INDIRECT Human Clinical

"Hauser and colleagues described that sex-chromatin analysis could aid the differentiation of MRKH syndrome from Turner syndrome and defined MRKH syndrome (at the time termed 'Mayer-Rokitansky-Küster syndrome') to include normal female chromosomes"

Cited indirectly: it establishes that karyotype is definitional for this syndrome and was introduced precisely to separate it from a karyotypic mimic, which is the same logic that separates it from 46,XY causes.

Imperforate hymen or transverse vaginal septum

Overlapping Features An obstructive anomaly with a normal uterus, mistaken for vaginal agenesis when only the introitus is examined. Ultrasound resolves it by showing a proximal vaginal canal and often haematocolpos. This is the differential with the most direct consequence of being got wrong in either direction: incising a blind pouch in a patient with agenesis achieves nothing and risks urethral or rectal injury, while leaving an obstruction undrained allows retrograde disease.

Unstimulated prepubertal or hypoestrogenic uterus

Overlapping Features A uterus that has never been exposed to estrogen — in 46,XX or 45,X ovarian insufficiency, or simply in a prepubertal child imaged incidentally — can be reported as absent. Exogenous estrogen induces uterine development in these patients, which proves the uterus was present and unstimulated rather than agenetic. Prepubertal pelvic imaging in particular should not be used to diagnose agenesis.

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Animal Models

2

Wnt7a-Cre;Hnf1b-floxed Müllerian duct epithelium conditional knockout mouse

The first mouse model of MRKH syndrome type II, and the only model in this entry that reproduces the genital and renal arms together from one lesion. Constitutive Hnf1b nulls die too early to be informative and lose the Müllerian duct secondarily to Wolffian duct degeneration, so the question of what Hnf1b does *in the duct* could not be asked until the lesion was restricted to Müllerian duct epithelium. Wnt7a-Cre confines recombination to that epithelium, sparing the Wolffian duct. Mutant females develop a hypoplastic uterus with a vestigial, non-differentiating epithelium, unilateral renal agenesis in a minority, and normal ovaries — the same combination, in the same proportions, as human type II disease.

Species

Mouse

Genotype

Wnt7a-Cre+;Hnf1b(fl/fl) — loxP sites flanking Hnf1b exon 4, recombined only where Wnt7a-Cre is expressed

Background

C57BL/6

Genes

HNF1B hgnc:11630

Publication

PMID:36282544

Pathograph links

Failure of Müllerian Duct Epithelial Proliferation and Elongation recapitulates fidelity: high observes: cellular The lesion is placed in exactly the cell population this node names, and the measured consequence is the cellular failure the node asserts: reduced epithelial proliferation from 13.5 dpc, a shorter uterus, and an epithelium that never organizes into its normal pseudostratified columnar form. The single-cell transcriptomic result is the direct basis for the three cellular processes annotated on this node.

Limitations: The mutant epithelium is hypoplastic and undifferentiated rather than absent, so the model reproduces the rudimentary-bud end of the human spectrum and not complete duct aplasia; the authors note it is milder than the Lhx1 conditional knockout, which loses the endometrial layer outright. Hnf1b sequence variants account for a small minority of human cases, so the cellular route shown here is not established as the route in most patients.

Readouts

Müllerian duct epithelial cell proliferation and uterine length

Proliferation in the Müllerian duct epithelium from 13.5 dpc, read out morphologically as uterine horn length at birth.

Direction: DECREASED

Interpretation: Proliferation failure preceding and explaining the shortened duct is the cellular claim this node makes.

Show evidence (1 reference)

PMID:36282544 SUPPORT Model Organism

"Hnf1b loss-of-function caused a decrease in MD epithelial cell proliferation, which started as early as 13.5 dpc, leading to the development of a shorter uterus."

Reports the measurement and its timing.

Uterine proliferation, migration and differentiation transcriptional programmes

Single-cell RNA sequencing of uterine tissue from Hnf1b-ablated embryos against littermate controls.

Direction: ALTERED

Interpretation: Dysregulation spread across three programmes rather than concentrated in one pathway is why this node is annotated with three GO processes and not with a single discrete mechanism.

Show evidence (1 reference)

PMID:36282544 SUPPORT Model Organism

"Using single-cell RNA sequencing of uterine tissue in the Hnf1b-ablated embryos, we analyzed the molecules and pathways downstream of Hnf1b, revealing a dysregulation of processes associated with cell proliferation, migration and differentiation."

Direct basis for the three cellular processes annotated on this node.

Endometrial gland development

Histology of the adult (4-month) mutant uterus.

Direction: DECREASED

Interpretation: Failure of the differentiation arm specifically, persisting into adulthood rather than resolving.

Show evidence (1 reference)

PMID:36282544 SUPPORT Model Organism

"Hnf1b mutant mice displayed a hypoplastic uterus, characterized by a simple cuboidal epithelium and reduced stromal thickness that failed to properly develop endometrial glands."

Reports the adult histological measurement behind this readout.

Show evidence (1 reference)

PMID:36282544 SUPPORT Model Organism

"We ablated Hnf1b specifically in the epithelium of the Müllerian ducts in mice and found that this caused hypoplastic development of the uterus, as well as kidney anomalies, closely mirroring the MRKH type II phenotype."

Establishes that the lesion sits in the cell population this node names, and that it produces the human phenotype.

Shared Intermediate Mesoderm Lineage Failure partially recapitulates fidelity: moderate observes: tissue Unilateral renal agenesis appeared in the mutants and never in controls or heterozygotes, at a frequency close to the human figure — which is the renal arm of type II arising from a lesion targeted at the Müllerian duct.

Limitations: Only a minority of mutants show it, and the authors themselves call the finding surprising: Wnt7a-Cre activity in mesonephric or metanephric cells may be ablating Hnf1b directly in the kidney, in which case the result is two lesions in one animal rather than one lineage failure reaching two organs. The same Cre line used against Lhx1 produced no kidney anomaly. The model therefore supports the co-occurrence this node records without settling the shared-lineage explanation for it.

Readouts

Unilateral renal agenesis frequency

Gross examination of mutant, control and heterozygous animals.

Direction: INCREASED

Interpretation: Penetrance in the model is of the same order as the human renal arm, which is what makes the comparison informative rather than merely directionally correct.

Show evidence (1 reference)

PMID:36282544 SUPPORT Model Organism

"We detected unilateral kidney agenesis in 6 of 36 mutant mice (16.7%), whereas it was never observed in controls"

Gives the frequency and the control comparison behind this readout.

Show evidence (1 reference)

PMID:36282544 SUPPORT Model Organism

"These results show that Hnf1b ablation results in uterine hypoplasia associated with kidney anomalies, providing a mouse model for MRKH syndrome type II."

Supports treating this model as informative for the combined genital and renal phenotype this node explains.

Spared Gonadal Ridge Lineage with Normal Ovarian Steroidogenesis recapitulates fidelity: moderate observes: organism Ovaries were indistinguishable from controls with follicles at every stage of folliculogenesis, and the mutants mated and plugged normally yet never conceived — the dissociation this node exists to record, with the gestational deficit isolated from the gametic one.

Limitations: Folliculogenesis and normal mating behaviour are indirect indices of ovarian endocrine function; no gonadotropin or steroid was measured, so the model does not directly attest the normal steroid output this node names. Nor can a mouse report the human consequence that makes the node load-bearing — normal puberty with primary amenorrhoea as the presenting sign.

Readouts

Ovarian folliculogenesis

Ovarian histology of mutant versus control females.

Direction: UNCHANGED

Interpretation: A negative result, and the informative one: the lesion reaches the duct derivatives and stops there.

Show evidence (1 reference)

PMID:36282544 SUPPORT Model Organism

"the ovaries of mutant animals did not show any difference compared with controls, displaying follicles at every stage of folliculogenesis"

Reports the ovarian measurement behind this readout.

Fertility with preserved mating behaviour

Mating trials with plug checks and pregnancy outcome.

Direction: ABOLISHED

Interpretation: Infertility against a normal ovarian and behavioural background is the model's version of absolute uterine factor infertility.

Show evidence (1 reference)

PMID:36282544 SUPPORT Model Organism

"Consistent with normal follicle dynamics, mutant female mice mated without apparent problems as evidenced by the presence of regular plugs. As expected, however, they failed to achieve pregnancy"

Reports the fertility outcome against preserved follicle dynamics.

Show evidence (1 reference)

PMID:36282544 SUPPORT Model Organism

"Overall, the Hnf1b mutant uterus resembled the histology of uterine rudiments found in MRKH syndrome, including a lower cell proliferation capacity and a simple, less differentiated epithelium"

Supports treating the model's uterus-versus-ovary dissociation as the human one rather than as an incidental mouse finding.

Kept distinct from the Lim1-null model below: the Hnf1b lesion is conditional and epithelium-restricted, which is what lets the renal finding be attributed to the same lineage rather than to generalized early lethality.

Show evidence (2 references)

PMID:36282544 SUPPORT Model Organism

"Thus, we establish that loss of Hnf1b function leads to an MRKH phenotype and generate the first mouse model of MRKH syndrome type II."

The authors' own statement of what the model is, and the basis for treating it as informative about this disease rather than about Hnf1b in general.

PMID:36282544 SUPPORT Model Organism

"we crossed a Wnt7a-Cre line with a mouse line carrying loxP sites flanking Hnf1b exon 4"

Source for the genotype recorded above.

Lim1 (Lhx1)-null mouse

The cleanest experimental statement of the ovary-spared, tract-absent dissociation that defines this syndrome clinically. Lim1 (the mouse orthologue of LHX1, the other gene in the recurrently deleted human 17q12 interval) is expressed in the developing Müllerian duct epithelium; null females have ovaries but no uterus or oviducts. A chimera assay places the requirement inside the duct epithelium itself rather than in surrounding tissue.

Species

Mouse

Genotype

Lim1 (Lhx1) null; Lim1 lacZ knock-in allele used for expression mapping, with a female chimera assay for cell autonomy

Genes

LHX1 hgnc:6593

Publication

PMID:14695376

Pathograph links

Failure of Müllerian Duct Epithelial Proliferation and Elongation recapitulates fidelity: moderate observes: cellular The chimera assay is the part that matters for this node: in a mosaic female, Lim1-null cells fail to contribute to Müllerian duct epithelium while wild-type cells in the same animal do, so the requirement is cell-autonomous within the epithelium and not a secondary consequence of the kidney or Wolffian duct phenotype.

Limitations: This is a germline null, so the reproductive-tract defect sits alongside severe head and kidney phenotypes and the animal is not a model of the human syndrome as a whole. More importantly, the human evidence runs the other way: LHX1 sequence variants have not been found in larger patient cohorts, so this model grounds a mechanism that in patients is reached through 17q12 deletion rather than through LHX1 point mutation, and the entry types the gene DISPUTED for that reason.

Readouts

Müllerian duct epithelium formation by Lim1-null cells in chimeras

Contribution of Lim1-null versus wild-type cells to Müllerian duct epithelium in female mouse chimeras.

Direction: ABOLISHED

Interpretation: Cell-autonomous failure localizes the defect to the epithelium this node names, which no whole-animal knockout can show on its own.

Show evidence (1 reference)

PMID:14695376 SUPPORT Model Organism

"A novel female mouse chimera assay was developed and revealed that Lim1 is required cell autonomously for Müllerian duct epithelium formation."

Reports the chimera measurement and its cell-autonomy conclusion.

Show evidence (1 reference)

PMID:14695376 SUPPORT Model Organism

"These studies demonstrate an essential role for Lim1 in female reproductive tract development."

Supports treating this model as informative for the duct-epithelium node.

Müllerian Duct Aplasia recapitulates fidelity: moderate observes: tissue Absence of uterus and oviducts in an otherwise female neonate is the tissue-level lesion this node names, arrived at from a single transcription-factor loss.

Limitations: The mouse loses the duct derivatives outright, whereas most patients retain rudimentary uterine buds — the remnants that carry the cyclic-pain arm of the human disease. The model is therefore informative about how the structure fails to form and silent about what survives. The vaginal boundary is also not addressed: the characteristic human finding is a blind pouch of urogenital-sinus origin, which this report does not assess.

Readouts

Presence of uterus and oviducts at birth

Gross anatomy of the female reproductive tract in Lim1-null neonates.

Direction: ABOLISHED

Interpretation: Loss confined to the duct derivatives, with the ovary present in the same animal.

Show evidence (1 reference)

PMID:14695376 SUPPORT Model Organism

"Although female Lim1-null neonates had ovaries they lacked a uterus and oviducts."

Reports the anatomical measurement behind this readout.

Show evidence (1 reference)

PMID:14695376 SUPPORT Model Organism

"These studies demonstrate an essential role for Lim1 in female reproductive tract development."

Supports treating this model as informative for the duct-aplasia node.

Cited in this entry's `genetic:` section through a review (PMID:38699388); the primary report is used here so the model's genotype, assay and readouts are attributable to the study that performed them.

Show evidence (2 references)

PMID:14695376 SUPPORT Model Organism

"Although female Lim1-null neonates had ovaries they lacked a uterus and oviducts."

The defining result of the model, and the reason it is curated here.

PMID:14695376 SUPPORT Model Organism

"the epithelium of the developing Müllerian duct that gives rise to the oviduct, uterus and upper region of the vagina of the female reproductive tract"

Establishes that Lim1 is expressed in the tissue whose failure this entry models, and names the derivatives lost.

{ }

Source YAML

click to show

name: Mayer-Rokitansky-Kuster-Hauser_Syndrome
creation_date: '2026-09-07T18:00:00Z'
category: Congenital
synonyms:
- MRKH
- MRKH syndrome
- Mayer-Rokitansky-Küster-Hauser syndrome
- Rokitansky syndrome
- Müllerian aplasia
- Müllerian agenesis
- congenital absence of the uterus and vagina
- vaginal agenesis
- MURCS association
description: >-
  Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is congenital aplasia of the
  uterus, cervix and upper two-thirds of the vagina in a person with a 46,XX
  karyotype, normal external genitalia and normal ovarian endocrine function.
  The lesion is developmental and prenatal: the paramesonephric (Müllerian)
  ducts either never form or fail to elongate and fuse between about the fifth
  and eighth week of gestation, so the structures they would have produced are
  absent at birth and there is no postnatal disease process at all. What the
  patient experiences is the consequence of an event that finished before
  birth.

  Mechanistically the entry is built around a single distinction that explains
  most of the clinical picture: the Müllerian ducts and the ovaries have
  different embryonic origins. The ducts arise from the intermediate mesoderm
  of the urogenital ridge; the ovary arises from the gonadal ridge and is
  spared. Ovarian steroidogenesis is therefore normal, puberty proceeds
  normally, and the only presenting sign is primary amenorrhea — which is why
  the diagnosis is characteristically made in adolescence rather than at birth.
  The same sparing has a second, less obvious consequence: endometrium retained
  inside a rudimentary uterine bud is exposed to normal cyclic ovarian steroids,
  so it cycles, and in a closed remnant that produces catamenial pain,
  haematometra and a strikingly elevated risk of endometriosis.

  The shared intermediate-mesoderm origin also explains the extragenital
  anomalies that define type II (MURCS). The nephric duct and the Müllerian
  duct develop side by side under an overlapping transcriptional program, so
  the genes implicated in MRKH syndrome — GREB1L, PAX8, HNF1B, LHX1 — are the
  genes of kidney development, and roughly a third of patients have a renal
  malformation. TBX6, at the recurrently deleted 16p11.2 locus, sits instead in
  paraxial mesoderm and somite patterning, which is the axial-skeletal arm of
  the same story.

  The entry is deliberately honest about how little of the etiology is settled.
  Recurrent copy-number variants account for about 10% of patients; GREB1L and
  PAX8 have segregating-pedigree and cohort-enrichment evidence and are curated
  as causative; most other candidates are not. Sporadic occurrence dominates
  and monozygotic twins are repeatedly discordant, so a purely germline
  monogenic account cannot be complete, and the alternative (somatic, mosaic,
  epigenetic or environmental) is curated as an ALTERNATIVE hypothesis rather
  than dismissed. The historical anti-Müllerian hormone overexpression
  hypothesis is retained as DEPRECATED with the negative evidence attached,
  because it is the one etiological question the field has actually closed.
disease_term:
  preferred_term: Mayer-Rokitansky-Küster-Hauser syndrome
  term:
    id: MONDO:0017771
    label: Mayer-Rokitansky-Kuster-Hauser syndrome
parents:
- Müllerian duct anomaly
- 46,XX disorder of sex development
- congenital genitourinary malformation
has_subtypes:
- name: Type 1
  display_name: Type 1 (isolated uterovaginal aplasia)
  subtype_term:
    preferred_term: MRKH syndrome type 1
    term:
      id: MONDO:0010173
      label: Mayer-Rokitansky-Kuster-Hauser syndrome type 1
  description: >-
    Uterovaginal aplasia with no extragenital malformation. This is the form the
    four original describing authors reported, and the more common of the two.
    Rudimentary uterine buds on the pelvic sidewalls, joined by a midline
    fibrous band, are the typical anatomy.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRKH syndrome may present as an isolated anomaly (type I) or in
      association with extragenital malformations (type II), typically involving
      the kidneys, skeleton, and heart
    explanation: >-
      States the two-way clinical classification that these subtypes encode.
- name: Type 2
  display_name: Type 2 (with extragenital malformations; MURCS association)
  subtype_term:
    preferred_term: MRKH syndrome type 2
    term:
      id: MONDO:0010989
      label: Mayer-Rokitansky-Küster-Hauser syndrome type 2
  description: >-
    Uterovaginal aplasia together with at least one extragenital malformation —
    most often renal, next most often axial skeletal, and less commonly cardiac
    or auditory. The MURCS acronym (Müllerian duct aplasia, renal aplasia,
    cervicothoracic somite dysplasia) names the severe end of this subtype and
    is subsumed within it rather than being curated separately. Complete absence
    of one Müllerian duct with ipsilateral renal agenesis is the characteristic
    anatomy, which is the anatomical signature of a shared lineage failure
    rather than of two independent malformations.
  genes:
  - preferred_term: GREB1L
    term:
      id: hgnc:31042
      label: GREB1L
  - preferred_term: HNF1B
    term:
      id: hgnc:11630
      label: HNF1B
  evidence:
  - reference: PMID:27609979
    reference_title: "Prevalence and patient characteristics of Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide registry-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Typical MRKH syndrome and atypical MRKH syndrome/Müllerian duct aplasia,
      Renal aplasia, and Cervicothoracic Somite dysplasia association were
      present in 56.5% and 43.5% of the patients, respectively.
    explanation: >-
      Nationwide registry-validated cohort quantifying the type 1 / type 2 split
      and naming MURCS as part of the type 2 group.
inheritance:
- name: Sporadic
  inheritance_term:
    preferred_term: Sporadic occurrence
    term:
      id: HP:0003745
      label: Sporadic
  description: >-
    Most cases occur with no family history of MRKH syndrome or of the
    associated renal and uterovaginal anomalies, and monozygotic twin pairs
    discordant for the syndrome have been reported repeatedly. Sporadic
    occurrence is therefore the rule rather than the exception. It is important
    not to read this as evidence against a genetic cause: absolute uterine
    factor infertility blocks mother-to-daughter transmission, so a dominant
    allele cannot accumulate in pedigrees the way it would in a fertile
    disorder, and the familial signal is structurally suppressed.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      several reports of discordant monozygotic twin pairs
    explanation: >-
      Monozygotic discordance is the observation that most directly supports
      non-inherited causation in at least some patients.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the disease nature of MRKH syndrome implies absolute infertility,
      hindering mother-to-offspring inheritance of a genetic cause, which may
      cause an underestimation of the genetic component of MRKH syndrome from
      family histories
    explanation: >-
      Supports the caveat that apparent sporadicity is partly an artefact of the
      disease blocking its own vertical transmission.
- name: Autosomal dominant with incomplete penetrance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    In the minority of families with recurrence, the pattern is autosomal
    dominant with incomplete penetrance and sex-limited expressivity: male
    carriers may show isolated renal agenesis, or nothing, while female carriers
    may show uterovaginal aplasia, an isolated renal anomaly, or no phenotype at
    all. This is the pattern the older literature called hereditary urogenital
    adysplasia, and GREB1L is the gene that has since been shown to segregate in
    it. Sex-limited expressivity has also been demonstrated directly for PAX8,
    where paternal transmission was confirmed in three cases.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing analysis in this family identified a segregating
      missense variant in GREB1L, supporting GREB1L variants as a novel
      monogenic cause of MRKH syndrome associated with incomplete penetrance and
      sex-limited expressivity
    explanation: >-
      Three-generation pedigree evidence for the dominant, incompletely
      penetrant, sex-limited pattern this block records.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In three cases with available parental DNA, paternal inheritance was
      confirmed, showing a sex-limited expressivity of infertility.
    explanation: >-
      Independent demonstration of sex-limited expressivity, at a second locus.
mechanistic_hypotheses:
- hypothesis_group_id: md_developmental_arrest
  hypothesis_label: Failure of paramesonephric duct formation, elongation or fusion between weeks 5 and 8
  status: CANONICAL
  description: >-
    The accepted account, and the only one that is not in dispute. The
    paramesonephric ducts form at about the fifth week as bilateral
    invaginations of the coelomic epithelium of the urogenital ridge, elongate
    caudally along the Wolffian ducts to reach the urogenital sinus, and from
    week 8 fuse caudally to build the uterus, cervix and upper vagina. MRKH
    syndrome is the failure of that sequence — either the ducts never form, or
    they form and do not complete elongation and fusion. Everything downstream
    is anatomical absence rather than tissue damage, which is why the syndrome
    has no progressive course and no active lesion to treat.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 5 weeks post gestation, bilateral invaginations of the coelomic
      epithelium of the urogenital ridges begin to form the MDs which extend
      caudally, guided by the Wolffian ducts, to reach the urogenital sinus in
      the midline
    explanation: >-
      Establishes the normal developmental sequence and its timing, which is the
      process this hypothesis says fails.
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Müllerian agenesis is caused by embryologic underdevelopment of the
      müllerian duct, with resultant agenesis or atresia of the vagina, uterus,
      or both.
    explanation: >-
      Professional-society statement of the same causal claim.
- hypothesis_group_id: mesodermal_transcriptional_program
  hypothesis_label: Heterogeneous monogenic loss of a shared intermediate/paraxial mesoderm transcriptional program
  status: EMERGING
  description: >-
    The genetic account with the strongest current support. Rather than one MRKH
    gene, a set of transcriptional regulators of intermediate and paraxial
    mesoderm — GREB1L, PAX8, HNF1B, LHX1, TBX6 — each account for a small share
    of patients, with the same haploinsufficiency-like dosage logic and the same
    dominant, incompletely penetrant, sex-limited pattern. The hypothesis
    predicts the observed comorbidity structure directly: these are kidney
    development genes, so type II with renal malformation is what a lesion in
    them looks like, and TBX6 in paraxial mesoderm is the axial-skeletal arm.
    It is curated EMERGING rather than CANONICAL because recurrent copy-number
    variants explain only about 10% of patients and the sequence-variant genes
    together explain a further minority, so the program is demonstrated but
    nowhere near complete.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, genes involved in the development of mesoderm and its derived
      structures are relevant candidates in the etiology of MRKH syndrome.
    explanation: >-
      States the lineage-based reasoning on which this hypothesis rests.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      epidemiological evidence of rare variant enrichment in larger cohorts, and
      functional evidence from knock-out mice, suggest GREB1L as a major
      causative gene in MRKH syndrome.
    explanation: >-
      The single best-supported gene in the program, with pedigree, cohort and
      mouse evidence converging.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, recurrent chromosomal imbalances in MRKH syndrome still only
      apply to a minor fraction of patients (around 10%).
    explanation: >-
      Bounds how much of the disease this program currently explains, which is
      why the hypothesis is EMERGING rather than CANONICAL. Cited as indirect
      because it quantifies the CNV share specifically, not the whole program.
- hypothesis_group_id: nonmendelian_somatic_or_environmental
  hypothesis_label: Somatic, mosaic, epigenetic or environmental disruption of duct development
  status: ALTERNATIVE
  description: >-
    A germline-monogenic account cannot cover the disease as observed:
    occurrence is overwhelmingly sporadic, monozygotic twins are repeatedly
    discordant, and recurrence after surrogate pregnancy has generally not been
    seen. Those observations are what a post-zygotic somatic or mosaic variant,
    a tissue-restricted epigenetic change, or an environmental insult during the
    fifth-to-eighth week would predict. Investigators have accordingly looked
    for somatic variation and differential methylation in surgically removed
    uterine remnants. The hypothesis is curated ALTERNATIVE rather than
    EMERGING because it is so far supported by the pattern of inheritance
    failing to fit, not by a positive finding: reported epigenetic results have
    been inconsistent, and no environmental exposure has firm evidence.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most cases of MRKH syndrome appear isolated with no clear indications of a
      familial/genetic trait (5, 30). In addition, several reports of discordant
      monozygotic twin pairs (5, 31–35) and patient-reported outcomes of most
      surrogate pregnancies also support non-Mendelian causes
    explanation: >-
      The inheritance-pattern argument for this hypothesis. Indirect because it
      argues from the absence of a Mendelian signal rather than from a
      demonstrated somatic or environmental lesion.
  - reference: PMID:41616459
    reference_title: "The genetic background of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: A systematic review."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Findings on epigenetic regulation show variability, with no consistent
      patterns of specific gene upregulation or downregulation.
    explanation: >-
      A 97-study systematic review finds no reproducible epigenetic signature,
      which counts against the epigenetic arm of this hypothesis specifically
      and is the reason it is not curated as EMERGING.
- hypothesis_group_id: amh_overexpression
  hypothesis_label: Ectopic anti-Müllerian hormone or AMHR2 activity drives Müllerian regression in a 46,XX fetus
  status: DEPRECATED
  description: >-
    The first serious etiological hypothesis, and the one question in MRKH
    syndrome that the field has actually closed. Because anti-Müllerian hormone
    physiologically regresses the Müllerian ducts in male embryos, ectopic AMH
    activity or an activating receptor change was an obvious candidate for
    Müllerian absence in a 46,XX fetus. Candidate-gene studies of AMH and AMHR2
    did not support it, and it is retained here as DEPRECATED — with the
    negative evidence attached — rather than deleted, because it is what
    distinguishes MRKH syndrome mechanistically from the 46,XY differential
    diagnoses in which absent Müllerian structures really are AMH-driven.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most of these studies had negative results and provided limited evidence
      for genetic factors in MRKH syndrome. This included investigations of AMH
      and AMHR2, encoding anti-Müllerian hormone and its receptor, respectively,
      involved in physiological MD regression in males
    explanation: >-
      Names AMH and AMHR2 among the candidate genes whose investigation returned
      negative results, which is the basis for deprecating this hypothesis.
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    The burden here is almost entirely reproductive and psychological rather
    than one of organ failure or shortened life: ovarian endocrine function is
    intact, puberty is normal, and most patients have no systemic illness. What
    the diagnosis delivers, in adolescence and usually all at once, is
    irreversible absolute uterine factor infertility, a threat to female
    identity, and the prospect of coital difficulty — and measured psychological
    distress is accordingly higher than in comparison women. Against that,
    treatment is effective on its own terms (dilation achieves a functional
    vagina in most patients without surgery) and the reproductive deficit is now
    partly addressable through uterus transplantation and gestational surrogacy,
    which is why this is MODERATE rather than HIGH. The type 2 renal arm can
    raise it for an individual patient; a solitary kidney carries its own
    lifelong surveillance burden that the genital anomaly does not.
  evidence:
  - reference: PMID:32819397
    reference_title: "Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of MRKH syndrome may have profound psychological and/or
      psychosexual impact
    explanation: >-
      States the dimension in which the burden of this syndrome principally
      falls, which is what the MODERATE assessment is weighing.
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The psychologic effect of the diagnosis of müllerian agenesis should not
      be underestimated. All patients with müllerian agenesis should be offered
      counseling and encouraged to connect with peer support groups.
    explanation: >-
      A professional society treats the psychological consequence as a routine
      part of the disease burden requiring its own management, not as an
      occasional complication.
  notes: >-
    Deliberately assessed at the level of the disease concept. Individual
    phenotypes carry their own severity: catamenial pain from a functional
    uterine remnant and the renal anomalies of type 2 are the two components
    that most often move an individual patient's burden above this.
pathophysiology:
- name: Loss of Mesodermal Developmental Transcription Factor Dosage
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    In the genetically explained minority of patients, the initiating lesion is
    reduced dosage or activity of a transcriptional regulator of intermediate
    and paraxial mesoderm. The recurrently deleted 17q12 interval removes both
    LHX1 and HNF1B; 16p11.2 removes TBX6; sequence variants have been reported
    in GREB1L, PAX8, HNF1B, LHX1 and TBX6. These are not a pathway in the
    signalling sense but a set of regulators acting on the same embryonic
    lineage, which is why loss of any one of them can reach the same anatomical
    endpoint. GREB1L is thought to act in retinoic acid signalling, though its
    protein is poorly characterised, and for the monoallelic missense variants
    that dominate the human reports the molecular consequence is still unknown.
  genes:
  - preferred_term: GREB1L
    term:
      id: hgnc:31042
      label: GREB1L
  - preferred_term: PAX8
    term:
      id: hgnc:8622
      label: PAX8
  - preferred_term: HNF1B
    term:
      id: hgnc:11630
      label: HNF1B
  - preferred_term: LHX1
    term:
      id: hgnc:6593
      label: LHX1
  - preferred_term: TBX6
    term:
      id: hgnc:11605
      label: TBX6
  molecular_functions:
  - preferred_term: developmental transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: transcriptional control of urogenital and somitic development
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: DECREASED
  - preferred_term: retinoic acid signalling (GREB1L)
    term:
      id: GO:0048384
      label: retinoic acid receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two candidate genes for MRKH syndrome, LHX1 and HNF1B, are located at this
      locus, both of them being involved in MD development.
    explanation: >-
      Identifies the two developmental regulators removed by the commonest
      recurrent deletion in this disease.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      GREB1L is considered to be involved in retinoic acid signaling, although
      its protein remains poorly characterized
    explanation: >-
      Basis for the retinoic acid signalling annotation on this node, and for
      hedging it.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the pathogenic mechanism of how these missense variants cause MRKH
      syndrome is still unknown requiring further functional analysis
    explanation: >-
      States explicitly that the molecular step between a GREB1L missense
      variant and this node is not established.
  downstream:
  - target: Failure of Müllerian Duct Epithelial Proliferation and Elongation
    causal_link_type: DIRECT
    hypothesis_groups:
    - mesodermal_transcriptional_program
    description: >-
      Reduced regulator dosage in the urogenital ridge epithelium is what the
      mouse models translate into a duct that does not elongate.
  - target: Shared Intermediate Mesoderm Lineage Failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - mesodermal_transcriptional_program
    description: >-
      The same regulators drive nephric duct and kidney development, so a single
      lesion reaches both organ systems.
  - target: Paraxial Mesoderm and Somite Patterning Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mesodermal_transcriptional_program
    description: >-
      TBX6 acts in paraxial mesoderm rather than in the duct, which is the
      lineage route to the axial skeletal anomalies of MURCS. Drawn as indirect
      because no mechanism has been established for monoallelic TBX6 variants in
      this disease.
- name: Failure of Müllerian Duct Epithelial Proliferation and Elongation
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    The cellular step. The Müllerian duct is an epithelial tube that must
    proliferate, migrate caudally along the Wolffian duct and differentiate on a
    fixed schedule. Conditional ablation of Hnf1b in Müllerian duct epithelium
    in mice produces a hypoplastic uterus with renal anomalies — an MRKH type II
    phenocopy — and single-cell RNA sequencing of the ablated embryonic uterus
    shows dysregulation of proliferation, migration and differentiation
    programmes rather than one discrete pathway. Lhx1-null females likewise lack
    a reproductive tract through a failure of duct elongation and epithelium
    formation, with normal ovaries, which is exactly the human dissociation.
  locations:
  - preferred_term: Müllerian duct epithelium
    term:
      id: UBERON:0003890
      label: Mullerian duct
  biological_processes:
  - preferred_term: paramesonephric duct development
    term:
      id: GO:0061205
      label: paramesonephric duct development
    modifier: DECREASED
  - preferred_term: epithelial cell proliferation
    term:
      id: GO:0050673
      label: epithelial cell proliferation
    modifier: DECREASED
  - preferred_term: epithelial cell migration
    term:
      id: GO:0010631
      label: epithelial cell migration
    modifier: DECREASED
  - preferred_term: epithelial cell differentiation
    term:
      id: GO:0030855
      label: epithelial cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:36282544
    reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We ablated Hnf1b specifically in the epithelium of the Müllerian ducts in
      mice and found that this caused hypoplastic development of the uterus, as
      well as kidney anomalies, closely mirroring the MRKH type II phenotype.
    explanation: >-
      Places the lesion in Müllerian duct epithelium specifically, and shows it
      reproduces the human type II combination.
  - reference: PMID:36282544
    reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using single-cell RNA sequencing of uterine tissue in the Hnf1b-ablated
      embryos, we analyzed the molecules and pathways downstream of Hnf1b,
      revealing a dysregulation of processes associated with cell proliferation,
      migration and differentiation.
    explanation: >-
      Direct basis for the three cellular processes annotated on this node.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Lhx1-null female mice have normal ovaries but lack their reproductive
      tract, which results from a disruption of MD elongation and epithelium
      formation
    explanation: >-
      Second gene reaching the same cellular failure, and the model that
      reproduces the ovary-spared dissociation seen in patients.
  downstream:
  - target: Müllerian Duct Aplasia
    causal_link_type: DIRECT
    description: >-
      An epithelial tube that does not elongate or differentiate leaves no
      structure behind.
- name: Müllerian Duct Aplasia
  biological_scale: TISSUE
  role: central_effector
  description: >-
    The defining lesion: the paramesonephric ducts are absent or aplastic, so
    the uterus, cervix and upper two-thirds of the vagina are never built. The
    lower vagina, which derives from the urogenital sinus rather than from the
    ducts, is present — which is why the anatomy is a short blind-ending pouch
    rather than complete vaginal absence. The Fallopian tubes, also
    duct-derived, are correspondingly rudimentary or absent, and their absence
    is thought to explain the characteristically lateral, more cranial position
    of the ovaries.
  locations:
  - preferred_term: Müllerian duct
    term:
      id: UBERON:0003890
      label: Mullerian duct
  biological_processes:
  - preferred_term: paramesonephric duct development
    term:
      id: GO:0061205
      label: paramesonephric duct development
    modifier: ABSENT
  - preferred_term: uterus development
    term:
      id: GO:0060065
      label: uterus development
    modifier: DECREASED
  - preferred_term: vagina development
    term:
      id: GO:0060068
      label: vagina development
    modifier: DECREASED
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also referred to as
      Müllerian aplasia, is a congenital disorder characterized by agenesis or
      aplasia of the uterus and upper part of the vagina.
    explanation: >-
      States the lesion this node represents and its anatomical extent.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, the caudal parts of the two MDs start to fuse to form the uterus and
      upper vagina starting from week 8.
    explanation: >-
      Establishes which structures are duct-derived, and therefore which are
      lost and which are spared.
  downstream:
  - target: Uterovaginal Aplasia with Rudimentary Uterine Buds
    causal_link_type: DIRECT
    description: >-
      What is left in the pelvis when the ducts fail is typically a pair of
      aplastic buds on the sidewalls joined by a midline fibrous band.
  - target: Cervical and Upper Vaginal Atresia with a Blind Vaginal Pouch
    causal_link_type: DIRECT
    description: >-
      The caudal, fusion-dependent segment of the duct is the cervix and upper
      vagina, so its absence leaves the sinus-derived lower vagina ending
      blindly.
- name: Uterovaginal Aplasia with Rudimentary Uterine Buds
  biological_scale: TISSUE
  role: effector
  description: >-
    The realised pelvic anatomy. Bilateral rudimentary or aplastic uterine horns
    are found in the large majority of patients — 84% of a systematically
    imaged and laparoscoped cohort of 284 — and uterine remnants of some kind
    are reported across a wide range of series. The buds are not inert: they
    contain myometrium, which can give rise to leiomyomas, and a variable
    proportion contain endometrium, which is the origin of the syndrome's only
    genuinely active pathology.
  locations:
  - preferred_term: uterus
    term:
      id: UBERON:0000995
      label: uterus
  evidence:
  - reference: PMID:22906151
    reference_title: "Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete atresia of Vagina (V5b) and bilateral atresia of Cervix (C2b)
      were found in 284 patients (100%).
    explanation: >-
      Establishes that cervical and vaginal atresia are invariant in this
      cohort, unlike the uterine and adnexal findings which vary.
  - reference: PMID:32819397
    reference_title: "Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Presence of uterine remnants have been reported in 48 – 95% of the
      patients
    explanation: >-
      Quantifies how commonly remnant tissue is present, and how widely the
      reported range varies between series.
  downstream:
  - target: Absolute Uterine Factor Infertility
    causal_link_type: DIRECT
    description: >-
      A rudimentary bud cannot implant an embryo or carry a pregnancy.
  - target: Primary amenorrhea
    causal_link_type: DIRECT
    description: >-
      There is no functional endometrial cavity with an outflow tract, so no
      menses occur despite normal ovarian cycling.
  - target: Aplasia of the uterus
    causal_link_type: DIRECT
    description: >-
      The imaging and operative finding that corresponds to this node.
  - target: Uterine leiomyoma in rudimentary uterine buds
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The buds retain myometrium, so the usual leiomyoma biology remains
      available to them; subserosal leiomyomas on the uterine buds are a
      described operative finding.
  - target: Retained Cycling Endometrium in Uterine Remnants
    causal_link_type: DIRECT
    description: >-
      Endometrium present within a bud is the substrate for the syndrome's
      cyclic pathology.
- name: Cervical and Upper Vaginal Atresia with a Blind Vaginal Pouch
  biological_scale: TISSUE
  role: effector
  description: >-
    Loss of the fused caudal duct segment leaves no cervix and no upper vagina.
    The urogenital-sinus-derived lower vagina persists as a short blind pouch,
    typically 0 to 3 cm deep with no cervix at its apex. This is the finding
    that makes the syndrome amenable to non-surgical treatment: a pouch lined
    with normal vaginal mucosa can be progressively elongated, whereas complete
    absence could not be.
  locations:
  - preferred_term: vagina
    term:
      id: UBERON:0000996
      label: vagina
  evidence:
  - reference: PMID:22906151
    reference_title: "Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete atresia of Vagina (V5b) and bilateral atresia of Cervix (C2b)
      were found in 284 patients (100%).
    explanation: >-
      Documents cervical and vaginal atresia in every classifiable patient of a
      284-woman cohort evaluated by examination, ultrasound, MRI and laparoscopy.
  downstream:
  - target: Blind-ending vagina
    causal_link_type: DIRECT
    description: >-
      The direct anatomical expression of this node on examination.
  - target: Dyspareunia
    causal_link_type: DIRECT
    description: >-
      A shortened pouch is the anatomical basis of apareunia and dyspareunia
      before treatment.
- name: Spared Gonadal Ridge Lineage with Normal Ovarian Steroidogenesis
  biological_scale: ORGANISM
  role: mediator
  description: >-
    The ovaries do not derive from the Müllerian ducts, so the lesion does not
    touch them: adnexa are normal in the large majority of patients, and
    gonadotropins, estradiol and androgens are in the normal female range. Two
    consequences follow, and between them they account for most of how the
    syndrome presents. First, puberty is normal — thelarche, pubarche and growth
    all proceed — so nothing is apparent until menses fail to arrive, which is
    why the median age at referral is in the late teens rather than at birth.
    Second, any endometrium retained in a uterine bud is exposed to ordinary
    cyclic ovarian steroids and therefore cycles. This node is included as a
    mechanistic mediator rather than as an incidental normal finding precisely
    because that second consequence is what generates the cyclic pain,
    haematometra and endometriosis arm of the disease.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients are characterized by having a normal female karyotype
      (46,XX), normal external genitalia, and normal pubertal development of
      secondary sex characteristics (thelarche and pubarche)
    explanation: >-
      Normal pubertal development is the clinical read-out of preserved ovarian
      endocrine function.
  - reference: PMID:22906151
    reference_title: "Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adnexa: normal Adnexa were found in 248 women (87.3%).
    explanation: >-
      Quantifies adnexal sparing in a systematically evaluated cohort, and shows
      it is high but not universal.
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with müllerian agenesis usually are identified when they are
      evaluated for primary amenorrhea with otherwise typical growth and
      pubertal development.
    explanation: >-
      States the presentation that follows from ovarian sparing: an isolated
      outflow failure against a normal endocrine background.
  downstream:
  - target: Retained Cycling Endometrium in Uterine Remnants
    causal_link_type: DIRECT
    description: >-
      Cyclic ovarian steroid output is what drives proliferation and shedding in
      remnant endometrium; without it the remnants would be quiescent.
- name: Retained Cycling Endometrium in Uterine Remnants
  biological_scale: TISSUE
  role: amplifier
  description: >-
    Where a rudimentary bud contains functional endometrium and has no outflow
    tract, that endometrium proliferates and sheds into a closed cavity. The
    clinical result is catamenial abdominal pain and, when enough blood
    accumulates, haematometra. The same cryptic menstruation is the best
    available explanation for endometriosis in a woman with no uterus: a
    systematic review and meta-analysis of 666 patients in whom the presence or
    absence of functional endometrium was actually verified found endometriosis
    in 32.0% of those with functional endometrium versus 1.5% of those without,
    an odds ratio of 12.0. That is a strong argument for retrograde
    menstruation from the remnant, and it is worth noting for what it does to a
    long-standing objection: MRKH syndrome has often been cited as a case of
    endometriosis without menstruation, and once functional endometrium is
    ascertained rather than assumed absent, most of the cases turn out to have a
    menstruating source. The residual 1.5% is not explained by this mechanism.
  locations:
  - preferred_term: uterus
    term:
      id: UBERON:0000995
      label: uterus
  evidence:
  - reference: PMID:40246293
    reference_title: "Prevalence of endometriosis in Mayer-Rokitansky-Küster-Hauser syndrome variants: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proportion of patients with endometriosis was 32.0% in the subgroup
      with FE (64/200; 95% CI, 25.9-38.8%) and 1.5% (7/466; 95% CI, 0.7-3.1%) in
      the subgroup without FE within UR/without UR.
    explanation: >-
      The quantitative contrast on which this node rests: endometriosis tracks
      the presence of functional endometrium in a remnant, not the syndrome
      itself.
  - reference: PMID:40246293
    reference_title: "Prevalence of endometriosis in Mayer-Rokitansky-Küster-Hauser syndrome variants: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A significantly increased risk of endometriosis was observed in MRKHSFE+
      patients compared with MRKHSFE- patients (overall odds ratio estimate was
      12.0; 95% CI, 5.1-28.3%).
    explanation: >-
      Meta-analytic effect size for the same association.
  - reference: PMID:40246293
    reference_title: "Prevalence of endometriosis in Mayer-Rokitansky-Küster-Hauser syndrome variants: a systematic review and meta-analysis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 71 MRKHS patients with endometriosis, 64 had coexisting FE, and
      only seven had no evidence of FE within UR or did not have UR.
    explanation: >-
      Seven patients had endometriosis with no demonstrable functional
      endometrium and no remnant, so retrograde menstruation from a remnant
      cannot be the whole account of endometriosis in this syndrome.
  downstream:
  - target: Cyclic abdominal pain
    causal_link_type: DIRECT
    description: >-
      Shedding into an obstructed remnant cavity produces catamenial pain.
  - target: Endometriosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Retrograde escape of shed remnant endometrium into the peritoneal cavity,
      followed by implantation, is the intermediate step.
- name: Shared Intermediate Mesoderm Lineage Failure
  biological_scale: TISSUE
  role: consequence
  description: >-
    The renal arm of type II, and the strongest structural argument that MRKH
    syndrome is a lineage disorder rather than an organ-specific one. The
    nephric duct and the Müllerian duct develop side by side out of the
    intermediate mesoderm, the Müllerian duct elongates guided by the Wolffian
    duct, and the transcriptional regulators implicated in the syndrome are the
    regulators of kidney development. Around 30% of patients accordingly have a
    renal malformation, unilateral renal agenesis being about half of those.
    The clinching detail is laterality: absence of one Müllerian duct is often
    accompanied by absence of the ipsilateral kidney, which is what a single
    unilateral lineage failure predicts and what two independent malformations
    would not.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  biological_processes:
  - preferred_term: intermediate mesoderm development
    term:
      id: GO:0048389
      label: intermediate mesoderm development
    modifier: ABNORMAL
  - preferred_term: mesonephric duct development
    term:
      id: GO:0072177
      label: mesonephric duct development
    modifier: ABNORMAL
  - preferred_term: kidney development
    term:
      id: GO:0001822
      label: kidney development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The close relationship between kidney and uterovaginal development is also
      reflected by the high prevalence (~30%) of kidney malformations in MRKH
      syndrome
    explanation: >-
      States the shared-lineage inference and the frequency that motivates it.
  - reference: PMID:27609979
    reference_title: "Prevalence and patient characteristics of Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide registry-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Kidney malformations were the most prevalent extragenital malformations,
      described in 38 of 111 patients (34.2%).
    explanation: >-
      Population-based figure for the renal arm; note that the same study
      reports a third of its cohort had no urinary tract imaging at all, so this
      is a floor rather than a point estimate.
  - reference: PMID:36282544
    reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, we establish that loss of Hnf1b function leads to an MRKH phenotype
      and generate the first mouse model of MRKH syndrome type II.
    explanation: >-
      A single-gene lesion producing the combined uterine and renal phenotype is
      what a shared lineage failure predicts.
  downstream:
  - target: Unilateral renal agenesis
    causal_link_type: DIRECT
    description: >-
      The commonest single renal malformation, and typically ipsilateral to the
      absent Müllerian duct.
  - target: Ectopic kidney
    causal_link_type: DIRECT
    description: >-
      Failure of normal ascent and positioning within the same lineage.
  - target: Horseshoe kidney
    causal_link_type: DIRECT
    description: >-
      Midline fusion anomaly reported in the same cohorts.
  - target: Duplicated collecting system
    causal_link_type: DIRECT
    description: >-
      Nephric-duct-derived collecting system anomaly in the same lineage.
- name: Paraxial Mesoderm and Somite Patterning Failure
  biological_scale: TISSUE
  role: consequence
  description: >-
    The skeletal arm of type II, and the reason the MURCS acronym names
    cervicothoracic somite dysplasia alongside Müllerian and renal aplasia.
    Paraxial mesoderm forms the axial skeleton, TBX6 patterns it, and the
    16p11.2 deletion that removes TBX6 is one of the recurrent copy-number
    variants in this syndrome — the same locus is independently associated with
    congenital scoliosis. Skeletal anomalies are the second most frequent
    extragenital finding and involve the axial skeleton preferentially. This
    node is nonetheless the weakest link in the entry's causal chain: the
    scoliosis association at this locus follows a compound inheritance dosage
    model requiring a second hypomorphic allele, no such second allele has been
    found in MRKH syndrome, and no biological mechanism has been established for
    the monoallelic TBX6 variants reported here.
  biological_processes:
  - preferred_term: paraxial mesoderm development
    term:
      id: GO:0048339
      label: paraxial mesoderm development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common extragenital anomalies include the skeleton and heart, which
      do also develop from the mesoderm, with the paraxial mesoderm forming the
      axial skeleton
    explanation: >-
      Establishes the paraxial mesoderm as the lineage linking this syndrome to
      axial skeletal anomalies.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As of now, no clear biological mechanism for monoallelic TBX6 variants
      causing MRKH syndrome has been established, which challenges
      interpretation and warrants further studies.
    explanation: >-
      Directly contradicts a confident mechanistic reading of this node, and is
      recorded here rather than only in a discussion so the node cannot be
      quoted as settled.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      requiring one TBX6-null allele and a particular hypomorphic trans allele,
      as described in the compound inheritance gene dosage model
    explanation: >-
      The genetic architecture established for TBX6 in congenital scoliosis;
      indirect here because it describes the scoliosis phenotype, and the second
      risk allele it requires has not been found in MRKH syndrome.
  downstream:
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Axial patterning failure expressed as a curvature deformity.
  - target: Cervical vertebral fusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Segmentation failure of the cervicothoracic somites, the Klippel-Feil end
      of the MURCS phenotype.
  - target: Hemivertebrae
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Failure of formation of one half of a vertebral body from a somite.
- name: Absolute Uterine Factor Infertility
  biological_scale: ORGANISM
  role: outcome
  description: >-
    The terminal consequence, and the one that defines the therapeutic problem.
    Absolute uterine factor infertility is infertility from anatomical absence
    of a uterus or presence of a non-functional one; MRKH syndrome is its
    congenital form, alongside acquired causes such as hysterectomy for
    malignancy or obstetric haemorrhage. Ovarian function being intact, the
    gametes are available and the deficit is purely gestational — which is
    precisely why uterus transplantation works here and why it was first
    performed in this disease.
  evidence:
  - reference: PMID:25301505
    reference_title: "Livebirth after uterus transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Uterus transplantation is the first available treatment for absolute
      uterine infertility, which is caused by absence of the uterus or the
      presence of a non-functional uterus.
    explanation: >-
      Defines the condition this node names and situates MRKH syndrome within it.
  downstream:
  - target: Female infertility
    causal_link_type: DIRECT
    description: >-
      The clinical phenotype corresponding to this node.
phenotypes:
- category: Reproductive
  name: Primary amenorrhea
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  diagnostic: true
  frequency: obligate
  description: >-
    The presenting sign in almost every case, and an outflow-tract amenorrhea
    rather than an endocrine one: gonadotropins and estradiol are normal and the
    ovarian cycle is intact, but there is no endometrial cavity draining to the
    exterior. MRKH syndrome is reported in about 16% of primary amenorrhea,
    making it the second most common cause after ovarian failure.
  evidence:
  - reference: PMID:32819397
    reference_title: "Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRKH syndrome has been reported in ~ 16% of patients with primary
      amenorrhea
    explanation: >-
      Quantifies how large a share of primary amenorrhea this syndrome accounts
      for.
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with müllerian agenesis usually are identified when they are
      evaluated for primary amenorrhea with otherwise typical growth and
      pubertal development.
    explanation: >-
      Establishes primary amenorrhea against normal puberty as the presenting
      pattern.
- category: Reproductive
  name: Aplasia of the uterus
  phenotype_term:
    preferred_term: Aplasia of the uterus
    term:
      id: HP:0000151
      label: Aplasia of the uterus
  diagnostic: true
  frequency: obligate
  description: >-
    Absent or rudimentary uterus on pelvic MRI, which is the diagnostic gold
    standard because it resolves whether uterine buds are present and whether
    they contain endometrium. Bilateral rudimentary or aplastic uterine horns
    were found in 84.2% of a systematically evaluated cohort of 284 women.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also referred to as
      Müllerian aplasia, is a congenital disorder characterized by agenesis or
      aplasia of the uterus and upper part of the vagina.
    explanation: >-
      Uterine aplasia is definitional for the syndrome.
- category: Reproductive
  name: Blind-ending vagina
  phenotype_term:
    preferred_term: Blind vagina
    term:
      id: HP:0040314
      label: Blind vagina
  diagnostic: true
  frequency: obligate
  description: >-
    A short blind-ending vaginal pouch, typically 0 to 3 cm, with no cervix at
    the apex. The lower vagina is present because it derives from the
    urogenital sinus; it is the upper two-thirds and the cervix that are absent.
  evidence:
  - reference: PMID:22906151
    reference_title: "Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete atresia of Vagina (V5b) and bilateral atresia of Cervix (C2b)
      were found in 284 patients (100%).
    explanation: >-
      Vaginal and cervical atresia were present in every classifiable patient of
      this cohort.
- category: Reproductive
  name: Female infertility
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  frequency: obligate
  description: >-
    Absolute uterine factor infertility. Oocytes and ovarian function are
    normal, so the deficit is gestational only — which is what makes both
    gestational surrogacy and uterus transplantation viable routes to genetic
    motherhood.
  evidence:
  - reference: PMID:25301505
    reference_title: "Livebirth after uterus transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Uterus transplantation is the first available treatment for absolute
      uterine infertility, which is caused by absence of the uterus or the
      presence of a non-functional uterus.
    explanation: >-
      Names the infertility category this phenotype belongs to.
- category: Reproductive
  name: Dyspareunia
  phenotype_term:
    preferred_term: Dyspareunia
    term:
      id: HP:0030016
      label: Dyspareunia
  frequency: common before treatment
  description: >-
    Apareunia or dyspareunia from vaginal hypoplasia, and a common presenting
    complaint at referral alongside primary amenorrhea. It is the phenotype
    that vaginal elongation therapy addresses.
  evidence:
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonsurgical vaginal elongation by dilation should be the first-line
      approach. When well-counseled and emotionally prepared, almost all
      patients (90-96%) will be able to achieve anatomic and functional success
      by primary vaginal dilation.
    explanation: >-
      Cited indirectly: the existence and success rate of a treatment aimed at
      anatomic and functional vaginal adequacy evidences the functional deficit
      it treats, rather than reporting dyspareunia frequency directly.
- category: Clinical
  name: Cyclic abdominal pain
  phenotype_term:
    preferred_term: Catamenial abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
    temporality: RECURRENT
  frequency: subset with functional endometrium in a remnant
  description: >-
    Catamenial pain from cyclic shedding of endometrium inside an obstructed
    uterine remnant, which may progress to haematometra. It occurs only in the
    subset of patients whose remnants contain functional endometrium, and it is
    the indication for laparoscopic removal of the remnant. HPO has no
    catamenial or cryptomenorrhoea term, so the phenotype is bound to the coarse
    Abdominal pain term with a RECURRENT temporality qualifier and the cyclic
    character carried in the preferred term.
  evidence:
  - reference: PMID:40246293
    reference_title: "Prevalence of endometriosis in Mayer-Rokitansky-Küster-Hauser syndrome variants: a systematic review and meta-analysis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The recent advent of high-resolution ultrasonography and magnetic
      resonance imaging (MRI) allowed the reliable preoperative identification
      of FE concealed within UR
    explanation: >-
      Establishes that functional endometrium concealed within a uterine remnant
      is a real, now preoperatively detectable entity — the substrate for this
      phenotype. Indirect because it concerns detection of the substrate rather
      than the pain itself.
- category: Reproductive
  name: Endometriosis
  phenotype_term:
    preferred_term: Endometriosis
    term:
      id: HP:0030127
      label: Endometriosis
  frequency: about 32% with functional endometrium in a remnant versus 1.5% without
  description: >-
    Endometriosis in a woman with no uterus, historically cited as a
    counter-example to the retrograde menstruation theory. Once the presence of
    functional endometrium in a uterine remnant is verified rather than assumed,
    the risk separates sharply along that line, which relocates most of the
    phenomenon back inside the retrograde-menstruation account without fully
    explaining the remainder.
  evidence:
  - reference: PMID:40246293
    reference_title: "Prevalence of endometriosis in Mayer-Rokitansky-Küster-Hauser syndrome variants: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The aggregate prevalence of endometriosis was considerably higher in
      MRKHS patients with FE (MRKHSFE+) than in those without FE (MRKHSFE-).
    explanation: >-
      The stratified frequency this phenotype records.
- category: Reproductive
  name: Uterine leiomyoma in rudimentary uterine buds
  phenotype_term:
    preferred_term: Uterine leiomyoma
    term:
      id: HP:0000131
      label: Uterine leiomyoma
  frequency: uncommon
  description: >-
    Leiomyomas arising in the myometrium of a rudimentary uterine bud — a
    reminder that the buds are functional smooth-muscle tissue and not scar.
    Subserosal leiomyomas on both uterine buds have been photographed
    intraoperatively during preparation for uterus transplantation.
  evidence:
  - reference: PMID:32819397
    reference_title: "Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Presence of uterine remnants have been reported in 48 – 95% of the
      patients
    explanation: >-
      Establishes that remnant uterine tissue is commonly present, which is the
      precondition for a leiomyoma arising in it. The leiomyoma finding itself
      is described in the same review's operative figure legend.
- category: Renal
  name: Unilateral renal agenesis
  phenotype_term:
    preferred_term: Unilateral renal agenesis
    term:
      id: HP:0000122
      label: Unilateral renal agenesis
  subtype: Type 2
  frequency: about half of the renal malformations
  description: >-
    The single commonest extragenital anomaly, and the one whose laterality
    carries mechanistic information: it is often ipsilateral to a completely
    absent Müllerian duct. Renal imaging is therefore recommended in every
    patient with a genital malformation, not only in those with symptoms.
  evidence:
  - reference: PMID:27609979
    reference_title: "Prevalence and patient characteristics of Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide registry-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Kidney malformations were the most prevalent extragenital malformations,
      described in 38 of 111 patients (34.2%).
    explanation: >-
      Population-based frequency for renal malformation as a class, of which
      unilateral agenesis is the largest component.
- category: Renal
  name: Ectopic kidney
  phenotype_term:
    preferred_term: Ectopic kidney
    term:
      id: HP:0000086
      label: Ectopic kidney
  subtype: Type 2
  frequency: uncommon
  description: >-
    Pelvic or otherwise malpositioned kidney, reported among the renal
    malformations of type II alongside agenesis.
  evidence:
  - reference: PMID:22906151
    reference_title: "Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      associated malformations were found in 126 of 282 evaluable women (44.7%),
      84 women (29.6%) had malformations of the renal system
    explanation: >-
      Frequency of renal malformations as a class in a systematically evaluated
      cohort; the individual anomaly types are enumerated in the same study.
- category: Renal
  name: Horseshoe kidney
  phenotype_term:
    preferred_term: Horseshoe kidney
    term:
      id: HP:0000085
      label: Horseshoe kidney
  subtype: Type 2
  frequency: uncommon
  description: >-
    Midline fusion anomaly, one of the recognised renal malformations of type II.
  evidence:
  - reference: PMID:22906151
    reference_title: "Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A variety of associated malformations were present, predominantly of the
      renal system.
    explanation: >-
      Establishes the renal system as the predominant site of associated
      malformation, within which this anomaly is reported.
- category: Renal
  name: Duplicated collecting system
  phenotype_term:
    preferred_term: Duplicated collecting system
    term:
      id: HP:0000081
      label: Duplicated collecting system
  subtype: Type 2
  frequency: uncommon
  description: >-
    Duplex kidney or duplicated ureter, a nephric-duct-derived anomaly within
    the same lineage as the Müllerian lesion.
  evidence:
  - reference: PMID:22906151
    reference_title: "Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is therefore recommended that all patients with genital malformations
      should be evaluated for renal abnormalities.
    explanation: >-
      The cohort's own recommendation, which follows from the breadth of renal
      anomaly types it found.
- category: Skeletal
  name: Scoliosis
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  subtype: Type 2
  frequency: reported in 10-40% depending on imaging performed
  description: >-
    Axial skeletal deformity, the second most frequent extragenital
    manifestation as a class. Reported frequency varies widely between cohorts
    because it depends on whether skeletal imaging was performed at all and on
    whether scoliosis was counted as a malformation.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common extragenital anomalies include the skeleton and heart, which
      do also develop from the mesoderm, with the paraxial mesoderm forming the
      axial skeleton
    explanation: >-
      Places skeletal anomalies among the common extragenital findings and
      assigns them to the paraxial mesoderm lineage.
- category: Skeletal
  name: Cervical vertebral fusion
  phenotype_term:
    preferred_term: Cervical vertebral fusion
    term:
      id: HP:0002949
      label: Fused cervical vertebrae
  subtype: Type 2
  frequency: uncommon
  description: >-
    Cervical vertebral fusion, the Klippel-Feil end of the phenotype and the
    finding that gave MURCS its cervicothoracic somite dysplasia component.
  evidence:
  - reference: PMID:27609979
    reference_title: "Prevalence and patient characteristics of Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide registry-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Typical MRKH syndrome and atypical MRKH syndrome/Müllerian duct aplasia,
      Renal aplasia, and Cervicothoracic Somite dysplasia association were
      present in 56.5% and 43.5% of the patients, respectively.
    explanation: >-
      Names cervicothoracic somite dysplasia as a defining component of the
      MURCS subgroup, which is what this phenotype records.
- category: Skeletal
  name: Hemivertebrae
  phenotype_term:
    preferred_term: Hemivertebrae
    term:
      id: HP:0002937
      label: Hemivertebrae
  subtype: Type 2
  frequency: uncommon
  description: >-
    Failure of formation of one half of a vertebral body, a segmentation defect
    of the same somitic origin as the fusion anomalies.
  evidence:
  - reference: PMID:22906151
    reference_title: "Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      associated malformations were found in 126 of 282 evaluable women (44.7%),
      84 women (29.6%) had malformations of the renal system
    explanation: >-
      Cited indirectly: it establishes the overall associated-malformation
      burden and that renal anomalies are only two-thirds of it, leaving the
      skeletal remainder to which this phenotype belongs.
- category: Auditory
  name: Hearing impairment
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  subtype: Type 2
  frequency: under 5% when not systematically sought, about 11% when it is
  description: >-
    Sensorineural or conductive hearing loss, including external meatus atresia
    and stapedial ankylosis. It is not routinely screened for, and systematic
    otorhinopharyngeal assessment finds ear abnormalities substantially more
    often than routine care does — so the low reported frequency is partly an
    ascertainment artefact.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRKH syndrome may present as an isolated anomaly (type I) or in
      association with extragenital malformations (type II), typically involving
      the kidneys, skeleton, and heart
    explanation: >-
      Cited indirectly: it establishes the extragenital malformation category
      this phenotype belongs to but lists the three commonest systems rather
      than the ear.
- category: Cardiovascular
  name: Atrial septal defect
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  subtype: Type 2
  frequency: under 5%
  description: >-
    Congenital heart defect, reported in fewer than 5% of patients. The heart
    derives from lateral plate mesoderm, which is why it appears in this
    syndrome's extragenital spectrum at all.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRKH syndrome may present as an isolated anomaly (type I) or in
      association with extragenital malformations (type II), typically involving
      the kidneys, skeleton, and heart
    explanation: >-
      Names the heart among the typical extragenital systems involved.
genetic:
- name: GREB1L
  gene_term:
    preferred_term: GREB1L
    term:
      id: hgnc:31042
      label: GREB1L
  association: Causative
  relationship_type: CAUSATIVE
  frequency: variants in about 8% of sporadic patients in one series
  notes: >-
    The best-supported gene in the syndrome, and the only one described as a
    major causative gene. It came into the field from the other end: GREB1L
    variants were identified in 2017 as a dominant cause of congenital anomalies
    of the kidney and urinary tract, and some of the affected female fetuses
    also had uterovaginal malformations. A three-generation family with four
    cases of renal agenesis, two of them adult female cousins with type II MRKH
    syndrome, then yielded a segregating missense variant. Homozygous Greb1l
    knock-out mice lack kidneys, Wolffian ducts and Müllerian ducts. The gap in
    the account is at the molecular end: human variants are monoallelic and
    mostly missense, and how such a variant produces the phenotype is unknown.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      epidemiological evidence of rare variant enrichment in larger cohorts, and
      functional evidence from knock-out mice, suggest GREB1L as a major
      causative gene in MRKH syndrome.
    explanation: >-
      The review's own summary judgement on this gene, based on pedigree,
      cohort-enrichment and mouse evidence together.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous knock-out of Greb1l in mice has been shown to cause absence of
      the kidneys, Wolffian ducts, and Müllerian ducts
    explanation: >-
      Mouse loss of function reproduces the combined renal and Müllerian
      phenotype, which is the functional half of the causality argument.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the pathogenic mechanism of how these missense variants cause MRKH
      syndrome is still unknown requiring further functional analysis
    explanation: >-
      Records the limit of the account: the human allele class is monoallelic
      missense and its mechanism is unresolved, so the mouse null is not a
      complete model of it.
- name: PAX8
  gene_term:
    preferred_term: PAX8
    term:
      id: hgnc:8622
      label: PAX8
  association: Causative
  relationship_type: CAUSATIVE
  notes: >-
    Established by a mutational burden analysis across 442 cases and 941
    controls that found enrichment of predicted loss-of-function variants, with
    replication and functional support for two of five missense variants tested.
    PAX8 was already a monogenic cause of congenital hypothyroidism from thyroid
    dysgenesis, and reverse-phenotyping of female congenital hypothyroidism
    cases found uterovaginal aplasia in one — so MRKH syndrome is a
    female-restricted arm of an existing pleiotropic gene, which the authors
    name CH-MRKHS. Paternal transmission confirmed in three cases is the
    cleanest available demonstration of sex-limited expressivity in this
    syndrome, since an unaffected father cannot be explained by reduced
    penetrance alone.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among cases, they found enrichment for predicted loss-of-function variants
      in PAX8.
    explanation: >-
      Case-control enrichment is the primary evidence for this gene.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This confirms MRKH syndrome as a part of the PAX8 disease spectrum in
      females
    explanation: >-
      States the pleiotropy claim this record encodes.
- name: HNF1B
  gene_term:
    preferred_term: HNF1B
    term:
      id: hgnc:11630
      label: HNF1B
  association: Causative
  relationship_type: CAUSATIVE
  notes: >-
    Implicated twice over: it lies in the recurrently deleted 17q12 interval,
    and it carries independent sequence-variant evidence. The oldest observation
    is from a 1999 Norwegian MODY5 family in which two of four female variant
    carriers had uterovaginal agenesis. The mechanistic case was closed
    experimentally in 2023 by conditional ablation of Hnf1b in Müllerian duct
    epithelium, which produced a hypoplastic uterus with renal anomalies — the
    first mouse model of MRKH type II — and showed that HNF1B acts here
    independently of LHX1 at the same locus.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, two of four female variant carriers also had uterovaginal
      agenesis, supporting MRKH syndrome as part of the HNF1B disease spectrum
    explanation: >-
      Human pedigree evidence, from a family ascertained for diabetes rather
      than for a genital anomaly.
  - reference: PMID:36282544
    reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, we establish that loss of Hnf1b function leads to an MRKH phenotype
      and generate the first mouse model of MRKH syndrome type II.
    explanation: >-
      Tissue-specific ablation establishes causality rather than association for
      this gene.
- name: LHX1
  gene_term:
    preferred_term: LHX1
    term:
      id: hgnc:6593
      label: LHX1
  association: Candidate gene at the 17q12 locus; sequence variants disputed
  relationship_type: DISPUTED
  notes: >-
    The other candidate in the 17q12 interval, and the one with the cleaner
    animal evidence but the weaker human evidence. Lhx1-null females have normal
    ovaries and no reproductive tract, from failure of duct elongation and
    epithelium formation — the exact human dissociation. But mutational analysis
    of larger patient cohorts has not found LHX1 sequence variants, so single
    nucleotide variation in this gene is not a major cause even though deletion
    of the interval containing it is recurrent. It is curated DISPUTED for that
    reason: the gene is plausibly a contributor to the 17q12 deletion phenotype
    while not being an independent monogenic cause.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Lhx1-null female mice have normal ovaries but lack their reproductive
      tract, which results from a disruption of MD elongation and epithelium
      formation
    explanation: >-
      The animal evidence in favour of a role for this gene.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LHX1 mutational analysis of larger cohorts did not report any variants,
      suggesting that sequence variants of LHX1 are no major cause of MRKH
      syndrome
    explanation: >-
      Negative cohort evidence against LHX1 sequence variation as a monogenic
      cause, which is why the relationship is recorded as DISPUTED.
- name: TBX6
  gene_term:
    preferred_term: TBX6
    term:
      id: hgnc:11605
      label: TBX6
  association: Susceptibility at the recurrent 16p11.2 deletion locus
  relationship_type: SUSCEPTIBILITY
  notes: >-
    The candidate gene at 16p11.2, the second commonest recurrent deletion in
    the syndrome. Rare TBX6 variants are enriched in a large patient cohort and
    seven of thirteen missense variants tested showed loss of function, so the
    genetic association is real. The mechanistic story is not. At this locus,
    congenital scoliosis requires a null allele plus a specific hypomorphic
    allele in trans, and no such second risk allele has been found in MRKH
    syndrome — leaving monoallelic variants with no established route to the
    phenotype. Recorded as SUSCEPTIBILITY rather than CAUSATIVE for exactly
    that reason.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ma et al. reported 16 rare TBX6 variants enriched in a large MRKH syndrome
      patient cohort compared to controls.
    explanation: >-
      Case-control enrichment supporting a genuine association with this gene.
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, in contrast to null alleles associated with scoliosis, no second
      risk alleles were reported in MRKH syndrome
    explanation: >-
      The compound-inheritance model that explains TBX6 in scoliosis does not
      transfer, which argues against a simple causative reading here.
- name: WNT9B
  gene_term:
    preferred_term: WNT9B
    term:
      id: hgnc:12779
      label: WNT9B
  association: Candidate gene; variants of uncertain significance
  relationship_type: UNKNOWN
  notes: >-
    A strong biological candidate with unresolved human genetics. Wnt9b is
    expressed in Wolffian duct epithelium and provides the signals guiding
    Müllerian duct elongation, and Wnt9b knock-down in mice causes uterovaginal
    and renal agenesis. Nine sequence variants have been reported in type I
    patients, but other studies found none, and the functional consequence of
    the reported variants has not been established.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Wnt9b is expressed in the Wolffian duct epithelium providing signals
      guiding MD elongation
    explanation: >-
      Establishes the biological candidacy, which is what this record rests on
      in the absence of settled human genetics.
- name: RBM8A
  gene_term:
    preferred_term: RBM8A
    term:
      id: hgnc:9905
      label: RBM8A
  association: Proposed candidate gene at the 1q21.1 locus; causality not established
  relationship_type: UNKNOWN
  notes: >-
    The proposed candidate within variable-sized 1q21.1 deletions reported in
    the syndrome. The same region causes thrombocytopenia-absent radius syndrome
    in compound heterozygosity with non-coding polymorphisms in trans, and TAR
    syndrome has been reported once alongside MRKH syndrome. Causality is
    explicitly not established, and the record exists so that the locus is
    findable rather than to assert a gene-disease relationship.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The possible causal role of 1q21.1 deletions/RBM8A gene variants in MRKH
      syndrome is, however, still unclear warranting further studies to
      establish causality.
    explanation: >-
      Graded NO_EVIDENCE because the cited review states the causal question is
      unresolved: it neither supports nor refutes a gene-disease relationship
      for RBM8A.
prevalence:
- population: Denmark, live female births 1974-1996
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 20.1
  rate_low: 17.0
  rate_high: 23.7
  rate_denominator: LIVE_BIRTHS
  notes: >-
    1 in 4982 (95% CI 4216-5887) live female births, from a nationwide registry
    cohort whose diagnoses were validated against cytogenetic registry data and
    medical records. The positive predictive value of the registry diagnosis
    code alone was only 55.3%, which is why the validation step matters and why
    unvalidated registry counts of this syndrome should be treated with caution.
    Denominator is live female births.
  evidence:
  - reference: PMID:27609979
    reference_title: "Prevalence and patient characteristics of Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide registry-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of MRKH syndrome in Denmark is 1 in 4982 (95% confidence
      interval (CI): 4216-5887) live female births.
    explanation: >-
      The population-based estimate and interval this record normalises.
- population: Worldwide (conventional estimate)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 20.0
  rate_denominator: LIVE_BIRTHS
  notes: >-
    The figure generally quoted, 1 in 5000 female live births. Note that only
    two population-based studies exist and both are European, so whether the
    prevalence differs in other populations is unknown rather than established
    as equal.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The estimated birth prevalence of MRKH syndrome is 1 in 5,000 female live
      births
    explanation: >-
      The conventional estimate as stated in a current review.
- population: United States clinical estimate
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 21.1
  rate_low: 20.0
  rate_high: 22.2
  rate_denominator: LIVE_BIRTHS
  notes: >-
    1 per 4,500-5,000 females, as stated by ACOG. Recorded as a range because
    the source gives one.
  evidence:
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Müllerian agenesis, also referred to as müllerian aplasia,
      Mayer-Rokitansky-Küster-Hauser syndrome, or vaginal agenesis, has an
      incidence of 1 per 4,500-5,000 females.
    explanation: >-
      Professional-society frequency statement.
diagnosis:
- name: Pelvic magnetic resonance imaging
  diagnosis_term:
    preferred_term: pelvic MRI of the internal genitalia
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    The reference standard. MRI confirms uterovaginal agenesis, distinguishes
    rudimentary uterine buds from complete absence, and — the clinically
    decisive part — shows whether a bud contains endometrium, which is what
    determines the risk of catamenial pain, haematometra and endometriosis and
    therefore whether the remnant should be removed. It also images the kidneys
    and can show extragenital anomalies in the same study.
  evidence:
  - reference: PMID:40246293
    reference_title: "Prevalence of endometriosis in Mayer-Rokitansky-Küster-Hauser syndrome variants: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The recent advent of high-resolution ultrasonography and magnetic
      resonance imaging (MRI) allowed the reliable preoperative identification
      of FE concealed within UR
    explanation: >-
      Establishes that imaging now answers the functional-endometrium question
      preoperatively, which is the diagnostic value this record claims.
- name: Pelvic ultrasonography
  diagnosis_term:
    preferred_term: transabdominal or transperineal pelvic ultrasonography
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  description: >-
    First-line imaging, showing an absent uterus with two present ovaries. It
    also excludes the mimics that matter most: an imperforate hymen or
    transverse vaginal septum will show a proximal vaginal canal and often
    haematocolpos, which uterovaginal agenesis will not — a distinction with
    real consequences, since operating on the wrong one is harmful.
  evidence:
  - reference: PMID:22906151
    reference_title: "Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      290 women with MRKH syndrome were clinically evaluated with using clinical
      examinations, abdominal and perineal/rectal ultrasound, MRI, and
      laparoscopy.
    explanation: >-
      Documents the diagnostic sequence in which ultrasound is used for this
      syndrome.
- name: Renal imaging
  diagnosis_term:
    preferred_term: renal ultrasonography or MRI
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  description: >-
    Screening for renal malformation in every patient, not only the symptomatic
    ones. A third of patients have a renal anomaly and most are asymptomatic; in
    the Danish cohort a third of patients had no urinary tract imaging at all,
    so under-ascertainment is the documented failure mode here.
  evidence:
  - reference: PMID:22906151
    reference_title: "Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is therefore recommended that all patients with genital malformations
      should be evaluated for renal abnormalities.
    explanation: >-
      The recommendation this record implements, from the cohort that motivates
      it.
- name: Karyotype
  diagnosis_term:
    preferred_term: karyotyping
    term:
      id: NCIT:C16768
      label: Karyotyping
  description: >-
    Confirms 46,XX, and its real purpose is to separate this syndrome from the
    46,XY differential diagnoses that share a blind vagina and absent uterus —
    complete androgen insensitivity syndrome and 17-hydroxylase/17,20-lyase
    deficiency. It is diagnostically confirmatory rather than
    aetiologically informative.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients are characterized by having a normal female karyotype
      (46,XX), normal external genitalia, and normal pubertal development of
      secondary sex characteristics (thelarche and pubarche)
    explanation: >-
      The karyotype finding this test establishes, which is part of the case
      definition.
- name: Chromosomal microarray
  diagnosis_term:
    preferred_term: chromosomal microarray analysis
    term:
      id: NCIT:C18477
      label: Microarray Analysis
  description: >-
    Optional rather than obligate. It detects the recurrent 17q12, 16p11.2,
    22q11 and 1q21.1 imbalances, but those together account for only about 10%
    of patients and interpreting them is not straightforward — so a negative
    result excludes very little and a positive one often needs careful
    counselling rather than delivering a clean answer.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, recurrent chromosomal imbalances in MRKH syndrome still only
      apply to a minor fraction of patients (around 10%).
    explanation: >-
      Quantifies the diagnostic yield, which is the basis for treating this test
      as optional.
treatments:
- name: Progressive Vaginal Dilation
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: progressive self-dilation of the vaginal dimple (Frank method)
    term:
      id: NCIT:C93165
      label: Vaginal Dilation Therapy
  description: >-
    First-line therapy for vaginal agenesis and has been the ACOG
    recommendation since 2002. Progressive dilators are applied to the vaginal
    apex for 10 to 30 minutes, one to three times daily. Anatomic and functional
    success is reached by 90-96% of patients, at a low complication rate and low
    cost, and comparative studies generally find dilation non-inferior to
    surgery. Two points are easy to lose. First, the method works because the
    residual pouch is lined with native vaginal mucosa, which surgical grafts do
    not reproduce — and that mucosal lining also supplies a normal vaginal
    microbiota, which matters if uterus transplantation is later contemplated.
    Second, success depends on maturity, motivation and supervised therapeutic
    education rather than on the device; poor compliance is the main mode of
    failure, and it is a legitimate outcome for a patient to choose no treatment
    at all.
  target_mechanisms:
  - target: Cervical and Upper Vaginal Atresia with a Blind Vaginal Pouch
    treatment_effect: RESTORES
    description: >-
      Mechanical elongation of the sinus-derived pouch addresses the vaginal
      arm of the lesion. It does nothing for the uterine arm, and does not treat
      infertility.
  evidence:
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonsurgical vaginal elongation by dilation should be the first-line
      approach. When well-counseled and emotionally prepared, almost all
      patients (90-96%) will be able to achieve anatomic and functional success
      by primary vaginal dilation.
    explanation: >-
      Establishes both the first-line status and the success rate quoted here.
- name: Vaginoplasty
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: vaginoplasty for vaginal agenesis
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  description: >-
    Reserved for patients in whom dilation has failed. Several techniques exist
    — laparoscopic Vecchietti traction, McIndoe split-skin graft, Davydov
    peritoneal graft, Williams vulvovaginoplasty, bowel graft, and more recently
    cultured autologous vulvar tissue and tissue-engineered constructs — and no
    comparative trial establishes one as best; most centres see too few patients
    to acquire more than one technique, which is itself a source of publication
    and reporting bias in the outcome literature. The point that most changes
    patient expectations is that surgery does not remove the need for dilation:
    post-operative dilation is still required to prevent strictures. NCIT has no
    clinical-action term for vaginoplasty, so the binding is the generic
    Surgical Procedure with the specificity carried in the preferred term.
  target_mechanisms:
  - target: Cervical and Upper Vaginal Atresia with a Blind Vaginal Pouch
    treatment_effect: RESTORES
    description: >-
      Surgical creation of a neovaginal canal in the space between bladder and
      rectum, substituting for the absent duct-derived segment.
  evidence:
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In cases in which surgical intervention is required, referrals to centers
      with expertise in this area should be considered because few surgeons have
      extensive experience in construction of the neovagina
    explanation: >-
      Supports both the second-line positioning and the centre-volume caveat.
- name: Uterus Transplantation
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: uterus transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  description: >-
    The first and still the only treatment for the infertility itself, as
    distinct from the anatomy. A living-donor uterus transplant in a 35-year-old
    woman with MRKH syndrome in Gothenburg in 2013 led to menstruation 43 days
    after transplantation, pregnancy after a single embryo transfer a year
    later, and a livebirth in September 2014. Three episodes of mild rejection
    were reversed with corticosteroids; delivery was by caesarean section at 31
    weeks and 5 days for pre-eclampsia. The mechanistic logic is that in this
    syndrome the deficit is purely gestational — ovaries and oocytes are normal
    — so replacing the uterus restores gestational, genetic and legal
    motherhood together, which neither surrogacy nor adoption does. It requires
    IVF beforehand and immunosuppression throughout pregnancy, so it is a
    serious intervention rather than a routine option.
  target_mechanisms:
  - target: Absolute Uterine Factor Infertility
    treatment_effect: RESTORES
    description: >-
      Supplies the missing organ, which is the only mechanism by which this node
      can be addressed.
  evidence:
  - reference: PMID:25301505
    reference_title: "Livebirth after uterus transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 2013, a 35-year-old woman with congenital absence of the uterus
      (Rokitansky syndrome) underwent transplantation of the uterus in
      Sahlgrenska University Hospital, Gothenburg, Sweden.
    explanation: >-
      Establishes that the index case of this treatment was a patient with this
      syndrome.
  - reference: PMID:25301505
    reference_title: "Livebirth after uterus transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe the first livebirth after uterus transplantation. This report
      is a proof-of-concept for uterus transplantation as a treatment for
      uterine factor infertility.
    explanation: >-
      The outcome that makes this a treatment rather than a proposal.
- name: In Vitro Fertilization with a Gestational Carrier
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: in vitro fertilization with gestational surrogacy
    term:
      id: NCIT:C16580
      label: In Vitro Fertilization
  description: >-
    IVF using the patient's own oocytes with embryo transfer to a gestational
    carrier, which yields genetic but not gestational motherhood. It has been
    the established route to biological parenthood since the mid-1990s and is
    effective, but it is prohibited in many jurisdictions on ethical, religious
    or legal grounds, so availability is a matter of geography rather than of
    medicine. One consequence worth recording: because surrogacy bypasses the
    infertility that otherwise blocks vertical transmission, mother-to-daughter
    recurrence of MRKH syndrome after surrogacy has now been reported, which is
    why recurrence-risk counselling is becoming a real part of care rather than
    a theoretical one.
  target_mechanisms:
  - target: Absolute Uterine Factor Infertility
    treatment_effect: BYPASSES
    description: >-
      Bypasses rather than corrects the missing organ, by gestating the
      patient's genetic embryo elsewhere.
  evidence:
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Assisted reproductive techniques with use of a gestational carrier
      (surrogate) have been shown to be successful for women with müllerian
      agenesis.
    explanation: >-
      Establishes efficacy of this route in this population.
- name: Psychological Counselling and Peer Support
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: psychological counselling and support
    term:
      id: NCIT:C15308
      label: Psychotherapy
  description: >-
    Not adjunctive. The diagnosis arrives in adolescence and simultaneously
    delivers infertility, a threat to female identity, and the prospect of
    coital difficulty; measured psychological distress is higher than in
    comparison women, and qualitative work identifies hindered independence,
    feeling different, difficulty managing intimacy and threatened female
    identity as the recurring themes. Group programmes reduce distress, and
    every patient should be offered counselling and encouraged to connect with a
    peer support group. Counselling also gates the anatomical treatments:
    dilation depends on maturity and motivation, so counselling precedes it
    rather than following it.
  target_mechanisms:
  - target: Absolute Uterine Factor Infertility
    treatment_effect: MODULATES
    description: >-
      Addresses the psychological consequences of this node, which no
      anatomical or reproductive intervention removes.
  evidence:
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The psychologic effect of the diagnosis of müllerian agenesis should not
      be underestimated. All patients with müllerian agenesis should be offered
      counseling and encouraged to connect with peer support groups.
    explanation: >-
      Professional-society statement that counselling and peer support are part
      of standard care here.
- name: Laparoscopic Excision of Symptomatic Uterine Remnants
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: laparoscopic excision of a uterine remnant
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  description: >-
    Indicated where a rudimentary bud contains functional endometrium and is
    causing catamenial pain or haematometra, and it is the one operation in this
    syndrome that treats an active lesion rather than an absence. Since MRI now
    identifies concealed functional endometrium preoperatively, the decision can
    be made on imaging rather than at diagnostic laparoscopy. Given that
    endometriosis risk tracks functional endometrium in a remnant at an odds
    ratio of about 12, removing the symptomatic remnant plausibly addresses the
    source of that risk as well as the pain — though the entry does not claim a
    demonstrated reduction in endometriosis incidence, which has not been shown.
  target_mechanisms:
  - target: Retained Cycling Endometrium in Uterine Remnants
    treatment_effect: INHIBITS
    description: >-
      Removes the cycling tissue, which is the substrate of the node.
  evidence:
  - reference: PMID:40246293
    reference_title: "Prevalence of endometriosis in Mayer-Rokitansky-Küster-Hauser syndrome variants: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A significantly increased risk of endometriosis was observed in MRKHSFE+
      patients compared with MRKHSFE- patients (overall odds ratio estimate was
      12.0; 95% CI, 5.1-28.3%).
    explanation: >-
      Quantifies the risk attached to the tissue this operation removes. It does
      not itself evidence that excision lowers that risk.
- name: Genetic Counselling
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counselling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  description: >-
    Increasingly relevant rather than routine. A detailed family history
    covering both MRKH syndrome and associated renal or uterovaginal anomalies
    in relatives is the single highest-yield step, since subtle anomalies in
    asymptomatic relatives may need imaging to find. Where a variant in GREB1L,
    PAX8 or HNF1B is identified, counselling covers recurrence risk with
    incomplete penetrance and sex-limited expressivity, and at-risk relatives
    can be tested. Two cautions belong in the same conversation: most reported
    variants remain of uncertain significance, and the recurrence question is
    only actionable at all because surrogacy and transplantation have made
    genetic parenthood possible.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, in the current state of knowledge, many reported variants
      associated with MRKH syndrome are still to be considered as variants of
      uncertain significance, which warrant cautious interpretations and
      counseling in clinical care.
    explanation: >-
      Supports the caution this record places on genetic counselling in this
      syndrome.
differential_diagnoses:
- name: WNT4-related Müllerian aplasia with hyperandrogenism
  disease_term:
    preferred_term: WNT4-related Müllerian aplasia with hyperandrogenism
    term:
      id: MONDO:0008019
      label: mullerian aplasia and hyperandrogenism
  description: >-
    The closest genetic mimic and deliberately not curated as part of this
    entry. WNT4 was the first gene with firm monogenic evidence for Müllerian
    agenesis, but the phenotype it causes includes clinical and biochemical
    hyperandrogenism, which classic MRKH syndrome does not, and it is generally
    treated as a separate entity (OMIM 158330). Larger MRKH cohorts have found
    no WNT4 variants. The separation matters practically: virilization in a
    patient with Müllerian agenesis should redirect the genetic workup rather
    than be filed as atypical MRKH syndrome.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MD agenesis caused by WNT4 variants is associated with clinical and
      biochemical hyperandrogenism, representing a phenotype distinct from MRKH
      syndrome in general
    explanation: >-
      States the discriminating feature and the reason for treating this as a
      separate entity.
  - reference: PMID:15317892
    reference_title: "A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An 18-year-old woman presented with primary amenorrhea and an absence of
      müllerian-derived structures, unilateral renal agenesis, and clinical
      signs of androgen excess--a phenotype resembling the
      Mayer-Rokitansky-Küster-Hauser syndrome and remarkably similar to that of
      female Wnt4-knockout mice.
    explanation: >-
      The index case, which shows how closely this entity mimics MRKH syndrome
      and that androgen excess is the feature that separates them.
- name: Complete androgen insensitivity syndrome
  disease_term:
    preferred_term: Complete androgen insensitivity syndrome
    term:
      id: MONDO:0021023
      label: complete androgen insensitivity syndrome
  description: >-
    Shares the presentation almost exactly: normal female appearance, breast
    development, a blind-ending vagina and an absent uterus, presenting as
    primary amenorrhea. The mechanism is the opposite — a 46,XY individual whose
    testes produce anti-Müllerian hormone, so the Müllerian structures regress
    normally rather than failing to form, and whose androgen receptor is
    non-functional. Sparse pubic hair and karyotype separate them.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hauser and colleagues described that sex-chromatin analysis could aid the
      differentiation of MRKH syndrome from Turner syndrome and defined MRKH
      syndrome (at the time termed 'Mayer-Rokitansky-Küster syndrome') to
      include normal female chromosomes
    explanation: >-
      Cited indirectly: it establishes that karyotype is definitional for this
      syndrome and was introduced precisely to separate it from a karyotypic
      mimic, which is the same logic that separates it from 46,XY causes.
- name: Imperforate hymen or transverse vaginal septum
  description: >-
    An obstructive anomaly with a normal uterus, mistaken for vaginal agenesis
    when only the introitus is examined. Ultrasound resolves it by showing a
    proximal vaginal canal and often haematocolpos. This is the differential
    with the most direct consequence of being got wrong in either direction:
    incising a blind pouch in a patient with agenesis achieves nothing and
    risks urethral or rectal injury, while leaving an obstruction undrained
    allows retrograde disease.
  notes: >-
    Deliberately uncited. The available cached sources support the imaging
    workup in general but none of them states the discrimination this
    differential turns on — a proximal vaginal canal or haematocolpos above a
    blind introitus. A clinically uncontroversial differential with no citation
    is more honest than one propped up by a quote that does not bear on it.
- name: Unstimulated prepubertal or hypoestrogenic uterus
  description: >-
    A uterus that has never been exposed to estrogen — in 46,XX or 45,X ovarian
    insufficiency, or simply in a prepubertal child imaged incidentally — can be
    reported as absent. Exogenous estrogen induces uterine development in these
    patients, which proves the uterus was present and unstimulated rather than
    agenetic. Prepubertal pelvic imaging in particular should not be used to
    diagnose agenesis.
  notes: >-
    Deliberately uncited. The cached ACOG 728 record is abstract-only and its
    text names no hypoestrogenic mimic; the general management principle it
    does state is not an assertion from which this differential follows, so
    citing it would misrepresent the source rather than support the claim.
animal_models:
- name: Wnt7a-Cre;Hnf1b-floxed Müllerian duct epithelium conditional knockout mouse
  species: Mouse
  genotype: Wnt7a-Cre+;Hnf1b(fl/fl) — loxP sites flanking Hnf1b exon 4, recombined
    only where Wnt7a-Cre is expressed
  background: C57BL/6
  genes:
  - preferred_term: HNF1B
    term:
      id: hgnc:11630
      label: HNF1B
  publication: PMID:36282544
  description: >-
    The first mouse model of MRKH syndrome type II, and the only model in this
    entry that reproduces the genital and renal arms together from one lesion.
    Constitutive Hnf1b nulls die too early to be informative and lose the
    Müllerian duct secondarily to Wolffian duct degeneration, so the question of
    what Hnf1b does *in the duct* could not be asked until the lesion was
    restricted to Müllerian duct epithelium. Wnt7a-Cre confines recombination to
    that epithelium, sparing the Wolffian duct. Mutant females develop a
    hypoplastic uterus with a vestigial, non-differentiating epithelium,
    unilateral renal agenesis in a minority, and normal ovaries — the same
    combination, in the same proportions, as human type II disease.
  evidence:
  - reference: PMID:36282544
    reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, we establish that loss of Hnf1b function leads to an MRKH phenotype
      and generate the first mouse model of MRKH syndrome type II.
    explanation: >-
      The authors' own statement of what the model is, and the basis for treating
      it as informative about this disease rather than about Hnf1b in general.
  - reference: PMID:36282544
    reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we crossed a Wnt7a-Cre line with a mouse line carrying loxP sites flanking
      Hnf1b exon 4
    explanation: >-
      Source for the genotype recorded above.
  modeled_mechanisms:
  - target: Failure of Müllerian Duct Epithelial Proliferation and Elongation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      The lesion is placed in exactly the cell population this node names, and
      the measured consequence is the cellular failure the node asserts: reduced
      epithelial proliferation from 13.5 dpc, a shorter uterus, and an epithelium
      that never organizes into its normal pseudostratified columnar form. The
      single-cell transcriptomic result is the direct basis for the three
      cellular processes annotated on this node.
    limitations: >-
      The mutant epithelium is hypoplastic and undifferentiated rather than
      absent, so the model reproduces the rudimentary-bud end of the human
      spectrum and not complete duct aplasia; the authors note it is milder than
      the Lhx1 conditional knockout, which loses the endometrial layer outright.
      Hnf1b sequence variants account for a small minority of human cases, so the
      cellular route shown here is not established as the route in most patients.
    readouts:
    - name: Müllerian duct epithelial cell proliferation and uterine length
      target: Failure of Müllerian Duct Epithelial Proliferation and Elongation
      description: >-
        Proliferation in the Müllerian duct epithelium from 13.5 dpc, read out
        morphologically as uterine horn length at birth.
      direction: DECREASED
      interpretation: >-
        Proliferation failure preceding and explaining the shortened duct is the
        cellular claim this node makes.
      evidence:
      - reference: PMID:36282544
        reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Hnf1b loss-of-function caused a decrease in MD epithelial cell
          proliferation, which started as early as 13.5 dpc, leading to the
          development of a shorter uterus.
        explanation: >-
          Reports the measurement and its timing.
    - name: Uterine proliferation, migration and differentiation transcriptional programmes
      target: Failure of Müllerian Duct Epithelial Proliferation and Elongation
      description: >-
        Single-cell RNA sequencing of uterine tissue from Hnf1b-ablated embryos
        against littermate controls.
      direction: ALTERED
      interpretation: >-
        Dysregulation spread across three programmes rather than concentrated in
        one pathway is why this node is annotated with three GO processes and not
        with a single discrete mechanism.
      evidence:
      - reference: PMID:36282544
        reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Using single-cell RNA sequencing of uterine tissue in the Hnf1b-ablated
          embryos, we analyzed the molecules and pathways downstream of Hnf1b,
          revealing a dysregulation of processes associated with cell
          proliferation, migration and differentiation.
        explanation: >-
          Direct basis for the three cellular processes annotated on this node.
    - name: Endometrial gland development
      target: Failure of Müllerian Duct Epithelial Proliferation and Elongation
      description: >-
        Histology of the adult (4-month) mutant uterus.
      direction: DECREASED
      interpretation: >-
        Failure of the differentiation arm specifically, persisting into
        adulthood rather than resolving.
      evidence:
      - reference: PMID:36282544
        reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Hnf1b mutant mice displayed a hypoplastic uterus, characterized by a
          simple cuboidal epithelium and reduced stromal thickness that failed to
          properly develop endometrial glands.
        explanation: >-
          Reports the adult histological measurement behind this readout.
    evidence:
    - reference: PMID:36282544
      reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We ablated Hnf1b specifically in the epithelium of the Müllerian ducts in
        mice and found that this caused hypoplastic development of the uterus, as
        well as kidney anomalies, closely mirroring the MRKH type II phenotype.
      explanation: >-
        Establishes that the lesion sits in the cell population this node names,
        and that it produces the human phenotype.
  - target: Shared Intermediate Mesoderm Lineage Failure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Unilateral renal agenesis appeared in the mutants and never in controls or
      heterozygotes, at a frequency close to the human figure — which is the
      renal arm of type II arising from a lesion targeted at the Müllerian duct.
    limitations: >-
      Only a minority of mutants show it, and the authors themselves call the
      finding surprising: Wnt7a-Cre activity in mesonephric or metanephric cells
      may be ablating Hnf1b directly in the kidney, in which case the result is
      two lesions in one animal rather than one lineage failure reaching two
      organs. The same Cre line used against Lhx1 produced no kidney anomaly.
      The model therefore supports the co-occurrence this node records without
      settling the shared-lineage explanation for it.
    readouts:
    - name: Unilateral renal agenesis frequency
      target: Shared Intermediate Mesoderm Lineage Failure
      description: >-
        Gross examination of mutant, control and heterozygous animals.
      direction: INCREASED
      interpretation: >-
        Penetrance in the model is of the same order as the human renal arm,
        which is what makes the comparison informative rather than merely
        directionally correct.
      evidence:
      - reference: PMID:36282544
        reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We detected unilateral kidney agenesis in 6 of 36 mutant mice (16.7%),
          whereas it was never observed in controls
        explanation: >-
          Gives the frequency and the control comparison behind this readout.
    evidence:
    - reference: PMID:36282544
      reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results show that Hnf1b ablation results in uterine hypoplasia
        associated with kidney anomalies, providing a mouse model for MRKH
        syndrome type II.
      explanation: >-
        Supports treating this model as informative for the combined genital and
        renal phenotype this node explains.
  - target: Spared Gonadal Ridge Lineage with Normal Ovarian Steroidogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Ovaries were indistinguishable from controls with follicles at every stage
      of folliculogenesis, and the mutants mated and plugged normally yet never
      conceived — the dissociation this node exists to record, with the
      gestational deficit isolated from the gametic one.
    limitations: >-
      Folliculogenesis and normal mating behaviour are indirect indices of
      ovarian endocrine function; no gonadotropin or steroid was measured, so
      the model does not directly attest the normal steroid output this node
      names. Nor can a mouse report the human consequence that makes the node
      load-bearing — normal puberty with primary amenorrhoea as the presenting
      sign.
    readouts:
    - name: Ovarian folliculogenesis
      target: Spared Gonadal Ridge Lineage with Normal Ovarian Steroidogenesis
      description: >-
        Ovarian histology of mutant versus control females.
      direction: UNCHANGED
      interpretation: >-
        A negative result, and the informative one: the lesion reaches the duct
        derivatives and stops there.
      evidence:
      - reference: PMID:36282544
        reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          the ovaries of mutant animals did not show any difference compared with
          controls, displaying follicles at every stage of folliculogenesis
        explanation: >-
          Reports the ovarian measurement behind this readout.
    - name: Fertility with preserved mating behaviour
      target: Spared Gonadal Ridge Lineage with Normal Ovarian Steroidogenesis
      description: >-
        Mating trials with plug checks and pregnancy outcome.
      direction: ABOLISHED
      interpretation: >-
        Infertility against a normal ovarian and behavioural background is the
        model's version of absolute uterine factor infertility.
      evidence:
      - reference: PMID:36282544
        reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Consistent with normal follicle dynamics, mutant female mice mated
          without apparent problems as evidenced by the presence of regular
          plugs. As expected, however, they failed to achieve pregnancy
        explanation: >-
          Reports the fertility outcome against preserved follicle dynamics.
    evidence:
    - reference: PMID:36282544
      reference_title: "Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Overall, the Hnf1b mutant uterus resembled the histology of uterine
        rudiments found in MRKH syndrome, including a lower cell proliferation
        capacity and a simple, less differentiated epithelium
      explanation: >-
        Supports treating the model's uterus-versus-ovary dissociation as the
        human one rather than as an incidental mouse finding.
  notes: >-
    Kept distinct from the Lim1-null model below: the Hnf1b lesion is conditional
    and epithelium-restricted, which is what lets the renal finding be attributed
    to the same lineage rather than to generalized early lethality.
- name: Lim1 (Lhx1)-null mouse
  species: Mouse
  genotype: Lim1 (Lhx1) null; Lim1 lacZ knock-in allele used for expression mapping,
    with a female chimera assay for cell autonomy
  genes:
  - preferred_term: LHX1
    term:
      id: hgnc:6593
      label: LHX1
  publication: PMID:14695376
  description: >-
    The cleanest experimental statement of the ovary-spared, tract-absent
    dissociation that defines this syndrome clinically. Lim1 (the mouse orthologue
    of LHX1, the other gene in the recurrently deleted human 17q12 interval) is
    expressed in the developing Müllerian duct epithelium; null females have
    ovaries but no uterus or oviducts. A chimera assay places the requirement
    inside the duct epithelium itself rather than in surrounding tissue.
  evidence:
  - reference: PMID:14695376
    reference_title: "Requirement of Lim1 for female reproductive tract development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Although female Lim1-null neonates had ovaries they lacked a uterus and
      oviducts.
    explanation: >-
      The defining result of the model, and the reason it is curated here.
  - reference: PMID:14695376
    reference_title: "Requirement of Lim1 for female reproductive tract development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the epithelium of the developing Müllerian duct that gives rise to the
      oviduct, uterus and upper region of the vagina of the female reproductive
      tract
    explanation: >-
      Establishes that Lim1 is expressed in the tissue whose failure this entry
      models, and names the derivatives lost.
  modeled_mechanisms:
  - target: Failure of Müllerian Duct Epithelial Proliferation and Elongation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The chimera assay is the part that matters for this node: in a mosaic
      female, Lim1-null cells fail to contribute to Müllerian duct epithelium
      while wild-type cells in the same animal do, so the requirement is
      cell-autonomous within the epithelium and not a secondary consequence of
      the kidney or Wolffian duct phenotype.
    limitations: >-
      This is a germline null, so the reproductive-tract defect sits alongside
      severe head and kidney phenotypes and the animal is not a model of the
      human syndrome as a whole. More importantly, the human evidence runs the
      other way: LHX1 sequence variants have not been found in larger patient
      cohorts, so this model grounds a mechanism that in patients is reached
      through 17q12 deletion rather than through LHX1 point mutation, and the
      entry types the gene DISPUTED for that reason.
    readouts:
    - name: Müllerian duct epithelium formation by Lim1-null cells in chimeras
      target: Failure of Müllerian Duct Epithelial Proliferation and Elongation
      description: >-
        Contribution of Lim1-null versus wild-type cells to Müllerian duct
        epithelium in female mouse chimeras.
      direction: ABOLISHED
      interpretation: >-
        Cell-autonomous failure localizes the defect to the epithelium this node
        names, which no whole-animal knockout can show on its own.
      evidence:
      - reference: PMID:14695376
        reference_title: "Requirement of Lim1 for female reproductive tract development."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          A novel female mouse chimera assay was developed and revealed that Lim1
          is required cell autonomously for Müllerian duct epithelium formation.
        explanation: >-
          Reports the chimera measurement and its cell-autonomy conclusion.
    evidence:
    - reference: PMID:14695376
      reference_title: "Requirement of Lim1 for female reproductive tract development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These studies demonstrate an essential role for Lim1 in female
        reproductive tract development.
      explanation: >-
        Supports treating this model as informative for the duct-epithelium node.
  - target: Müllerian Duct Aplasia
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Absence of uterus and oviducts in an otherwise female neonate is the
      tissue-level lesion this node names, arrived at from a single
      transcription-factor loss.
    limitations: >-
      The mouse loses the duct derivatives outright, whereas most patients retain
      rudimentary uterine buds — the remnants that carry the cyclic-pain arm of
      the human disease. The model is therefore informative about how the
      structure fails to form and silent about what survives. The vaginal
      boundary is also not addressed: the characteristic human finding is a
      blind pouch of urogenital-sinus origin, which this report does not assess.
    readouts:
    - name: Presence of uterus and oviducts at birth
      target: Müllerian Duct Aplasia
      description: >-
        Gross anatomy of the female reproductive tract in Lim1-null neonates.
      direction: ABOLISHED
      interpretation: >-
        Loss confined to the duct derivatives, with the ovary present in the same
        animal.
      evidence:
      - reference: PMID:14695376
        reference_title: "Requirement of Lim1 for female reproductive tract development."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Although female Lim1-null neonates had ovaries they lacked a uterus and
          oviducts.
        explanation: >-
          Reports the anatomical measurement behind this readout.
    evidence:
    - reference: PMID:14695376
      reference_title: "Requirement of Lim1 for female reproductive tract development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These studies demonstrate an essential role for Lim1 in female
        reproductive tract development.
      explanation: >-
        Supports treating this model as informative for the duct-aplasia node.
  notes: >-
    Cited in this entry's `genetic:` section through a review (PMID:38699388);
    the primary report is used here so the model's genotype, assay and readouts
    are attributable to the study that performed them.
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      Placed with the disorders of the female reproductive system, which is
      where Harrison's carries Müllerian agenesis and the primary-amenorrhoea
      workup that leads to it. The assignment is by clinical encounter rather
      than by mechanism: the lesion is structural and the endocrine axis is
      intact, which is the point of the ovary-spared node in this entry. It is
      recorded here rather than under GENETICS_ENVIRONMENT_DISEASE because most
      cases are sporadic with no identified variant, so a mechanism-defined
      chapter would overstate what is known.
  - classification_value: KIDNEY_URINARY_TRACT
    notes: >-
      Second assignment for the type 2 arm only. Around a third of patients have
      a renal malformation, unilateral agenesis being about half of those, and
      that arm carries its own lifelong surveillance. Not applicable to type 1,
      which is confined to the genital tract.
discussions:
- discussion_id: mrkh_unexplained_etiology
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of Mesodermal Developmental Transcription Factor Dosage
  - mechanistic_hypotheses#mesodermal_transcriptional_program
  prompt: >-
    What causes MRKH syndrome in the large majority of patients who have no
    recurrent copy-number variant and no variant in a known candidate gene?
  rationale: >-
    Recurrent chromosomal imbalances account for around 10% of patients, and the
    sequence-variant genes with real evidence — GREB1L, PAX8, HNF1B — add a
    further minority. The initiating node of this entry is therefore
    unpopulated for most patients, which is unusual for a curated dismech
    entry: the canonical hypothesis about what fails developmentally is secure,
    while the hypothesis about why it fails covers a small fraction of cases.
    The gap is not simply "more sequencing needed": sporadic occurrence and
    repeated monozygotic discordance mean a germline monogenic explanation
    cannot cover the whole disease however deeply cohorts are sequenced, so the
    somatic, mosaic, epigenetic and environmental alternatives have to be tested
    on their own terms. Reported epigenetic findings are so far inconsistent.
  proposed_experiments:
  - experiment_id: exp_mrkh_discordant_twin_somatic_variation
    name: Somatic variant and methylation profiling of uterine remnant tissue in discordant monozygotic twins
    description: >-
      Deep sequencing and methylation profiling of surgically removed uterine
      remnant tissue from monozygotic twins discordant for MRKH syndrome,
      against matched blood from both twins, to test whether a post-zygotic
      somatic or epigenetic lesion restricted to the affected twin's urogenital
      tissue explains the discordance. Interpretation is limited by a caveat the
      field has already identified: gene expression in adult remnant tissue may
      not represent embryonic expression, so a negative result would not exclude
      a developmental epigenetic mechanism.
    would_support:
    - mechanistic_hypotheses#nonmendelian_somatic_or_environmental
    would_refute:
    - mechanistic_hypotheses#mesodermal_transcriptional_program
    supporting_outcome:
    - >-
      A somatic variant or differentially methylated region present in the
      affected twin's remnant tissue and absent from both twins' blood and from
      the unaffected twin.
    refuting_outcome:
    - >-
      No tissue-restricted somatic or epigenetic difference, with a shared
      germline variant in a mesodermal developmental regulator found instead in
      both twins.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, recurrent chromosomal imbalances in MRKH syndrome still only
      apply to a minor fraction of patients (around 10%).
    explanation: >-
      Quantifies the size of the gap this discussion records.
- discussion_id: mrkh_tbx6_monoallelic_mechanism
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Paraxial Mesoderm and Somite Patterning Failure
  - genetic#TBX6
  prompt: >-
    Does the compound-inheritance gene dosage model established for TBX6 in
    congenital scoliosis apply to MRKH syndrome, given that no second
    hypomorphic allele has been found in MRKH patients?
  rationale: >-
    This is a model-fidelity problem rather than an absence of evidence, which
    is why it is recorded as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP.
    Evidence for TBX6 exists on both sides: rare variants are enriched in a
    large MRKH cohort and several are loss-of-function in assays, and the
    16p11.2 deletion is recurrent. The mechanism borrowed to explain it comes
    from congenital scoliosis at the same locus, where disease requires a null
    allele plus a particular hypomorphic allele in trans. That second allele has
    not been found in MRKH syndrome. So either the Müllerian phenotype has a
    lower dosage threshold than the axial-skeletal one, or a different
    modifier is involved, or the monoallelic variants are not causal at all —
    and the review states plainly that no clear biological mechanism has been
    established. This entry therefore draws the TBX6 route to the skeletal node
    as indirect and records the gene as SUSCEPTIBILITY rather than CAUSATIVE.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As of now, no clear biological mechanism for monoallelic TBX6 variants
      causing MRKH syndrome has been established, which challenges
      interpretation and warrants further studies.
    explanation: >-
      States the mismatch this discussion records.
- discussion_id: mrkh_endometriosis_without_functional_endometrium
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Retained Cycling Endometrium in Uterine Remnants
  - phenotypes#Endometriosis
  prompt: >-
    What accounts for endometriosis in the MRKH patients who have no functional
    endometrium and no uterine remnant at all?
  rationale: >-
    The meta-analysis that ties endometriosis in this syndrome to functional
    endometrium in a remnant is strong — 32.0% versus 1.5%, odds ratio 12.0 —
    and it substantially rehabilitates retrograde menstruation as the mechanism
    in a population long cited as the counter-example to it. But it does not go
    to zero. Seven of 71 patients with endometriosis had no demonstrable
    functional endometrium and no remnant. Those cases cannot be explained by
    retrograde menstruation from a remnant, and they are the residue that keeps
    coelomic metaplasia or embryonic-remnant origins in play. The question is
    worth keeping open rather than treating the meta-analysis as settling the
    theory, because this population is one of the few in which the two competing
    origins can be separated by ascertaining a single anatomical variable.
  evidence:
  - reference: PMID:40246293
    reference_title: "Prevalence of endometriosis in Mayer-Rokitansky-Küster-Hauser syndrome variants: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 71 MRKHS patients with endometriosis, 64 had coexisting FE, and
      only seven had no evidence of FE within UR or did not have UR.
    explanation: >-
      The residual cases that motivate this question.
notes: >-
  Scope and lump/split. The stub for this concept was UNDECIDED. It is curated
  as a single DISEASE entry with MONDO's own two children as `has_subtypes`,
  rather than as two entries or a grouping, for three reasons. The MONDO term
  itself is written as a spectrum with type 1 and type 2 as its classification.
  The two types share one mechanism entirely — the same Müllerian duct failure,
  the same anatomy, the same treatment pathway — and differ only in whether the
  shared mesodermal lineage failure extended beyond the duct, which this entry
  models as extra branches off one causal graph rather than as a second disease.
  And the boundary between them is set by how hard anyone looked: renal imaging
  reclassifies type 1 as type 2, one cohort had no urinary tract imaging in a
  third of its patients, and systematic ear assessment finds abnormalities at
  roughly twice the routinely reported rate. A classification whose boundary
  moves with ascertainment intensity is a subtype axis, not a split.

  MURCS is deliberately not a separate entry or subtype. It names the severe end
  of type 2 and is grouped into it in current usage; giving it its own record
  would assert a boundary that the literature reports as a continuum.

  Ontology gaps encountered. Two phenotypes could not be bound precisely.
  Catamenial (cyclic) abdominal pain and cryptomenorrhoea have no HPO term, so
  the phenotype is bound to `HP:0002027` Abdominal pain with
  `temporality: RECURRENT` and the cyclic character carried in
  `preferred_term`; haematometra likewise has no HPO term and is described in
  prose rather than given a phenotype record of its own. On the treatment side,
  NCIT has no clinical-action term for vaginoplasty, so that treatment binds the
  generic `NCIT:C15329` Surgical Procedure. These are recorded as unbound rather
  than bound to something approximate.

  What this entry does not carry. No ICD-10-CM or Orphanet mapping block: the
  relevant codes (ICD-10 Q51.0/Q52.0, ORPHA 3109) are named in the source
  literature but neither prefix could be validated offline from the committed
  caches in this session, and an unvalidated mapping is worse than none. No
  `biochemical` section, because the point about laboratory values here is that
  they are normal — gonadotropins, estradiol and androgens all in the normal
  female range — and a marker record asserting normality would misrepresent
  what is known. One caveat on that: biochemical hyperandrogenaemia without
  clinical signs has been reported in about half of patients in a single study,
  which the source review flags as requiring validation; it is left out for that
  reason and because it would confuse the WNT4 differential, where
  hyperandrogenism is the discriminating feature.

  Evidence base. Ten references, all cached: two current genetics reviews
  (PMID:38699388, PMID:41616459), the functional-genomics HNF1B paper that
  produced the first type 2 mouse model (PMID:36282544), the comprehensive
  clinical review (PMID:32819397), the ACOG committee opinion (PMID:29266078),
  the Danish nationwide prevalence cohort (PMID:27609979), the 284-woman
  malformation cohort (PMID:22906151), the endometriosis meta-analysis
  (PMID:40246293), the index uterus transplantation livebirth report
  (PMID:25301505), and the index WNT4 case report (PMID:15317892) cited on the
  differential it defines. Snippets were taken preferentially from clean full-text XML
  and structured abstracts; the two quotations from PMID:32819397 avoid the
  hyphenated line breaks that PDF extraction introduces elsewhere in that file.

Mayer-Rokitansky-Kuster-Hauser_Syndrome

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